Biomed Res Int. 2014;2014:247218. doi: 10.1155/2014/247218. Epub 2014 Jun 4.
Methodological issues and evidence of malfeasance in research purporting to show thimerosal in vaccines is safe.
Hooker B1, Kern J2, Geier D3, Haley B4, Sykes L5, King P5, Geier M3.
1
Simpson University, 2211 College View Drive, Redding, CA 96001, USA.
2
Institute of Chronic Illness, Inc., 14 Redgate Court, Silver Spring, MD 20905, USA ; University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75235, USA.
3
Institute of Chronic Illness, Inc., 14 Redgate Court, Silver Spring, MD 20905, USA.
4
University of Kentucky, Lexington, KY 40506, USA.
5
CoMeD, Inc., Silver Spring, MD, USA.
Abstract
There are over 165 studies that have focused on Thimerosal, an organic-mercury (Hg) based compound, used as a preservative in many childhood vaccines, and found it to be harmful. Of these, 16 were conducted to specifically examine the effects of Thimerosal on human infants or children with reported outcomes of death; acrodynia; poisoning; allergic reaction; malformations; auto-immune reaction; Well's syndrome; developmental delay; and neurodevelopmental disorders, including tics, speech delay, language delay, attention deficit disorder, and autism. In contrast, the United States Centers for Disease Control and Prevention states that Thimerosal is safe and there is "no relationship between [T]himerosal[-]containing vaccines and autism rates in children." This is puzzling because, in a study conducted directly by CDC epidemiologists, a 7.6-fold increased risk of autism from exposure to Thimerosal during infancy was found. The CDC's current stance that Thimerosal is safe and that there is no relationship between Thimerosal and autism is based on six specific published epidemiological studies coauthored and sponsored by the CDC. The purpose of this review is to examine these six publications and analyze possible reasons why their published outcomes are so different from the results of investigations by multiple independent research groups over the past 75+ years.
PMID:
24995277
PMCID:
DOI:
[Indexed for MEDLINE]
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Publication types, MeSH terms, Substances
1. Introduction
Thimerosal
is an organic-mercury (Hg) based compound, used as a preservative in many
childhood vaccines, in the past and present. To date, there have been over 165
studies that focused on Thimerosal and found it to be harmful [1, 2]. (A
comprehensive list of these studies is shown at http://mercury-freedrugs.org/docs/20140329_Kern_JK_ExcelFile_TM_sHarm_ReferenceList_v33.xlsx.)
Of these studies, 16 were conducted to specifically examine the effects of
Thimerosal on human infants and/or children [3–18]. Within these studies, which
focused on human infants and/or children, the reported outcomes following
Thimerosal exposure were (1) death [3]; (2) acrodynia
[4]; (3) poisoning [5]; (4) allergic reaction [6]; (5) malformations [7]; (6)
autoimmune reaction [8]; (7) Well’s syndrome [9]; (8) developmental delay [10–13];
and (9) neurodevelopmental disorders, including tics, speech delay, language delay,
attention deficit disorder, and autism [10, 11, 14–18].
However,
the United States (US) Centers for Disease Control and Prevention (CDC) still
insists that there is “no relationship between [T]himerosal[-]containing
vaccines and autism rates in children” [19]. This is a puzzling conclusion
because, in a study conducted directly by the CDC, epidemiologists assessed the
risk for neurologic and renal impairment associated with past exposure to
Thimerosal-containing vaccine (TCV) using automated data from the Vaccine
Safety Datalink (VSD) and found a 7.6-fold increased risk of autism from
exposure to Thimerosal during infancy [20]. The database for that study was
“from four health maintenance organizations [HMOs] in Washington, Oregon, and
California, containing immunization, medical visit, and demographic data on
over 400,000 infants born between 1991 and 1997.” In that initial study, Verstraeten et al. [20] “categorized the cumulative
ethyl-Hg exposure from [T]himerosal[-]containing vaccines after one month of life and assessed
the subsequent risk of degenerative and developmental neurologic disorders and
renal disorders before the age of six.” They “applied proportional hazard
models adjusting for HMO, year of birth, and gender, and excluded premature babies.”
The reported results showed that “the relative risk (RR) of developing a
neurologic development disorder was 1.8 (95% confidence intervals [CI] 1.1–2.8)
when comparing the highest exposure group at 1 month of age (cumulative dose
> 25 μg)
to the unexposed group.” Similarly, they “also found an elevated risk for the
following disorders: autism (RR 7.6, 95% CI = 1.8–31.5), nonorganic sleep
disorders (RR 5.0, 95% CI = 1.6–15.9), and speech disorders (RR 2.1, 95% CI =
1.1–4.0)” in the highest exposure group.
Considering
the many peer-reviewed published research studies that have shown harm from
Thimerosal, including studies in which Thimerosal exposure is associated with
the subsequent diagnosis of neurodevelopmental disorders (16 studies) such as
autism, and the just-described evidence from the CDCs own research, which found
evidence of a relationship between the level of Thimerosal exposure and the
risk of a subsequent autism diagnosis, how does the CDC conclude that there is
no evidence of that relationship? The foundation for the CDC’s current stance
apparently is based primarily on six specific published epidemiological studies
that the CDC has completed, funded, and/or cosponsored, starting in the late
1990s. These studies include (1) the Madsen et al. [21] ecological study of
autism incidence versus Thimerosal exposure in Denmark, (2) the Stehr-Green et al. [22] ecological study of autism
incidence versus Thimerosal exposure in Denmark, Sweden, and California, (3)
the Hviid et al. [23] study of autism incidence
versus Thimerosal exposure in Denmark (also ecological), (4) the Andrews et al.
[24] cohort study of autism incidence and Thimerosal exposure in the United
Kingdom, (5) the published Verstraeten et al. [25]
CDC cohort study of autism incidence and Thimerosal exposure in the United
States, and (6) the more recent Price et al. [26] case-control study of autism
incidence and Thimerosal exposure in the United States. Although the CDC cites
several other publications to purport the safety of Thimerosal, only these six
specifically consider its putative relationship to autism.
The
purpose of this review is to examine these six publications [21–26] which were
“overseen” by the CDC and which claim that prenatal and early childhood
vaccine-derived Thimerosal exposures are not related to the risk of a
subsequent diagnosis of autism or autism spectrum disorder (ASD). This review
analyzes possible reasons why their published outcomes are so different from
the results of investigations by multiple independent research groups over the
past 75+ years. The review begins with an examination of the Madsen et al. [21]
study.
2. The Madsen et al. 2003 Study
The
CDC-sponsored Madsen et al. [21] study examined whether discontinuing the use
of TCVs in Denmark led to a decrease in the incidence of autism. Data were
obtained from the Danish Psychiatric Central Research Register, which contains
all psychiatric admissions since 1971 and all outpatient contacts in
psychiatric departments in Denmark since 1995. The study authors examined the
data from 1971 to 2000 and reported that rate of autism increased with the
removal of Thimerosal from vaccines (starting in 1992, the year that
Thimerosal-containing early childhood vaccines were phased out).
Although
there are several concerns about the methodology used, the most serious concern
involves diagnosis. As described in the paper, estimates of total autism cases
in Denmark were only based on diagnoses occurring during inpatient visits from
1971 to 1994 and then during both inpatient and outpatient visits from 1995 to
the last year of the study in 2000. Thus, the inclusion criteria are greatly
expanded two years after the phaseout of Thimerosal
from infant vaccines in Denmark, creating an “artificial increase” in autism
prevalence. The authors conceded that “the proportion of outpatient to
inpatient activities was about 4 to 6 times as many outpatients as inpatients
with variations across time and age bands.” However, in an earlier publication
by Madsen et al. [27], the same authors had stated regarding this same data, “in our cohort, 93.1% of the children were treated only as
outpatients…” Unlike the statement in the Madsen et al. [21] study, the 2002
paper indicates that the ratio between outpatients and inpatients in the
1971–2000 dataset was 13.5 : 1, which would account for an even
greater increase in cases diagnosed starting in 1995 (i.e., after the probable
completion of the phaseout of TCVs that started in
1992).
In
addition, the authors stated that the Danish registry which was used to count
cases did not include a large Copenhagen clinic before 1993. This clinic
accounted for as many as 20% of the autism cases nationwide, which would again
artificially inflate the autism incidence observed in Denmark after the phaseout of TCVs was initiated in 1992. The authors do not
mention this change in inclusion criteria (i.e., the addition of a new clinic
in the registry) neither do they attempt to adjust their analysis in accordance
with the anomaly. It was revealed, instead, in a similar paper by Stehr-Green et al. [22] where the authors state regarding
the Denmark registry of autistic patients, “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).”
Also,
the diagnosis criteria for “autism” changed within the course of the study.
From 1971 to 1993, the ICD-8 standards for diagnosis (psychosis protoinfantilis 299.00 or psychosis infantilis
299.01) were used to measure autism incidence. However, from 1994 to 2000, the
ICD-10 standard (infantile autism, F84.1) was used. Although the authors did
not address the impact of the change in diagnostic criteria, this could result
in as much as a 25-fold increase in cases as the instantaneous change in autism
prevalence in Denmark, due to this change, went from a low of 1.2/10,000 to a
high of 30.8/10,000 [28].
Another
disconcerting methodological issue was that the 2001 data, which showed a
strong downward trend in autism rates in at least two of the three age groups
(continuing from 1999 through 2001), was not included in the final publication.
This was apparent because when the paper was initially submitted for
publication, it included the 2001 data. After the paper was rejected for
publication by the Journal of the American Medical Association (JAMA) and the
Lancet, it was submitted to the journal Pediatrics again including the 2001
data. As stated by one of the peer-reviewers of the Pediatrics submission, “The
drop of incidence shown for the most recent years is perhaps the most dramatic
feature of the figure, and is seen in the oldest age group as well as the
youngest. The authors do not discuss whether incomplete ascertainment in the
youngest children or delay in recording of data in the most recent years might
play a role in this decline, or the possibility that this decrease might have
come about through elimination of [T]himerosal”
(January 23, 2003, communication between Dr. Poul Thorsen, Aarhus University, and Dr. Coleen Boyle, CDC
scientist). In response to this criticism, the authors removed the 2001
incidence numbers. The authors’ decision to withhold these data resembles
scientific malfeasance, especially when coupled with the previously discussed
problematic methods for counting autism cases. If the scientists believed that
downward trend between 1999 and 2001 was caused by some phenomenon unrelated to
the phaseout of the TCVs, these scientists should
have included those data and then explained the trend within the discussion of
the data.
If
the 2001 data had been included in the final publication, the results would
have been consistent with a more recent CDC study [29] where a decreasing trend
of autism prevalence in Denmark after the removal of Thimerosal in 1992 was
reported. Instead of large increases in autism prevalence after 1992, the
recent Danish study revealed that the autism spectrum disorder prevalence in
Denmark fell steadily from a high of 1.5% in 1994-95 (when children receiving
Thimerosal-free formulations were too young to receive an autism diagnosis and,
because of the known offset in diagnosis, most of those being diagnosed had
been born 4 to 8 years earlier [from 1985 to 1990]) to a low of 1.0% in
2002–2004 (more than 10 years after the phasein of the
use of Thimerosal-free vaccine formulations was started in 1992).
3. The Stehr-Green
et al. 2003 Study
The
CDC’s Stehr-Green et al. [22] study compared the
prevalence/incidence of autism in California, Sweden, and Denmark with average
exposures to TCVs. Graph-based ecologic analyses were used to examine
population data from the state of California (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).
The
study followed and appeared to be conducted in response to California study
data [30], which was presented to the Institute of Medicine’s Immunization
Safety Review Committee. The California data showed that increased uptake of
Thimerosal-containing vaccines in California during the 1990s correlated with a
corresponding increase in autism diagnoses. In the Stehr-Green
et al. [22] study, the researchers stated that the reliability of the autism
prevalence data, citing that the California data included autism spectrum
disorder diagnoses such as pervasive development disorder (PDD), could account
for the increase. However, in a published response to this paper, Blaxill and Stehr-Green [31]
stated that the California prevalence rates were reported based solely on
autism cases.
In
the Stehr-Green paper, the Sweden autism prevalence
data showed an increase in autism rates from 5- 6 cases per 100,000 in 1980–82
to a peak of 9.2 cases per 100,000 in 1993. In Sweden, TCVs were phased out
starting in 1987. Denmark's autism prevalence data was identical to that
reported in the Madsen et al. [21] study critiqued previously. For Denmark, the
authors reported an astounding 20-fold increase in autism prevalence between
1990 and 1999, despite the phaseout of TCVs that
started in 1992.
In
addition, the data from Sweden were based on inpatient (hospital) visits only.
This limitation (counting a small fraction of the total number of cases) likely
accounted for the erratic swings in the annual numbers of autism cases reported
in that country. Also, the Thimerosal exposure level based on the Swedish
vaccination schedule during this time period was much less (a nominal maximum
of 75 μg
of Hg by two years of age) than that possible in California (and the United
States as a whole) where developing children nominally received up to 237.5 μg of Hg by 18
months of age through the standard immunization schedule. In conclusion, the Stehr-Green et al. study was problematic in its attempt to
combine ecological data from three different countries that, relative to each other,
demonstrated different vaccination policies and widely different Thimerosal
exposure levels.
4. The Hviid
et al. (2003) Study
The
Hviid et al. [23] population-based cohort study,
widely cited by the CDC, compared rates of autism prevalence among individuals
who received Thimerosal-free vaccines to those receiving TCVs. The authors
report that there was no evidence of increased autism prevalence with
Thimerosal exposure.
The
study authors stated that the mean age of autism diagnosis within their population
was 4.7 years with a standard deviation of 1.7 years. However, cases and
controls as young as 1 year of age were included within the analysis.
Accordingly, controls that were less than the mean age of diagnosis minus two
standard deviations (1.3 years) from that age had a 97.5% probability of
actually being individuals who will later develop autism and are therefore
possibly misclassified. Similarly, in this study, the mean age for an ASD
diagnosis was 6.0 years with a standard deviation of 1.9 years. Thus, the study
methodology is questionable because it appears to have underascertained
the number of cases diagnosed with autism and ASD.
In
addition, rather than counting persons within the cohort, the authors counted
“person-years of follow up.” With this technique, each age group
(one-year-olds, two-year-olds, etc.) was considered equally, despite the fact
that younger age groups were much less likely to receive an autism diagnosis.
This again contributed to the undercounting of the cases with a diagnosis of
autism and ASD and biased the study towards the null hypothesis (that there is
no statistically significant Thimerosal exposure effect on the outcomes
observed).
5. The Andrews et al. (2004)
Study
The
Andrews et al. [24] study was a retrospective cohort study completed using
records from a database in the United Kingdom, where autism prevalence rates
were compared for children receiving Thimerosal-containing DTaP
and DT vaccines. In the Andrews et al. [24] study, Cox’s proportional-hazards
ratios were used to evaluate periods of followup in
the cohort examined by the investigators using the records in the general
practitioner research database (GPRD), a database that was known to have a
significant level of errors. These investigators reported that increased
organic-Hg exposure from TCVs was associated with a significantly reduced risk
for diagnosed general developmental disorders and for unspecified developmental
delay (although there was a significantly higher risk for diagnosed tics).
Considering
that there are several studies conducted by independent investigators that have
found that exposure to Thimerosal is a risk factor for neurodevelopmental delay
and disorders [10, 11, 16], the reduced rate
of neurodevelopmental delay and disorders with Thimerosal exposure found in the
Andrews et al. [24] study suggests possible methodological issues.
This
result may have occurred, in part, because other studies examined cohorts with
significantly different childhood vaccine schedules and with different diagnostic
criteria for outcomes. This difference may also exist because these other
studies that found Thimerosal to be a risk factor for neurodevelopmental delay
and disorders employed different epidemiological methods, especially with
respect to the issue of follow-up period for individuals in the cohorts
examined. The method used to measure follow-up period for individuals is a
critical issue in all studies examining the relationship between exposures and
the subsequent risk of a neurodevelopmental disorder diagnosis, especially in
those instances where the postexposure periods for
all of the participants in the study are essentially the same. This is because
the risk of an individual being diagnosed with a neurodevelopmental disorder is
not uniform throughout his/her lifetime. As observed in the present study, the
initial mean age for any neurodevelopmental disorder diagnosis was 2.62 years
old, and the standard deviation of mean age of the initial diagnosis of
neurodevelopmental disorder was 1.58 years old. These findings are highly
problematic because (1) any follow-up method that fails to consider the lag
time between birth and age of initial neurodevelopmental disorder diagnosis
will likely not be able to observe the true relationship between exposure and the
subsequent risk of a neurodevelopmental disorder diagnosis and (2)
statistically, the mean and standard deviation age of diagnosis as reported
lead to the nonsensical result that a significant portion (2.5%) of the
children in this study were diagosed with a
neurodevelopmental disorder more than six months before they were born (i.e.,
the mean age minus two standard deviations, 2.62 − [2 × 1.58] =
−0.54 years of age).
Another
issue with this study is that the authors used a nontransparent, multivariate
regression technique to analyze vaccine uptake and autism prevalence data. The
study included one dependent variable (autism) and multiple independent
variables, including two independent variables (Thimerosal exposure levels and
year of birth) that were “correlated” with each other, since Thimerosal
exposures increased with time. Thus, the researchers did not report a
statistical analysis of the effect of Thimerosal exposure on autism incidence,
despite the fact that the authors stated that no such effect was observed.
Moreover, the methods used in this study can create a problem in regression
known as “multicolinearity.” In this case, since the
time variable and the vaccine exposure variable are correlated, they actually
compete to explain the outcome effect. Inclusion of the time variable reduces
the significance of the exposure variable. Yet, the authors did not explain why
they included a time variable that competes with the exposure variable.
Unfortunately, the authors of this study never released the raw data so that a
valid single-variable analysis could be conducted to ascertain the probability
of an association between Thimerosal exposure and the risk of autism.
It
is also important to note that the UK Thimerosal exposure (a maximum of 75 μg of Hg by 4
months of age) was not comparable to that in the United States (a maximum of 75 μg of Hg by 2
months of age and 187.5 μg
of Hg by 6 months of age). Thus, this study should not be extrapolated to the
probability of an autism-Thimerosal association based on the US vaccination
schedule.
6. The Verstraeten et al. (2003) Study
The
CDC’s published Verstraeten et al. [25] study
consists of a cohort analysis of a subset of records from the medical records
databases for several of the HMOs whose records were maintained in a central
data repository, the Vaccine Safety Datalink (VSD). This study was conducted in
at least five separate phases. In the final phase (i.e., the results reported
in the publication), the authors stated that there was no relationship between
Thimerosal exposure in vaccines and autism incidence. However, no data are
reported in the published study to support this conclusion.
Results
from the first phase of the study released in an internal presentation abstract
by Verstraeten et al. [20] (mentioned earlier) using
records from four (4) HMOs showed that infants who were exposed to greater than
25 μg
of Hg in vaccines and immunoglobulins at the age of one month were 7.6 times
more likely to have an autism diagnosis than those not exposed to any vaccine-derived
organic Hg. Within the same abstract, Verstraeten
reports that the risk for any neurodevelopmental disorder was 1.8, the risk for
speech disorder was 2.1, and the risk for nonorganic sleep disorder was 5.0.
All relative risks were statistically significant.
In
the second phase of the study, a different approach was taken: exposure was
compared at 3 months of age, rather than one month. Results of this phase
showed that children exposed to the maximum amount of organic Hg in infant
vaccines (62.5 μg)
were 2.48 times more likely to have autism diagnosis compared to those exposed
to less than 37.5 μg
of Hg in vaccines. These results were also statistically significant. No
assessment against a “no exposure” control was apparently completed in this study
phase.
In
the third phase of the study, in which more data stratification methods and
different inclusion/exclusion criteria were applied to the analysis, the
relative risk of autism for children at three months of Thimerosal exposure
dropped to 1.69. At this point, evidence in an email from Verstraeten,
the lead investigator, written to a colleague outside of the CDC (obtained by
the authors via the US Freedom of Information Act of 1950 as amended), suggests
that Verstraeten could have been receiving pressure
within the CDC to apply unsound statistical methods to deny a causal
relationship between Thimerosal and autism. In this email, Verstraeten
states (Figure 1),
“I do not wish to be the advocate of the anti-vaccine lobby and sound like
being convinced that thimerosal is or was harmful, but at least I feel we
should use sound scientific argumentation and not let our standards be dictated
by our desire to disprove an unpleasant theory.”
July 14, 2000, email from Verstraeten to
Philippe Grandjean regarding the risk of harm due to
Thimerosal (obtained by the authors via the US Freedom of Information Act of
1950 as amended).
The
fourth and fifth phase of the study used records from only two of the original
HMOs and incorporated a third HMO, Harvard Pilgrim, into the analysis. Some
critics of the study questioned the use of Harvard Pilgrim, as this HMO
appeared to be riddled with uncertain record keeping practices, and the state
of Massachusetts had been forced to take it over after it declared bankruptcy.
In addition, the HMO used different diagnostic codes than the other two HMOs
used in phases 2 and 3. Other criticisms include that the study used younger
children, from 0 to 3 years of age, even though the average age for an autism
diagnosis at the time was 4.4 years. Since half of the children receiving an
autism diagnosis would be over 4.4 years of age, far greater than the maximum
age in the study at 3 years, this analysis excluded more than 50% of all autism
cases from this HMO. Also, the cohort from this HMO contained 7 times fewer
individuals than the main cohort from the previous study (i.e., HMO B), and
there was no apparent attempt to assess the power of this HMO to show any
statistically significant effect.
Also
of note is the lack of variability within strata among the different HMOs in
the Verstraeten et al. [25] study. By design, a
cohort study seeking to assess the effect of some treatment on a subsequent
outcome should be designed to maximize the range of the independent “treatment”
variable (Thimerosal exposure in this instance) in order to determine if there
is indeed an “effect” in the dependent postexposure
outcome variable (neurological disorders in this study). However, the authors
knowingly stratified the analysis based on the participants’ gender, year of
birth, month of birth, and clinic most often visited. This effectively reduced
the variability of Thimerosal exposure within the strata to the point that it
reduced the capability of the final analysis to find any but the “strongest”
Thimerosal exposure-related outcome effects. The problems with such
“overmatching” practices have been discussed in detail in peer-reviewed
scientific literature and will be treated in greater detail in the forthcoming
review of the CDC’s Price et al. [26] paper.
Another
methodological concern about the Verstraeten et al. [25]
study is related to the issue of the minimum follow-up period required for
individuals in the cohorts examined to ensure that all the cases in the cohort
will have been identified with a high degree of certainty. This issue has been
mentioned as a problem in the previous studies. As mentioned earlier, the method
used to determine the minimum follow-up period for individuals is a critical
issue in all studies examining the relationship between exposures and the
subsequent risk of a neurodevelopmental disorder diagnosis, especially in those
instances where the exposures to all participants in the study are the same or
essentially the same. This is the case because the risk of an individual being
diagnosed with a neurodevelopmental disorder is not uniform throughout his/her
lifetime. Any follow-up method that fails to consider the lag time between
birth and age of initial neurodevelopmental disorder diagnosis will likely not
be able to observe the true relationship between exposure and the subsequent
risk of a neurodevelopmental disorder diagnosis. Verstraeten
et al. [25] included children in the control group who were too young (down to
“0” years of age) to receive a neurodevelopmental disorder diagnosis.
Within
this study, Verstraeten et al. [25] still found
significantly increased risk ratios for tics and language delay. However, the
authors stated that, because these results were not consistent between the HMOs
tested, these significantly increased risk ratios could not be used to make a
determination of the potential adverse consequences of organic-Hg exposure from
TCVs.
7. The Price et al. 2010 Study
In
2010, the CDC published another epidemiology study on Thimerosal and autism [26].
This case-control study was conducted using the records from three managed care
organizations (MCOs) consisting of 256 children with an ASD diagnosis and 752
controls that were matched by birth year, gender, and MCO to the children with
an ASD diagnosis. Exposure to Thimerosal in vaccines and immunoglobulin
preparations was determined from electronic immunization registries, medical charts,
and parent interviews. Conditional logistic regression was used to assess
associations between ASD, autistic disorder (AD), and ASD with regression and
exposure to ethyl-Hg during prenatal, birth-to-1-month, birth-to-7-month, and
birth-to-20-month periods. Their published finding was that prenatal and infant
Thimerosal exposure from TCVs and Thimerosal-containing immunoglobulin posed no
statistically significant risk of autism.
As
mentioned earlier, in case-control studies, the main methodological concern is
the phenomenon called “overmatching.” This concern for overmatching in the
Price et al. [26] study was voiced previously by DeSoto
and Hitlan [32]. In their comprehensive analysis of
overmatching errors specific to the Price paper, DeSoto
and Hitlan [32] stated that “Matching cannot—or
should not—be done in a way that artificially increases the chance that within[-] strata exposure is the same; this happens when a
matching variable is a significant predictor of exposure and is called
overmatching.”
Cases
were matched with controls of the same age and sex, within the same HMO and
essentially the same vaccination schedule, using the same vaccine
manufacturers. DeSoto and Hitlan
then state further, regarding the lack of variability of Thimerosal exposure in
the Price study, “Across the different years, the average cumulative exposure
varies from 42.3 μg
to 125.46 μg;
while within the birth year stratas (sic), the mean
exposures do not vary by more than 15 micrograms.” In other words, the maximum
level of variation in Thimerosal exposure in the cases and controls being
compared was 15 μg
of Hg, as compared to the “83” μg
of Hg range for the average cumulative exposures in the cohort studies.
Moreover, this range is much less than the range of Thimerosal exposures that
could have been used to determine risk including (a) 0 to 50 μg of Hg for
one-month exposures, (b) 0 to 190 μg
of Hg for seven-month exposures, and (c) 0 to 300 μg of Hg for 20-month exposures.
Finally, regarding the Price study, DeSoto and Hitlan [32] concluded, “this paper
is flawed. Unfortunately, there is not an analytic fix for overmatching: it is
[a] design flaw.”
Prenatal
Thimerosal exposure for the children within the study arose from the
Thimerosal-preserved inactivated-influenza vaccine given during pregnancy and
the Rho immunoglobulin administered to pregnant women to prevent Rh-factor
incompatibility injury to the developing child. Unlike postnatal exposure from
TCVs in the recommended childhood vaccination schedule, prenatal exposures
would not be overmatched in a study design that stratified the participants
based on their birth year or HMO. Evidence from the background CDC report
regarding the Price study showed a significant risk of regressive autism due to
prenatal Thimerosal exposure levels, at exposure levels as low as 16 μg of Hg [33].
However, the risk of regressive autism due to prenatal Thimerosal exposure
reported in that paper was 1.86 and yielded a value
of 0.072 which was deemed as insignificant based on the authors’ “cut-off”
value of .
However, values
between 0.05 and 0.10 are “marginally significant” and should merit further
study. In addition, upon further analysis, it was found that the 2009
background report [33] to the Price et al. [26] study showed that the prenatal
Thimerosal exposure model was run in six different ways and that the most
reliable methods (those that factored out the postnatal Thimerosal exposure
effects) found highly statistically significant relative risks of up to 8.73 ()
for regressive ASD due to prenatal Thimerosal exposures from
Thimerosal-containing influenza vaccines and Rho immunoglobulin products
relative to no such prenatal Thimerosal exposures. Curiously, these more
compelling results were not reported in the paper. Withholding these data from
the publication and, instead, reporting a significantly lower value could
appear to constitute scientific malfeasance on the part of the authors of this
study.
8. Conclusion
As
seen in this review, the studies upon which the CDC relies and over which it
exerted some level of control report that there is no increased risk of autism
from exposure to organic Hg in vaccines, and some of these studies even
reported that exposure to Thimerosal appeared to decrease the risk of autism.
These six studies are in sharp contrast to research conducted by independent
researchers over the past 75+ years that have consistently found Thimerosal to
be harmful. As mentioned in the Introduction section, many studies conducted by
independent investigators have found Thimerosal to be associated with
neurodevelopmental disorders. Several studies, for example, including three of
the six studies covered in this review, have found Thimerosal to be a risk
factor for tics [10, 17, 24, 25, 34, 35]. In addition, Thimerosal has been found to be a risk
factor in speech delay, language delay, attention deficit disorder, and autism [10, 11, 15–17, 24, 25, 34].
Considering
that there are many studies conducted by independent researchers which show a
relationship between Thimerosal and neurodevelopmental disorders, the results
of the six studies examined in this review, particularly those showing the
protective effects of Thimerosal, should bring into question the validity of
the methodology used in the studies. A list of the most common methodological
issues with these six studies is shown in Table 1.
Importantly, other than the Hviid et al. [23] study,
five of the publications examined in this review were directly commissioned by
the CDC, raising the possible issue of conflict of interests or research bias,
since vaccine promotion is a central mission of the CDC. Conceivably, if serious
neurological disorders are found to be related to Thimerosal in vaccines, such
findings could possibly be viewed as damaging to the vaccine program.
|
||||||||||||||||||||||||||||||
Methodological issues most common in each of the six reviewed
studies.
Conflict of Interests
All
of the investigators on the present study have been involved in
vaccine/biologic litigation.
Acknowledgment
Funding
was provided by the nonprofit Institute of Chronic Illnesses, Inc. and CoMeD, Inc.
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