Studies Investigating Thimerosal Exposure with Autism and Other Developmental Outcomes.
Autism spectrum disorders (ASDs) encompass a group of chronic developmental disorders characterized by repetitive or stereotypic behaviors, interests and activities, along with marked impairments in a child’s ability to socialize and communicate. These debilitating conditions impact every aspect of the life of a child and his/her family. Modern advances in science and technology have provided successful explanations and interventions for many previously life-threatening conditions such as bacterial meningitis and extreme prematurity. However, a scientific cause or definitive treatment for ASDs remains elusive. This lack of evidence regarding the biological causes of ASDs and successful, standardized treatment modalities challenges both parents/caregivers and health care providers in their understanding of these conditions, and effectively addressing the needs of this pediatric population. In some instances, the lack of evidence has fueled the development of hypotheses and possible associations based on the publication of case reports and small cohort studies.
The prevalence of ASDs has increased over the past several decades, but it is unclear whether this is due to a true increase, increasing awareness, or differences in the methods used to diagnose these conditions and assess their prevalence. Given the irrefutable increase in the prevalence of ASDs, there has been interest in both genetic influences and environmental exposures that may have led to this increase over the past several decades. Although a small proportion of ASDs are associated with known congenital conditions, and several genes involved in ASDs have been identified, in most cases the etiology of ASDs is unknown. Some of the environmental triggers for ASDs that have been postulated include lack of breastfeeding, supplemental feeding with infant formulas that do not contain docosahexaenoic acid and arachidonic acid supplementation, childhood vaccinations, the use of acetaminophen and other analgesics, certain viral infections, and sundry other environmental exposures. Among these exposures, vaccinations have received the most widespread interest and attention by both the lay public as well as the medical and scientific communities. Young children are receiving more vaccines than ever, with multiple vaccines given at each visit, to provide protection against a plethora of infectious diseases. ASDs are often diagnosed in children at about the same chronologic age as the peak time for vaccine delivery. Unfortunately, a small, but vocal minority of people have attributed the rise in rates of ASDs to the increase in childhood vaccinations, despite the lack of rigorous scientific evidence to support this contention. The question about vaccines and ASDs continues to cause conflict between public health authorities and worried parent groups. This chapter will provide further details of the arguments on both sides and an analysis of the scientific evidence that supports the view that ASDs and vaccines are unlikely to be linked.
2. Vaccines - victims of their own success?
Vaccination is among the greatest achievements of modern medicine, leading to the eradication of naturally occurring smallpox and the near elimination of polio . Most of the lay public as well as many scientists and physicians do not realize that the first vaccines against smallpox and rabies proved their effectiveness even before the identification of viruses as infectious agents . Vaccination has a short history in medicine and public health when measured against the centuries during which human beings have fought desperately to prevent and treat various plagues and pestilences. Routine vaccination of large populations is a phenomenon of the 20th century . Despite its relatively recent entry into the field of medicine and public health, vaccination has helped in the world-wide eradication/control of 12 major infectious diseases, including smallpox, diphtheria, tetanus, yellow fever, pertussis,
Parents and many health care providers of the 21st century, particularly in more developed areas of the world such as the United States and Western Europe, have limited or no experience with the devastating effects of these diseases. In the United States public health officials now recommend 28 to 31 vaccine doses before the age of 18 years, many of which are administered together to provide protection early in life, for the convenience of families and health care providers, and to decrease distress to the infant. Public health experts recommend that 95% of the population be vaccinated to provide herd immunity and minimize the possibility of resurgence of these deadly infections. However, parents in developed countries who have not seen these diseases or their disastrous consequences sometimes feel that they are being pressured into immunizing their children involuntarily for public good rather than personal benefit . Some parents even perceive a greater risk to their children from vaccination than from the diseases themselves, not recognizing that the threat from these diseases is reduced simply because we do have effective vaccines to prevent them. Vaccination has thus regrettably become a polarized issue with some parents stressing their own child’s well-being at the one extreme and health experts advocating for public health outcomes on the other extreme.
3. Genesis of the “vaccines cause autism” theory
One of the first claims that vaccines might cause autism was made in a book entitled “A Shot in the Dark” by Harris L. Coulter and Barbara Loe Fisher . In it the authors wrote, “With the increasing number of vaccinations American babies have been required to use has come increasing numbers of reports of chronic immune and neurologic disorders … including … autism.” At the time, little attention was paid to this assertion. The hypothesis received far greater support after a British physician and researcher Dr. Andrew Wakefield along with 12 co-authors published an article describing abnormal gastrointestinal features among 12 children who had been referred to their university pediatric gastroenterology clinic . All of the children were reported to have some type of developmental disorder, and 9 of them had been diagnosed with autism. In 6 of these 9 children, either the parent or a physician had linked the onset of developmental regression with the receipt of the MMR vaccine. In this paper, Wakefield
Additional theories of the putative association between vaccines and ASDs include:
Concern about the mercury-containing preservative thimerosal (which was used in childhood vaccines for many years) and its potential toxic effects on the developing central nervous system in children;
Worry that a combination of MMR and thimerosal-containing vaccines produces additive or synergistic toxic insults on children’s brains;
Apprehension related to the simultaneous administration of multiple vaccines which might “overwhelm” or “weaken” the relatively immature immune system in young children.
These theories will be explored later in this chapter, but let us first further discuss the most well-known controversy surrounding vaccines and ASDs.
4. Impact of the “MMR causes autism” scare
As a consequence of the publications by Wakefield and his colleagues, many parents anxious about the risk of autism, particularly in the UK, began to refuse the MMR vaccine for their children. After the controversy began, the MMR vaccination compliance dropped in the UK from 92% in 1996 to 82% in 2002 . In some parts of London, it was as low as 62% in 2003, far below the rate needed to avoid an epidemic of measles . By 2006, coverage for MMR for children at 24 months of age in the UK was 85%, significantly lower than the 94% coverage rate for other vaccines . Predictably, the fall in vaccination rates for MMR vaccine was followed by an increase in the incidence in the UK of two of the three diseases that are prevented by it. In 1998 there were 56 confirmed cases of measles in the UK. By the first five months of 2006, there were 449 cases of measles reported in the UK, with the first death since 1992. As expected, the cases occurred in inadequately vaccinated or unvaccinated children .
Mumps cases also began rising in 1999 after many years, and by 2005 the UK was in the midst of a mumps epidemic with almost 5000 reports in the first month of 2005 alone . A total of 56,390 notified cases of mumps were reported in England and Wales that year . Interestingly, most patients were aged between 15 and 24 years, too old to have received the routine MMR vaccine around the time the paper by Wakefield
Measles and mumps cases continued in 2006, at incidence rates 13 and 37 times greater than their respective 1998 levels . Two children were severely and permanently injured by measles encephalitis in London . Measles outbreaks also resulted in casualties in nearby countries. Three deaths and 1,500 cases of measles were reported in an outbreak in Ireland, which occurred as a direct result of decreased vaccination rates following the MMR scare . Another study reported the hospitalization of 111 cases of measles mostly with pneumonia, tracheitis or dehydration, with 13 of them requiring ICU admission and 7 of the children needing mechanical ventilation . One editorial has described this as the “fallout” of the paper published by Wakefield et al. . In 2008, for the first time in 14 years, measles was declared to be endemic again in the UK. This was caused by the preceding decade's low MMR vaccination rates, which in turn created a population of susceptible children who could spread the disease . MMR vaccination rates for English children remained at 85% in 2007–08, unchanged from the year before and at too low a level to prevent serious measles outbreaks . In May 2008, a British 17-year-old with an underlying immunodeficiency died of measles . In 2008, measles epidemics were reported from Austria, Italy, and Switzerland .
In a study conducted in the US, selective MMR nonreceipt, occurring in as few as 0.77% of children in the 1995 cohort, rose to 2.1% according to the 2000 National Immunization Survey . Children included in the 2000 National Immunization Survey were born at around the time that the putative link between MMR and autism surfaced in the medical literature. Sporadic importations of measles into the US had occurred since the disease was declared eliminated from the US in 2000. However, in 2008, a measles outbreak occurred in the US involving 16 states . Of the individuals affected, 94% were US residents, 93% were unvaccinated and 86% of the cases were imported (69% from Europe).
5. Lack of evidence to support the “MMR causes autism” theory
The scientific limitations of the paper published by Wakefield
In 2004, 10 of the 12 coauthors of Wakefield’s acknowledged that “no causal link was established between MMR vaccine and autism as the data were insufficient” in their original paper and asked to “formally retract the interpretation” of their findings . Moreover, an investigation by D’Souza
Despite the scientific difficulty with proving a negative, the Institute of Medicine (IOM) in a report on vaccine safety has stated conclusively that there is no causal relationship between the administration of the MMR vaccine and the onset of ASDs . This eighth and final report of the Immunization Safety Review Committee examined the hypothesis that vaccines, specifically the MMR vaccine and thimerosal-containing vaccines, are causally associated with autism. The committee reviewed the extant published and unpublished epidemiological studies regarding causality and studies of potential biologic mechanisms by which immunizations might cause autism and concluded that the body of epidemiological evidence favored
6. MMR and autism - honest error or deliberate fraud?
The Office of Research Integrity in the United States defines fraud as fabrication, falsification, or plagiarism in proposing, performing, or reviewing research, or in reporting research results . They further explain that:
Fabrication is making up data or results and recording or reporting them.
Falsification is manipulating research materials, equipment, or processes, or changing or omitting data or results such that the research is not accurately represented in the research record.
Plagiarism is the appropriation of another person's ideas, processes, results, or words without giving appropriate credit.
Research misconduct does not include honest error or differences of opinion.
Editors at the BMJ claim that it has taken the diligent skepticism of one man, Brian Deer, a journalist standing outside the realms of medicine and science, to show that the initial paper by Wakefield
While the disciplinary panel was examining the children’s medical records in public, Deer compared them with what was published in the
7. Consequences of the “MMR causes autism” fraud
Nearly 12 years after its original publication, the journal
The Wakefield case and its aftermath have resulted in a reevaluation of how biomedical research is regulated. There have been calls for a national Health Research Agency to be established in the UK to oversee the regulation and governance of health research . Others have advocated for public access to raw data, arguing that the apparent discrepancies between the patient records and the data in the article by Wakefield
Based on the above referenced body of knowledge, few people could deny that Wakefield
8. Origins of the thimerosal and autism controversy
Another hot button issue that has been debated in relationship to the onset of ASDs is exposure to thimerosal, a preservative that has been present in vaccines since the 1930s . Multidose vaccine vials have the antibacterial agent thimerosal added to preserve the sterility of the contents. Thimerosal contains 49.6% mercury by weight and metabolizes into
the chemical form of mercury
the age of the person exposed (the fetus is the most susceptible)
the duration of exposure
the route of exposure -- inhalation, ingestion, dermal contact, etc.
the health of the person exposed.
Various agencies have developed guidelines for “safe” exposure to
In 1997, Frank Pallone, a U.S. congressman from New Jersey, added an amendment to a (FDA) reauthorization bill which gave the FDA 2 years to “compile a list of drugs and foods that contain intentionally introduced mercury compounds and provide a quantitative and qualitative analysis of the mercury compounds in the list” . The bill was signed into law as the FDA Modernization Act of 1997, and garnered little public or press attention at the time. To abide by this law, the FDA conducted a comprehensive review of the use of thimerosal in childhood vaccines in 1999, and notably, found
As more thimerosal-containing vaccines were added to the recommended infant and child immunization schedule, theoretical concerns based on the cumulative amounts of thimerosal that a child was receiving in the first two years of life were raised. As a precautionary measure, the US Public Health Service (USPHS) (which includes the FDA, National Institutes of Health (NIH), Centers for Disease Control and Prevention (CDC) and the Health Resources and Services Administration (HRSA)) and the American Academy of Pediatrics issued two Joint Statements, urging vaccine manufacturers to reduce or eliminate thimerosal in vaccines as soon as possible [90, 91]. This was done through an “abundance of caution,” even though there was no evidence that thimerosal-containing vaccines contributed to toxic mercury levels in children, and in fact
9. Insufficient scientific evidence linking thimerosal with autism
The signs and symptoms of autism are clearly distinct from those of mercury poisoning. Children with mercury poisoning show characteristic motor, speech, sensory, psychiatric, visual, and head circumference changes that are fundamentally different from those of or absent in children with autism. Concerns about mercury as a cause of autism therefore seemed biologically implausible . Nevertheless, it began to be suggested that there may be adverse neurological effects including autism due to
Meanwhile, several other studies performed by various groups of researchers did not support the postulated association between thimerosal and ASDs [33, 105-112]. Three ecological studies were performed in 3 different countries comparing the incidence of autism with thimerosal exposure from vaccines [33, 109, 110]. In each case, thimerosal had been removed from childhood vaccines, allowing robust comparisons of vaccination with thimerosal-containing and thimerosal-free products. A large study from Denmark showed no difference in the incidence of autism among children who had received vaccines containing different amounts of thimerosal . Despite the removal of thimerosal from vaccines in 1992 in Sweden and Denmark, the incidence of autism increased steadily from 1990 to 2000 . Thimerosal exposure and pervasive developmental disorder diagnosis were found to be independent variables in a study from Canada . In this study, the highest rates of pervasive developmental disorder were found in children who had received thimerosal-free vaccines .
Additional epidemiologic studies also failed to show any association between thimerosol exposure and ASDs. In a large study from Denmark, researchers found that the risk of autism did not differ between children vaccinated with thimerosal-containing vaccines and those vaccinated with thimerosal-free vaccines or between children who received larger or smaller quantities of thimerosal . They also reported that the rates of autism increased after the removal of thimerosal from all vaccines. In the United States, researchers at the CDC used the Vaccine Safety Data Link to examine the health records of 140,887 children born during 1991–1999, including over 200 children diagnosed with autism . They found no relationship between receipt of thimerosal-containing vaccines and autism. In a large study conducted in the UK, researchers evaluated the vaccination records of 100,572 children born during 1988–1997, 104 of whom were affected with autism . No relationship between thimerosal exposure and developmental disorders was observed. In a separate study from the UK, researchers prospectively followed 12,810 children born during 1991–1992, for whom they had complete vaccination records, and again found no relationship between early thimerosal exposure and subsequent adverse neurological or psychological outcomes .
A long-term follow-up study by the CDC showed that early thimerosal exposure from vaccines did not cause adverse neuropsychological outcomes after 7-10 years . In another long-term follow-up study performed in Italy, 2 groups of children with exposure to different doses of thimerosol were examined . Among the 24 neuropsychological outcomes that were evaluated, only 2 were significantly associated with thimerosal exposure. The authors noted that due to the large number of statistical comparisons performed, the few associations found between thimerosal exposure and neuropsychological development might be attributable to chance . The associations found, although statistically significant, were based on small differences in mean test scores, and their clinical relevance could not be determined. A case-control study was conducted in 3 managed care organizations (MCOs) in the US that included 256 children with ASD and 752 matched controls . The authors report that in their study, prenatal and early-life exposure to
Interestingly, comparisons of
|Type of Study||Outcome Measure||Association with Thimerosal Exposure|
|Andrews et al., 2004||Cohort||Autism||No|
|Croen et al., 2008||Case-Control||Autism||No|
|Geier and Geier, 2007||Case-Control||Autism||Yes|
|Heron et al., 2004||Cohort||Developmental Disorders||No|
|Hviid et al., 2003||Cohort||Autism||No|
|Madsen et al., 2003||Ecologic||Autism||No|
|Miles and Takahashi, 2007||Cross-Sectional||Autism||No|
|Thompson et al., 2007||Cohort||Neuropschological Functioning||No|
|Verstraeten et al., 2003||Cohort||Autism||No|
|Young, Geier, and Geier, 2008||Ecologic||Autism||Yes|
Thimerosal has been removed from all childhood vaccines in the US, but this has also increased production costs which are ultimately passed on to the consumer. Only some preparations of influenza vaccine still contain thimerosal (See Table 3). However, largely unfounded concerns about the adverse effects of thimerosal have made many parents reluctant to have their children receive this vaccine. What goes unrecognized by the lay public and even many health care providers is that influenza virus causes hundreds of thousands of hospitalizations and an average of 100 deaths among children every year. Mistakenly attempting to protect their children from a theoretical risk, these parents inadvertently place them at the real risk of being hospitalized or killed by influenza. An alarming recent trend has been that physicians, scientists, government policy advisors, and child advocates who publicly state that vaccines do not cause neurologic problems or autism have been harassed, threatened, and vilified, receiving hate mail and occasionally even death threats .
|Diphtheria & Tetanus Toxoids Adsorbed USP multi-dose single dose||sanofi pasteur||.01%||25|
|Tetanus and Diphtheria Toxoids Adsorbed||sanofi pasteur||*||*|
|Tetanus Toxoid Adsorbed USP||sanofi pasteur||.01%||25|
|Tetanus Toxoid Adsorbed Adult Use||.01%||25|
|PedvaxHIB liquid (2)||Merck|
|Engerix-B preservative free||GlaxoSmithKline|
|Recombivax HB preservative free||Merck|
|Afluria multi-dose single dose||CSL Limited||.01%||24.5|
|Fluzone 5 mL vial No Preservative||sanofi pasteur||.01%||25|
|Influenza A (H1N1) 2009 Monovalent Vaccine multi-dose single dose||CSL Limited||.01%||24.5|
|Influenza A (H1N1) 2009 Monovalent Vaccine multi-dose single dose||Novartis||.01%||24.5|
|Influenza A (H1N1) 2009 Monovalent Vaccine multi-dose single dose||sanofi pasteur||.01%||25|
|Influenza A (H1N1) 2009 Monovalent Vaccine||GlaxoSmith Kline||.01%||25|
|Influenza A (H1N1) 2009 Monovalent Vaccine Live, Intranasal||MedImmune|
|IPOL Ixiaro commercial | military||sanofi pasteur Intercell Bio|
|MENOMUNE-A/C/Y/W-135 multi-dose single dose||sanofi pasteur||.01%||25|
|Typhim Vi||sanofi pasteur|
10. If vaccines are not to blame, why are ASDs increasing?
The increase in prevalence of the ASDs may be explained by three reasons as described by Scahill
11. Role of multiple vaccines and emergence of alternative schedules
With the revelations of the likely fraudulent claims about the MMR vaccine causing ASDs and well-designed studies of thimerosal-containing vaccines failing to show an association with autism, alternative theories about the role of vaccines in causing ASDs have been proposed. The most prominent among these is that the simultaneous administration of multiple vaccines “overwhelms” or “weakens” the immature immune system in young children and through some interaction with the nervous system “triggers” autism in a susceptible host. Sensationalized cases in the media have given credence to this theory. The case that has garnered the most attention is that of a 9-year-old girl with a mitochondrial enzyme deficiency whose encephalopathy, which included features of ASD, was judged to have worsened following the receipt of multiple vaccines at age 19 months . Her family was able to successfully obtain compensation through the US Vaccine Injury Compensation Program (VICP) which was developed in the 1980s to fairly compensate individuals who feel they have been harmed by a vaccine. In the wake of this case, despite reassurances by the CDC that the VICP’s action should not be interpreted as scientific evidence that vaccines cause autism, the theory that multiple vaccines given simultaneously can trigger autism has gained credence among the lay press and public.
The idea that multiple vaccines given to young children might either overwhelm an immature immune system or generate a pathologic, autism-inducing autoimmune response is flawed for several reasons. Although the infant immune system is relatively naive, it is capable of generating a vast array of protective responses, starting at birth. In fact, vaccines represent a small fraction of the challenges to a young child’s immune system. For example, the average child is infected with 4-6 viruses per year , exposing its immune system to numbers of antigens that far exceed those present in simultaneously administered childhood vaccines. Proponents of the theory point to the increasing number of vaccines that are administered to young children. However, most people do not recognize that although the number of recommended childhood vaccines has increased during the past 30 years, with advanced technologies that are used to manufacture modern vaccines, the immunologic load has actually decreased. The childhood vaccines given today contain <200 bacterial and viral antigens, compared with >3000 of these immunological components in the vaccines administered to children in 1980 . In fact, combinations of vaccines are actually known to induce immune responses that are comparable to those given individually .
Susceptibility to non-vaccine-preventable infections does not differ in vaccinated and unvaccinated children [127–129]. Put in another way, vaccination does not appear to suppress the immune system in young children in a clinically relevant manner. On the contrary, infections with some vaccine-preventable diseases are known to predispose children to severe, invasive infections with other pathogens [130,131]. Therefore, the available data suggest that vaccines do not “weaken” the immune system. Furthermore, it should be recognized that autism is not an immune-mediated disease such as multiple sclerosis. There is no evidence of immune activation or inflammatory lesions in the brains of autistic people . Instead, new research suggests that genetic variation in neuronal circuitry that affects synaptic development in the brain might in part account for the symptoms of autism . Therefore, the theory that an exaggerated or inappropriate immune response to vaccination results in autism is at variance with current scientific data that address the pathogenesis of autism.
In 2007, Dr. Robert Sears, a pediatrician from Southern California published
12. Legal repercussions
Perhaps inevitably in a litiginous society, the question of whether childhood vaccines cause autism has moved from the scientific into the legal realm [137-139]. Parents of children with autism have submitted thousands of claims to the federal VICP, seeking damages because they believe that their child’s autism was caused by vaccines. In 2002, to resolve such claims more expeditiously, the VICP announced that some “test cases” would examine the general causation question, putting aside the question of harm to any particular child. On February 12, 2009, the U.S. Court of Federal Claims published decisions about these claims, which were considered as a group under the Omnibus Autism Proceeding. The Court, after reviewing 5,000 pages of transcripts, 939 medical articles, 50 expert reports, and hearing testimony from 28 experts, found that the MMR and thimerosal-containing vaccines, independently or together, were not causal factors in the development of autism or ASD [48, 50, 140]. Finally, in
13. Role of the media
As described above, many parents are hesitant about vaccinating their children. Vaccine hesitancy can be explained in part by a lack of trust in those who make vaccine recommendations; a suspicion of profit motive driven by pharmaceutical companies;
misinformation on the Internet; failure to appreciate the seriousness of vaccine-preventable
diseases, given their low rates; and constant stories in the media claiming that vaccines cause a variety of illnesses, ranging from allergies to autism . In spite of overwhelming scientific evidence to the contrary, the debate over vaccines and ASDs rages on, with media reports fueling the general public’s fear. The disconnect between the scientific community and the popular media is clear in a study published by researchers at the Stanford University School of Medicine . They found that while 41 percent of research funding and published scientific papers on autism dealt with brain and behavior research, only 11 percent of newspaper stories in the United States, United Kingdom and Canada dealt with those issues. Instead, 48 percent of the media coverage dealt with environmental causes of autism, particularly the childhood MMR vaccine . However, in a study by Smith et al., there was a significant increase in selective MMR non-receipt in the US that was temporally associated with the publication of the original scientific literature suggesting a link between MMR and autism. This decline in MMR vaccination preceded media coverage of the MMR-autism controversy and suggests a limited influence of mainstream media on MMR immunization in the United States .
Poland and Jacobson note that there has been opposition to vaccination published in newspapers since the introduction of the first vaccine for smallpox over 200 years ago . According to them, little has changed since that time, although now the antivaccinationists' media of choice are typically television and the Internet, including its social media outlets, which are used to sway public opinion and distract attention from scientific evidence . The authors propose various remedies to the misinformation about vaccines that may be presented in the media. Chief among these is enhanced public education and public persuasion, with increasing scientific literacy at all levels of education. They also recommend public-private partnerships of scientists and physicians be developed to make accurate vaccine information accessible to the public in multiple languages, on a range of reading levels, and through various media outlets.
Due to the vaccine discoveries of the 20th century and implementation of successful immunization programs around the world, many infectious diseases such as smallpox, polio and measles have either been eradicated or become rare. Parents and many health care providers of the 21st century have limited or no experience with the devastating effects of these diseases. In parallel, over the last few decades there has been an alarming increase in the number of children diagnosed with autism spectrum disorders (ASDs). Why this increase has occurred is not entirely known, although some explanations have been offered by the medical and scientific community. ASDs are often diagnosed in children at about the same chronologic age as the peak time for vaccine delivery. This congruence in time of two separate but important health issues, has led to the peculiar situation where fear of disease has shifted to concerns about vaccine safety, particularly ASDs among some members of the public. Although scientific evidence has refuted many of the misconceptions regarding vaccines and ASDs, this information has not been disseminated sufficiently among the lay public. The unfortunate result has been an erosion of public confidence in vaccines. Consequently, some vaccine-preventable diseases such as measles and polio have reappeared in parts of the world where they had been nearly eliminated. In order to restore the public’s trust, all stakeholders including parents, healthcare providers and public health authorities need to ensure that rigorously researched scientific information on the issue of vaccines and autism be accurately collected and disseminated.