Early thimerosal exposure and neuropsychological outcomes at 7 to 10 years
William W Thompson 1 , Cristofer Price, Barbara Goodson, David K Shay, Patti Benson, Virginia L Hinrichsen, Edwin Lewis, Eileen Eriksen, Paula Ray, S Michael Marcy, John Dunn, Lisa A Jackson, Tracy A Lieu, Steve Black, Gerrie Stewart, Eric S Weintraub, Robert L Davis, Frank DeStefano; Vaccine Safety Datalink Team
N Engl J Med. 2007 Sep 27;357(13):1281-92.
doi: 10.1056/NEJMoa071434.
Abstract
Background: It has been hypothesized that early exposure to thimerosal, a mercury-containing preservative used in vaccines and immune globulin preparations, is associated with neuropsychological deficits in children.
Methods: We enrolled 1047 children between the ages of 7 and 10 years and administered standardized tests assessing 42 neuropsychological outcomes. (We did not assess autism-spectrum disorders.) Exposure to mercury from thimerosal was determined from computerized immunization records, medical records, personal immunization records, and parent interviews. Information on potential confounding factors was obtained from the interviews and medical charts. We assessed the association between current neuropsychological performance and exposure to mercury during the prenatal period, the neonatal period (birth to 28 days), and the first 7 months of life.
Results: Among the 42 neuropsychological outcomes, we detected only a few significant associations with exposure to mercury from thimerosal. The detected associations were small and almost equally divided between positive and negative effects. Higher prenatal mercury exposure was associated with better performance on one measure of language and poorer performance on one measure of attention and executive functioning. Increasing levels of mercury exposure from birth to 7 months were associated with better performance on one measure of fine motor coordination and on one measure of attention and executive functioning. Increasing mercury exposure from birth to 28 days was associated with poorer performance on one measure of speech articulation and better performance on one measure of fine motor coordination.
Conclusions: Our study does not support a causal association between early exposure to mercury from thimerosal-containing vaccines and immune globulins and deficits in neuropsychological functioning at the age of 7 to 10 years.
EMBARGOED RELEASE Contact: Cheri Jacobus
Wednesday, September 26, 2007 202/547-7358
6:00 PM EDT Sallie Bernard
970/544-3466
sbernard@safeminds.org
VACCINE STUDY IN NEW ENGLAND JOURNAL OF MEDICINE WRONG IN
CONCLUDING MERCURY EXPOSURES ARE HARMLESS, STATES
SAFEMINDS “STUDY FINDINGS AND LIMITATIONS REQUIRE FURTHER
INVESTIGATIONS,” SAYS DISSENTING PANEL MEMBER
ATLANTA, GA – A Centers for Disease Control (CDC) study on the relationship
between mercury (thimerosal) in vaccines and children’s brain functioning draws a
misleading conclusion, says one of the study’s external consultants, Sallie Bernard,
Executive Director of SafeMinds.
“Early Thimerosal Exposure and Neuropsychological Outcomes at 7 to 10 Years,”
appearing in the New England Journal of Medicine (NEJM, 9/27/07 issue), concludes that
the study “does not support a causal association” between thimerosal and
neuropsychological outcomes in children. The conclusion misleads the public, implying
without qualification that a relationship has been disproved. In fact, “the study was unable
to prove either the presence or absence of a causal relationship,” noted Bernard, the
panel’s only consumer representative.
According to Bernard, unlike gold-standard randomized clinical trials, an observational
study such as this cannot address causation. If, however, the findings confirm those of
other studies, it can contribute to assessments of causality. This study confirmed
associations detected in other studies, such as increased rates of motor and verbal tics and
poorer language ability. Replication of previous studies was noted in the text but ignored
in the Abstract and Concluding statement, which are the sections routinely read by the
wider public.
The study’s many limitations preclude sweeping conclusions on thimerosal’s effects. The
small sample size and few children in the highest and lowest exposure groups reduced the
study’s precision and ability to establish statistical significance. The study only obtained a
30% participation rate, well below the commonly accepted scientific standard of 70%.
Early interventions which may have reduced or eliminated some deficits such as speech
delays by age 7 to10 years were not controlled. An analysis of combined prenatal and
postnatal mercury exposures was lacking. Newborns weighing 5lbs 8 ounces or less (9%
of births) were excluded even though these infants may be more vulnerable to mercury’s
effects.
The conclusions should have referenced these and other limitations, as well as confirming
thimerosal-associated impairments found in other studies, and as a result, called for further
investigation. “Children in the U.S. and worldwide are still given vaccines containing
mercury. Health officials should be erring on the side of caution,” said Bernard. The data
set will be made available to other researchers by the CDC, and Bernard hopes other
scientists will apply alternative methodologies to study this important public health issue.
She has asked the NEJM to publish her dissenting comments when the study appears
online at www.nejm.org.
SafeMinds focuses on the role of mercury in neurodevelopmental disorders, including
autism. This study did not address autism. A separate CDC-sponsored study investigating
thimerosal and autism is underway.
14Studies.org
Wins award for most conflicts with seven different vaccine companies mentioned. But, study doesn’t even look at autism as an outcome, so doesn’t apply to this debate at all. Had a panel member dissent from study conclusions, a bad sign. May be interesting to some, but not anyone studying autism.
Actual Question This Study Asked & Answered:
Q: Did exposure to thimerosal in early childhood impact certain neurological outcomes, but not autism?
A: No.
Did the study look at unvaccinated children?
No.
Conflict of Interest (from the study itself):
“Dr. Thompson reports being a former employee of Merck; Dr. Marcy, receiving consulting fees from Merck, Sanofi Pasteur, GlaxoSmithKline, and MedImmune; Dr. Jackson, receiving grant support from Wyeth, Sanofi Pasteur, GlaxoSmithKline, and Novartis, lecture fees from Sanofi Pasteur, and consulting fees from Wyeth and Abbott and serving as a consultant to the FDA Vaccines and Related Biological Products Advisory Committee; Dr. Lieu, serving as a consultant to the CDC Advisory Committee on Immunization Practices; Dr. Black, receiving consulting fees from MedImmune, GlaxoSmithKline, Novartis, and Merck and grant support from MedImmune, GlaxoSmithKline, Aventis, Merck, and Novartis; and Dr. Davis receiving consulting fees from Merck and grant support from Merck and GlaxoSmith- Kline. No other potential conflict of interest relevant to this article was reported.”
[Seven separate vaccine manufacturers are mentioned — a record!]
Ability to Generalize:
Yes, but unhelpful for the autism debate, because autism was not considered.
Post-Publication Criticism:
Moderate. One of the original board members of the study dissented (see below).
Scoring (Out of 40 possible points):
Asked the Right Question: 0
Ability to Generalize: 4
Conflict of Interest: 0
Post-Publication Criticism: 1
Total Score: 5
Choice Excerpt from the Study:
“Of 3648 children selected for recruitment, 1107 (30.3%) were tested. Among children who were not tested, 512 did not meet one or more of the eligibility criteria, 1026 could not be located, and 44 had scheduling difficulties; in addition, the mothers of 959 children declined to participate.”
Meaning:
Participation level was low, could have excluded children with adverse outcomes.
Guest Critic #1: Sallie Bernard, SafeMinds, who was a panelist for the study
To the Editor: Thompson et al. (Sept. 27 issue) 1 report the results of a study investigating the neuropsychological outcomes of early exposure to thimerosal. As a dissenting member of the panel of external consultants for this study, I object to the authors’ conclusion that there is no causal association between thimerosal and children’s brain function. The sample comprised children who were least likely to exhibit neuropsychological impairments. Specifically, children with congenital problems, those from multiple births, those of low birth weight, and those not living with their biological mother were excluded. The sample was skewed toward higher socioeconomic status and maternal education — factors that are associated with lower rates of neurobehavioral problems and higher intervention rates and that were not measured. The sampling frame included only children enrolled from birth in the health maintenance organization (HMO) and still enrolled after 7 to 10 years, excluding children in higher-mobility families, who tend to have lower academic and behavioral function. 2 Children with neurobehavioral problems may have been less likely to remain with the HMO. Only 30% of families selected for recruitment participated, a low rate for scientific research. Among the families selected for recruitment, 26% refused to participate. Another 28% “could not be located,” which included families that did not respond to multiple recruitment attempts (internal documentation from the study contractor, Abt Associates) — another form of refusal.
Sallie Bernard, B.A.
SafeMinds
Aspen, CO 81611
sbernard@safeminds.org
References
1. Thompson WW, Price C, Goodson B, et al. Early thimerosal exposure and neuropsychological outcomes at 7 to 10 years. N Engl J Med 2007;357:1281-1292. [Free Full Text]
2. Rumberger RW. Student mobility and academic achievement. In: Child & adolescent development. MentalHelp.net. January 23, 2003. (Accessed December 12, 2007, at http://mentalhelp.net/poc/view_doc.php?type=doc&id=2084&cn=28.)
Guest Critic #2: Autism Speaks
Autism Speaks Statement Regarding “Early Thimerosal Exposure and Neuropsychological Outcomes at 7-10 years” in the New England Journal of Medicine
September 26, 2007
This afternoon the New England Journal of Medicine published a CDC study examining the hypothesis that exposure to thimerosal during early development is associated with neuropsychological deficits in children. The authors of the report, entitled “Early Thimerosal Exposure and Neuropyschological Outcomes at 7 to 10 Years,” concluded that findings from the study do not “support a causal association between early exposure to mercury from thimerosal-containing vaccines and immune globulins and deficits in neuropsychological functioning at age of 7 to 10 years.”
While the study conclusions are supported by the data presented, the study had significant limitations that argue for the need for additional study. The researchers acknowledged there are limitations to the study, including a 30% recruitment rate, which did not allow them to adequately control for potential selection bias, and difficulty in controlling for treatment or intervention, such as speech therapy, which could potentially lessen or compensate for the possible negative effects of thimerosal exposure.
Among the 42 neuropsychological parameters examined, only a small number of very modest associations were detected. For instance, higher thimerosal exposure was found to be associated with poorer performance in some areas, such as behavioral regulation and tics in boys, and better performance in other measures, such as performance IQ and fine motor coordination. The authors highlighted these findings in their discussion because similar associations had been reported in a few earlier studies and suggested “the potential need for further studies.” Since the reported associations are weak and essentially equally divided between positive and negative effects, the investigators concluded that they are more likely due to chance or statistical artifacts and do not lend meaningful support to a causal connection between thimerosal and neuropsychological deficits in children.
Although the general study conclusions are supported by the data presented and are consistent with past findings, given the significant study limitations and some of the intriguing albeit inconclusive associations involving behavioral regulation and tics, this study isn’t and shouldn’t be seen as the “last word” on the topic. If anything, it is a great example why we must take a systematic, rigorous approach to the science involved if there is ever going to be hope for a compelling and satisfactory answer. Just as important is the understanding that in science, it is rare that any given study would deliver a definitive conclusion. The prudent and scientifically responsible thing to do is to evaluate multiple lines of evidence and look at the totality of the data before drawing any conclusion, especially when it comes to something as complex a scientific challenge as this.
While the study does not specifically examine the link between thimerosal and autism spectrum disorders, it does explore neuropsychological functioning, such as language development, attention, and fine motor coordination, that are affected in some individuals with autism. The Centers for Disease Control are currently studying the potential association between autism and thimerosal and are expected to report findings next year.
From www.autismspeaks.org
Critique by Mark D. Noble, Phd – Professor of Genetics and of Neurobiology and Anatomy, University of Rochester Medical Center: [68]
Poor Confirmation of Cases – “One of the most critical problems with the studies of Andrews et al. is the very poor validation for the data that they analyzed. Validation responses were received from 162 of 166 general practices that were queried, of which it appears that each was asked about a single child. Of this group, 19% of diagnoses could not be confirmed. Of those with a confirmed diagnosis, 39% were considered to be transient problems (which is not a description that would normally be applied to autism) and the duration of the problem could not be determined for an additional 35% of cases. Thus, only 26% of the validation attempts established that problems were long-term in children with a confirmed diagnosis.”
Low Number of Unexposed Children – “The number of individuals reported to receive no thimerosal exposure during the first 4 months of life was very low, representing only 3.4% of infants delivered at term and 5.8% of pre-term infants.”
“The small numbers of children with behavioral differences were spread in unspecified distributions across the ten years of information, and attempts at validation provided confirmation of long-term problems in only 20.5% of cases. (This) renders analysis of the data base of Andrews and colleagues fraught with uncertainty. In the specific context of autism, any decreased representation in the zero-exposure cohort (i.e., less than a total of 3 cases identified) seems unlikely to be suitable for accurate statistical comparisons.”
Mercury As “Neuro-protective”?: “Claims made that increased exposure to thimerosal was associated with equal or even lower levels of hazard thus appear to be conjectural. Moreover, children also exposed to hepatitis B and/or influenza vaccinations in the first six months of life were excluded from the analysis, thus excluding those children known to have still higher levels of thimerosal exposure and further limiting the values of the comparisons conducted.”
Critique by Mary Catherine DeSoto, PhD, and Robert T. Hitlan, PhD, Department of Psychology, University of Northern Iowa:[69]
Seven of the authors had received fees from Merck, Kaiser Permanente and other pharmaceutical companies that may have or had an interest in disproving any link to thimerosal and/or mercury exposure and developmental disorders. First, it is important to be very clear that we do not believe that authors would purposefully change their data, or consciously misstate conclusions. Not only would this be unethical, but the stakes are very high. But this does not mean there is no bias; the bias would be subtle and far less nefarious than any sort of purposeful altering of data. If a person has publicly staked his/her career on a certain position being right, it may become harder to keep a truly open mind, even when new data become available and even when the original intent was to be objective. A way this bias might manifest itself is an overstatement or slight misstatement of results. We feel that both sides have been guilty of this, and this happens when a person becomes so confident in the correctness of his/her own view that he/she no longer reviews evidence to the contrary. Unconscious bias may exist even in the best scientists
This is the sort of bias, whether conscious or unconscious, that occurs. Because some of the authors of the Thompson study have publicly aligned with opposing a mercury-autism link (by taking consulting fees), they may be unconsciously more prone to review studies that support their view, less likely to review opposing viewpoints, and may eventually become unaware of relevant research (e.g., Newland et al. 2008). By using 42 measures and finding only a small handful of effects, it is easy to say the obtained relations are chance occurrences. Then, another scholar summarizes the study and slightly changes the results based on a world view that there is no effect of thimerosal, “found no evidence of neurological problems in children exposed to mercury containing vaccines” (Offit 2007, p. 1279). Then this assessment gets quoted by those who do not bother to look carefully at the original study, and scientific advancement becomes stifled.
OTHER CRITIQUES OF THE STUDY
■ The response rate was extremely low. Of 3,648 children selected for recruitment only 1,107 (30.3%) were tested. Among those not responding, 1,026 could not be located, while the mothers of 959 children refused participation. 68% of those refusing cited lack of time, but 13% reported “distrust of or ambivalence toward research
■ Mothers with special needs kids are usually those with the least amount of free time. With such a low response rate, the children studied were likely healthier than the general population.
■ Among a population of 1,026 children, one could expect to find about 45 students on medication for ADD/ADHD. Was that the case? “There were a small number of kids” with ADD/ADHD, Dr. Thompson said, without providing a number.
■ It is possible that low birth-weight kids had increased deficits, but children born below 5.5lbs were excluded from the study.
■ Some children had probably received years of therapy to treat outcomes they were being tested for. An unreported number had been treated with prescription drugs, speech therapy, psychotherapy and/or other forms of treatment. Investigators conceded that prior therapy “may have ameliorated the potential negative effects of thimerosal exposure,” and “could have biased the results toward” finding nothing.
■ Despite the mix of positive and negative associations, there remained a “higher likelihood” of motor and phonic tics in boys, something found in previous studies, including Verstraeten (US) and Andrews (UK).
■ Boys exposed to the highest amounts of mercury by 7 months of age were 2.19 times more likely to have motor tics, and 2.44 times more likely to have phonic tics than boys in the lowest exposure rates.
■ The authors failed to differentiate between “transient” tics, which go away within a year, and “chronic” tics, which can last a lifetime. Nor did they distinguish between “simple” and “complex” tics. “We did not categorize them, and some of them may have been chronic,” Dr. Thompson said.
■ In fact, “The replication of the (2003) findings regarding tics suggests the potential need for further studies,” the authors wrote.
■ There were also small but negative associations with speech-articulation in children, and lower verbal IQs among girls, which together “suggest a possible adverse association between neonatal exposure to mercury and language development,” the authors said. A similar “increased risk of language delays at one HMO associated with thimerosal-containing vaccines,” was found in Verstraeten’s 2003 VSD study.
■ It is illogical to cite an increased risk for tics (one replicated in a prior study and which may need “further study”) and increased language deficits (also found in the same prior study), but still conclude that there is “no causal association” between thimerosal neuropsychological deficits.
■ Sallie Bernard of SafeMinds, the only consumer representative on the study’s panel of advisors, said the final conclusions were mere “conjecture.” The many limitations “preclude any reasonable determination of the ‘truth.’ The authors’ arbitrary selection of one explanation for their conclusion risks misleading the reader into thinking that the absence of a relationship has been proved.”[70]
■ Dr. Lawrence Rosen, a pediatrician who treats ASD in Tappan, NJ, said the mixed results and severe limitations “make the study kind of worthless. They are picking and choosing what they want to report. It’s not a well-designed study. So either don’t publish it; or do so with all sorts of explanations. You can’t have it both ways. This study doesn’t answer any questions. It makes things even muddier.”[71]
■ Extremely few children received no thimerosal: the investigators largely compared medium-to-high exposures to low exposures, instead of zero exposure.
DEFENSE OF THE STUDY
■ Dr. Ted Schettler, science director of the Science and Environmental Health Network, said there were “only a few significant associations, small and equally divided. When looking at multiple outcomes, some favorable and some unfavorable, it’s very common for authors to conclude that chance variability is the reason.”[72]
■ Dr. Thompson said tics were “likely to be transient,” and not of clinical importance. They were also detected by trained experts, not parents, meaning they were “probably” not severe enough for parents to notice. “And given that kids that age (7-10) have the greatest degree of transient tics,” he added, “we believe these were transient.”[73]
■ Although a 30% response rate “could have an impact on selection bias,” it’s impossible to know which way the bias may have gone. Parents with concerns about their child’s development might be more likely to participate.
SUMMARY: The response rate to this study was extremely low, suggesting possible selection bias in the recruitment of patients. Moreover, the children were examined years after their thimerosal exposure, and many of them had presumably received medical and behavioral treatments in the intervening period. It is illogical to conclude there is “no causal association” between thimerosal neuropsychological deficits, and then cite an increased risk for tics (one replicated in a prior study “further study”) and increased language deficits (also found in the same prior study).