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Thimerosal exposure and increased risk for diagnosed tic disorder in the United States: a case-control study
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Abstract
A hypothesis testing, case-control study evaluated automated medical records for exposure to organic-Hg from Thimerosal-containing hepatitis B vaccines (TM-HepB) administered at specific intervals in the first six-months-of-life among cases diagnosed with a tic disorder (TD) or cerebral degeneration (CD) (an outcome not biologically plausibly linked to TM exposure) in comparison to controls; both cases and controls were continuously enrolled from birth (born from 1991–2000) within the Vaccine Safety Datalink (VSD) database. TD cases were significantly more likely than controls to have received increased organic-Hg from TM-HepB administered within the first month-of-life (odds ratio (OR)=1.59, p<0.00001), first two-months-of-life (OR=1.59, p<0.00001), and first six-months-of-life (OR=2.97, p<0.00001). Male TD cases were significantly more likely than male controls to have received increased organic-Hg from TM-HepB administered within the first month-of-life (OR =1.65, p<0.0001), first two-months-of-life (OR=1.64, p<0.0001), and first six months-of-life (OR=2.47, p<0.05), where as female TD were significantly more likely than female controls to have received increased organic-Hg from TM-HepB administered within the first six-months-of-life (OR=4.97, p<0.05). By contrast, CD cases were no more likely than controls to have received increased organic-Hg exposure from TM-HepB administered at any period studied within the first six-months-of-life. Although routine childhood vaccination is considered an important public health tool to combat infectious diseases, the present study associates increasing organic-Hg exposure from TM-HepB and the subsequent risk of a TD diagnosis.Keywords: ethylmercury, merthiolate, thiomersal, tic, tourette, vaccine
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Introduction
Tic disorder (TD) is a neurodevelopmental disorder characterized by repetitive, involuntary movements and vocalizations called tics (Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition; DSM-5, 2013; Roessner et al., 2011). TD includes Tourette's syndrome, which is characterized by vocal as well as motor tics. Symptoms of TD typically begin in childhood, with the average onset between 3 and 9 years of age. Males are affected approximately three to four times more often than females. TD is considered a chronic condition that lasts a lifetime (National Institute of Neurological Disorders and Stroke, 2012). Psychopathology and co-morbidity occur in approximately 80–90% of clinical cohorts (Hariz et al., 2010). Two of the most common co-occurring psychiatric conditions are: (1) attention deficit/hyperactivity disorder (ADHD), occurring in about half the cases (Roessner et al., 2011; Freeman 2007) and (2) obsessive–compulsive disorder (OCD), also occurring in about half the cases (Roessner et al., 2011). Other common co-morbid conditions are depression, anxiety, and behavioral disorders (Hariz et al., 2010). Also reported are social difficulties and ritualistic behaviors such as counting, repeating, ordering, and arranging. Along with the dramatic rise in neurodevelopmental disorders in general in the last two decades, there has also been an increase in TD (Boyle et al., 2011; Cubo 2012). Although TD was once considered rare, today TD is considered the most common movement disorder, with 0.2–46.3% of schoolchildren experiencing tics during their lifetime (Cubo, 2012). To date, there is no consensus on the causes or contributing factors related to this increase. Many questions regarding the potential contribution of genetic inheritance and susceptibility, gene/environment interaction, and epigenetic or environmental factors to TD remain unanswered.In 2000, investigators described the apparent first childhood case report of mercury (Hg) intoxication with tics as its only manifestation (Li et al., 2000). Subsequently, a series of epidemiological studies evaluated the potential relationship between exposure to organic-Hg from Thimerosal (TM) in childhood vaccines and the risk of a child being diagnosed with a TD (Thompson et al., 2007; Verstraeten et al., 2003; Andrews et al., 2004; Barile et al., 2012; Geier & Geier, 2005; Young et al., 2008). These previous studies employed various epidemiological methods such as case-control or cohort designs, and were conducted on children from several different countries. Each of these studies revealed a significant association between organic-Hg exposure from TM in childhood vaccines and the risk of a child being diagnosed with a TD, and several even observed a significant dose-dependent relationship between increasing organic-Hg exposure from TM-containing vaccines administered at specific intervals within the first year of life and the eventual risk of a child being diagnosed with a TD.
The purpose of the present study was to further evaluate the potential relationship between exposure to organic-Hg from TM-containing hepatitis B vaccines (TM-HepB) administered at specific intervals during the first six months of life, and the subsequent risk of a child being diagnosed with a TD, by conducting a case-control epidemiological study of automated medical records in the Vaccine Safety Datalink (VSD) database.
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Materials and methods
The study protocol employed was approved by the US Centers for Disease Control and Prevention (CDC), the Institutional Review Board (IRB) of Kaiser Permanente North-West (KPNW), and the IRB of Kaiser Permanente Northern California (KPNC). The data was analyzed at the secure Research Data Center of the National Center for Health Statistics in Hyattsville, MD. The views expressed in this study do not necessarily reflect those of the CDC or those of Kaiser Permanente.The VSD project was created in 1991 by the National Immunization Program (NIP) of the CDC. The VSD's data collection and study methods have been previously described (Chen et al., 1997, 2000; Wassilak et al., 1995; Geier & Geier, 2004). The project links medical event information, specific vaccine history, and selected demographic information from the computerized databases of several health maintenance organizations (HMOs). The specific epidemiological methods of analysis employed in the present study were described in a recent study (Geier et al., 2013).
Determining the population at risk
A cohort of over 1 million infants enrolled in the VSD project (updated through the end of 2000) from KPNW, Kaiser Permanente Colorado (KPC), and KPNC was examined using SAS
software. The cohort examined was comprised of individuals who were HMO-enrolled from their date of birth and whose records specified their gender.Determining Cases
The outcome files (inpatient and outpatient diagnoses) from this population were then reviewed to find the first instance of TD for each child as defined by the International Classification of Disease, 9th revision (ICD-9). The TD-associated ICD-9 diagnostic codes examined included: tic disorder, unspecified (307.20), transient tic disorder (307.21), chronic motor or vocal tic disorder (307.22), and Tourette's disorder (307.23). If there were multiple instances of the same diagnosis in a child, only the first instance was counted. In addition, to ensure that exposure preceded the diagnosis of a TD, for vaccinated individuals diagnosed with a TD, only those individuals diagnosed with a TD following administration of the vaccines under study were included as cases in the present analyses (less than 10% of individuals diagnosed with a TD were excluded because of this criterion).A total of 344 cases diagnosed with TD (males = 253, females = 91, male/female ratio = 2.8), born from 1991 through 2000, were identified. These individuals diagnosed with TD were evaluated to determine their mean age of initial diagnosis of TD ± standard deviation of mean age of initial diagnosis of TD (5.10±2.01 years-old).
In addition, the putative generally accepted biologically non-plausible linkage between TM exposure and a subsequent diagnosis of cerebral degeneration was examined as a control outcome. The outcome files (inpatient and outpatient diagnoses) from this population were reviewed to find the first instance of cerebral degeneration for each child defined as 330.xx or 331.xx by ICD-9 coding. If there were multiple instances of the same diagnosis in a child, only the first instance was counted. In addition, to ensure the potential for an association between exposure and outcome, for vaccinated individuals diagnosed with cerebral degeneration, only those individuals diagnosed with cerebral degeneration following administration of the vaccines under study were included as cases in the present analyses.
A total of 647 cases diagnosed with cerebral degeneration (males = 359, females = 288, male/female ratio = 1.25), born from 1991 through 2000, were identified. These individuals diagnosed with cerebral degeneration were evaluated to determine their mean age of initial diagnosis of TD ± standard error of mean age of initial diagnosis of cerebral degeneration (0.63±0.04 years-old).
Determining controls
In order to identify controls without a diagnosis of TD who would have only a minimal chance of subsequently receiving such a diagnosis, controls had to have been continuously enrolled from birth for at least 7.11 years (mean age of initial diagnosis of TD plus the standard deviation of mean age of initial diagnosis of TD). Applying this follow-up criterion yielded a total of 28,016 controls without a TD diagnoses (males = 14,327, females = 13,689, male/female ratio = 1.05) born from 1991 through 1993.In order to identify controls without a diagnosis of cerebral degeneration who would have only a minimal chance of subsequently receiving such a diagnosis, controls had to have been continuously enrolled from birth for at least 2.6 years (mean age of initial diagnosis of cerebral degeneration plus two times the standard deviation of mean age of initial diagnosis of cerebral degeneration). Applying this follow-up criterion yielded a total of 135,888 controls without a cerebral degeneration diagnoses (males = 69,426, females = 66,462, male/female ratio = 1.05) born from 1991 through 1998.
Hepatitis B vaccine exposure
The vaccine file for cases and controls was then reviewed to determine the exact dates of HepB administration. Those cases and controls receiving no doses of HepB were also included in the present study. Hg exposure was assigned as 12.5 microgram (μg) of organic-Hg per dose for those receiving a pediatric HepB or 0 μg of organic-Hg per dose for those receiving either combined haemophilus influenzae type b (Hib)-HepB or neither of the aforementioned vaccines. The Hg content of the vaccine doses was based upon the report of the Committee on Infectious Disease and Committee on Environmental Health of the American Academy of Pediatrics report of the TM content in US-licensed vaccines from 1999 (American Academy of Pediatrics 1999). Overall among the cases and controls, the maximum exposure to Hg from pediatric HepB was 37.5 μg of organic-Hg (from children receiving three doses of TM-HepB) administered within the first six months of life.Statistical analyses
The Fisher's exact test contained in the SAS software was utilized for statistical analyses, and a two-sided p-value <0.05 was considered statistically significant. Three different levels of Hg exposure from TM-HepB were examined. In the first case-control experimental group (Experiment I), the data were examined to determine the frequency of exposure to 12.5 μg of organic-Hg from TM-HepB in the first month of life, in comparison to the frequency of 0 μg of organic-Hg from TM-free hepatitis B vaccine (TM-free-HepB) or no HepB in the first month of life, among cases and controls. In the second case-control experimental group (Experiment II), the data were examined to determine the frequency of receiving two TM-HepB within the first two months of life or a total of 25 μg of organic-Hg, in comparison to the frequency of receiving 0 μg of organic-Hg from TM-free-HepB and/or no HepB in the first two months of life, among cases and controls. In the third case-control experimental group (Experiment III), the data were examined to determine the frequency of receiving three TM-HepB within the first six months of life, or a total of 37.5 μg of organic-Hg, in comparison to the frequency of receiving 0 μg of organic-Hg in the first sixth months of life, from TM-free-HepB and/or no HepB among cases and controls. In addition, because the ratio of males to females was 2.8, using the aforementioned exposures and exposure windows, additional separate analyses were completed where male cases were compared to male controls (Experiments IV–VI) and female cases were compared to female controls (Experiments VII–IX). Finally, using the aforementioned exposures and exposure windows, cases diagnosed with the putative non-biological plausibly linked TM-associated diagnosis of cerebral degeneration, a medical condition that is generally accepted as biologically not plausibly linked to TM exposure was compared to controls (Experiments X–XII). The overall null hypothesis for each of these case-control experimental groups was that there would be no difference in the frequency of exposure to organic-Hg doses from TM-HepB between the cases and the controls.Results
Table 1 displays the relationship between cases diagnosed with a TD and controls receiving increasing doses of organic-Hg from TM-HepB at several specific points within the first six months of life. Experiment I documented that cases diagnosed with TD were significantly more likely (odds ratio = 1.59, p<0.0001) than controls to have received 12.5 μg of organic-Hg from TM-HepB in comparison to 0 μg of organic-Hg from TM-free-HepB or no HepB within the first month of life. Experiment II documented that cases diagnosed with a TD were significantly more likely (odds ratio = 1.59, p<0.0001) than controls to have received 25 μg of organic-Hg from TM-HepB in comparison to 0 μg of organic-Hg from TM-free-HepB and/or no HepB within the first two months of life. Finally, in Experiment III, cases diagnosed with a TD were significantly more likely (odds ratio = 2.97, p<0.005) than controls to have received 37.5 μg of organic- Hg from TM-HepB in comparison to 0 μg of organic-Hg from TM-free-HepB and/or no HepB within the first six months of life.Table 1
A summary of exposure to organic-Hg from Thimerosal-containing hepatitis B vaccine administration among cases diagnosed with TD in comparison to controls.| Experiment I | 12.5 μg organic-Hg within 1st month | 151 (43.90) | 9,222 (32.92) | 1.59 (1.29–1.98) | <0.00001 |
| 0 μg organic-Hg within 1st month | 193 (56.10) | 18,794 (67.08) | |||
| Experiment II | 25 μg organic-Hg within first 2 months | 151 (44.54) | 9,236 (33.62) | 1.59 (1.28–1.97) | <0.00001 |
| 0 μg organic-Hg within first 2 months | 188 (55.46) | 18,233 (66.38) | |||
| Experiment III | 37.5 μg organic-Hg within first 6 months | 33 (76.74) | 1,292 (52.63) | 2.97 (1.46–6.05) | 0.005 |
| 0 μg organic-Hg within first 6 months | 10 (23.26) | 1,163 (47.37) |
CONTINUE HERE: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4961900/
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