 |
|
 |
|
 |
 |
|
 |
 |
 |
 |
 |
 |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
* Epidemic Intelligence Service Program, Epidemiology Program Office, Centers for Disease Control and Prevention, Atlanta, Georgia
Vaccine Safety and Development Activity, Epidemiology and Surveillance Division, National Immunization Program, Centers for Disease Control and Prevention, Atlanta, Georgia
University of Washington and Group Health Cooperative of Puget Sound, Seattle, Washington
|| Center for Child Health Care Studies, Department of Ambulatory Care and Prevention, Harvard Pilgrim Health Care and Harvard Medical School, and Division of General Pediatrics, Children’s Hospital, Boston, Massachusetts
¶ Kaiser Permanente Vaccine Study Center, Oakland, California
 |
ABSTRACT |
|---|
 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
|---|
Methods. A 2-phased retrospective cohort study was conducted using computerized health maintenance organization (HMO) databases. Phase I screened for associations between neurodevelopmental disorders and thimerosal exposure among 124 170 infants who were born during 1992 to 1999 at 2 HMOs (A and B). In phase II, the most common disorders associated with exposure in phase I were reevaluated among 16 717 children who were born during 1991 to 1997 in another HMO (C). Relative risks for neurodevelopmental disorders were calculated per increase of 12.5 µg of estimated cumulative mercury exposure from TCVs in the first, third, and seventh months of life.
Results. In phase I at HMO A, cumulative exposure at 3 months resulted in a significant positive association with tics (relative risk [RR]: 1.89; 95% confidence interval [CI]: 1.05–3.38). At HMO B, increased risks of language delay were found for cumulative exposure at 3 months (RR: 1.13; 95% CI: 1.01–1.27) and 7 months (RR: 1.07; 95% CI: 1.01–1.13). In phase II at HMO C, no significant associations were found. In no analyses were significant increased risks found for autism or attention-deficit disorder.
Conclusions. No consistent significant associations were found between TCVs and neurodevelopmental outcomes. Conflicting results were found at different HMOs for certain outcomes. For resolving the conflicting findings, studies with uniform neurodevelopmental assessments of children with a range of cumulative thimerosal exposures are needed.
Key Words: cohort study • computerized medical record systems • language development disorders • speech disorders • thimerosal • vaccines
Abbreviations: Hg, mercury • EPA, Environmental Protection Agency • TCV, thimerosal-containing vaccine • HMO, health maintenance organization • VSD, Vaccine Safety Datalink • CDC, Centers for Disease Control and Prevention • LBW, low birth weight • ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification • ADD, attention-deficit disorder • RR, relative risk • HBV, hepatitis B vaccine
From the 1930s to the late 1990s, many routinely administered vaccines in the United States contained thimerosal, an organic compound that is 49% mercury (Hg) by weight and is metabolized to ethylmercury and thiosalicylate. To meet Food and Drug Administration guidelines, thimerosal was added to vaccines to prevent bacterial and fungal contamination of multidose vaccine vials (except live viral vaccines).1 Another organic Hg compound, methylmercury, has been found in studies of fish and grain ingestion to affect human neurologic and renal systems.2–4 These studies, along with studies of prenatal Hg exposure, have been used by regulatory agencies to develop guidelines on exposure limits for methylmercury, the most stringent of which was set by the Environmental Protection Agency (EPA).5–8 During a Food and Drug Administration review of Hg and other metals in drugs, it was determined that some infant immunization schedules that use thimerosal-containing vaccines (TCVs) adopted in 1991 may have exceeded the 1995 EPA guidelines for exposure to organic Hg (1 µg/kg/d vs 3 µg/kg/d in the previous 1985 EPA guidelines).1,9–11 In July 1999, the American Academy of Pediatrics and the US Public Health Service recommended removing thimerosal from childhood vaccines as soon as possible as a precautionary measure.12–14
Although oral ingestion of organic Hg has been studied, information concerning the effects of parenteral exposure to these compounds in humans is limited to a few case reports,15–18 none of which involved exposure from vaccines. Vaccines, however, constitute a nearly universal exposure for children in the United States and most other countries. To evaluate the theoretical concerns of the potentially toxic effects of thimerosal in vaccines, we studied neurodevelopmental outcomes among a large group of children with documented exposure to varying levels of thimerosal from vaccinations in several health maintenance organizations (HMOs).
|
METHODS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
|---|
Study Participants
For phase I, we studied a cohort of infants from the VSD project, which was created in 1991 by the National Immunization Program of the Centers for Disease Control and Prevention (CDC). The VSD methods have been described previously.19–21 The project links medical event information, specific vaccine history (including manufacturer and lot number), and selected demographic information from the computerized databases of several HMOs. Because most of the neurodevelopmental outcomes of interest would have been cared for only in the outpatient setting, we restricted our analyses to children who were born from January 1992 through December 1998 at the 2 HMOs (HMO A and HMO B) with the most complete computerized outpatient data. At HMO A, clinic data for outcomes were available throughout the study period; for HMO B, clinic data were available starting in January 1995. For both HMOs, children had follow-up data through the end of 2000. For phase II, we used computer databases similar to those of the VSD to study children in a third HMO (HMO C), where data were available on children who were born from January 1991 through December 1997, with follow-up through May 1998.
To capture all vaccinations in the first year of life, we restricted the cohorts to children who were born into the HMO and remained enrolled continuously for the first year of life. To be certain that we studied children who actually received most of their primary care through the HMO, we excluded children who did not have documentation in the HMO databases of at least 2 polio vaccines by the age of 1 year.
We excluded from the main analysis infants with low birth weight (LBW) of <2500 g and those with a diagnosis of a congenital or severe perinatal disorder or born to mothers with serious medical problems of pregnancy (Appendix 1). We performed a separate analysis of infants with birth weights between 1500 and 2499 g.
Exposure Assessment
We assessed cumulative exposure at 1, 3, and 7 months of life, when the exposure burden relative to body weight was highest. During the years of the study, the HMOs routinely used multidose vials for the vaccines of interest, and the exposure estimates were based on the mean Hg content of each vaccine in multidose vials (Table 1).
|
Speech and language disorders were important outcomes, but coding practices for these conditions varied by HMO. At HMO B, separate codes for language delay (ICD-9 315.31) and speech delay (315.39) were used. At HMO A, only the code for speech delay was used, and there were no language delay codes. At HMO C, the Costar code was for combined language and speech disorders. Theoretically, the "language delay" code should be indicative of problems with expressive language development (eg, vocabulary, tense, word recall, sentence length and complexity) and the "speech delay" code should indicate difficulties or delays in development of speech sounds appropriate for age (eg, substituting one sound for another, omission of final consonants). The distinction between the diagnostic terms attention-deficit/hyperactivity disorder and attention-deficit disorder (ADD) can also be confusing. In this report, we use the term ADD to be consistent with the ICD-9 code (314.0) that we used in our analyses.
To assess the validity of the computerized diagnoses, we reviewed medical charts for selected diagnoses codes ascertained through 1998. For speech and language delay, autism, and ADD, we reviewed the medical charts of all 618 children in HMOs A and B and 826 children in HMO C with at least 2 automated diagnoses of speech delay, and a sample of 377 children in HMOs A and B and 100 children in HMO C with at least 1 automated diagnosis of ADD, and 120 children in HMOs A and B with at least 1 automated diagnosis of autism. For verification, we required documentation in the medical record that the diagnosis was made by an appropriate clinical or behavioral specialist.
Statistical Analyses
In the primary analyses, relative risks (RRs) were calculated for the cumulative exposure to thimerosal by 1, 3, and 7 months of age. Because of power considerations, we decided a priori to perform an evaluation only of the cumulative effect of thimerosal exposure on the risk of outcomes with at least 50 or more cases. We estimated RRs separately for each HMO, using proportional hazards models stratified by sex and year and month of birth at HMO A and by sex and year and month of birth and clinic most often visited at HMO B. The time variable in the models started at the first birthday for children in HMO A or at the first birthday or January 1, 1995 (whichever came later), for children at HMO B; for children in each HMO, the time of follow-up ended at the date of diagnosis or the last date of follow-up. Temporary disenrollment with reenrollment was allowed, but person-time and diagnoses were used only while the child was enrolled in the HMO. We used P < .05 to define statistical significance.
We were concerned that parents who had their children vaccinated on time (and therefore were more likely to have increased thimerosal exposure at each of the time periods studied) were also more likely to seek medical care for common pediatric ambulatory conditions. Support for this concern was provided by analyses indicating that in each year from 1994 to 1998, children who received >75 µg Hg in the first 7 months of life, compared with children who received 0 to 75 µg Hg in the first 7 months of life, had significantly more well child care visits and significantly more visits for "upper respiratory infections" in both the second and third years of life (Appendix 2). To try to control for health care-seeking behavior, we performed the analyses in phase I restricted to children who had made at least 1 visit to a clinic or an emergency department at the same month of age as cases. For phase II, this extent of health care visits data was not available in the analytic data set and no such adjustment for health care-seeking behavior was possible. We also were not able to make such adjustments in the subanalysis of LBW infants.
|
62.5 µg at 3 months and 0 to 75 µg, 87 to 162.5 µg, and 175 µg at 7 months, respectively. We restricted these analyses to outcomes for which significant associations were found in the analysis of exposure as a linear variable and certain outcomes of particular interest (eg, ADD, autism). In the analyses restricted to moderately LBW infants, we included children who weighed from 1500 to 2499 g at birth, were enrolled in the HMO in the first month of life and remained enrolled past 1 year of age, and had 2 or more polio vaccinations by 1 year. We were not able to maintain the other exclusion criteria listed in Appendix 1 because insufficient numbers would have remained in the analysis. The statistical analyses were stratified by HMO, year of birth, and sex and controlled for birth weight (250-g intervals).
|
|
RESULTS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
|---|
|
|
|
|
62.5 micrograms) and language delay. For the categorical analyses of cumulative exposure at 7 months of age (Table 5), there was a borderline statistically significant negative association of speech delay with medium and high levels of thimerosal exposure at HMO A. There were no significant associations between exposure and ADD.
|
Phase II: HMO C
Cohort Selection
A total of 21 471 children were born into HMO C and were also continuously enrolled for the first year of life (the numbers of the entire birth cohort, including those not continuously enrolled for the first year of life, were unavailable). After children who did not receive at least 2 polio vaccinations in the first year or who had LBW or a serious congenital or perinatal anomaly were excluded, the final study cohort size was 16 717 (Fig 1).
Outcome Assessment
A total of 1134 children had a speech/language delay, 91 children had stammering, 499 children had sleep disorders, and 97 children had ADD from the computerized clinic records. The median age at first diagnosis was 24 months for speech or language disorder, 50 months for ADD, 35 months for stammering, and 19 months for sleep disorder, and similar to phase 1, there was a male excess for each disorder. Among the children for whom medical records were reviewed, we confirmed 647 (78%) and 44 (44%) of the automated diagnoses of speech or language delay and ADD, respectively.
Risk Estimates
There were no significant associations between cumulative thimerosal exposures at 1, 3, or 7 months of age and speech/language disorder, ADD, stammering, or sleep disorder (Table 6).
|
|
|
DISCUSSION |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
|---|
The discrepant findings have several possible explanations, including differences in outcome ascertainment. HMO B is the only HMO in our study where speech therapy is not covered by the health plan. Because such therapy is not provided, primary care providers in this HMO may have screened less aggressively for speech or language disorders among young children. Thus, parental concern may have been a more important factor in the ascertainment of these disorders. If parents at this HMO who were more concerned about subtle neurodevelopmental delays were also more likely to adhere to a timely vaccination schedule, then ascertainment bias might have resulted in falsely elevated estimates of the association between thimerosal and these disorders. We attempted to control for differences in health care-seeking behavior by matching on clinic visits. Nevertheless, some significant associations remained for language delay.
The biological plausibility of the small doses of ethylmercury present in vaccines leading to increased risks of neurodevelopmental disorders is uncertain. The effect of organic Hg on neurologic development has been the focus of several studies.5,7,22–24 Two prospective cohort studies of prenatal exposure to methylmercury from fish consumption have resulted in conflicting findings. In the Seychelles, Davidson et al5,25 found no effect of pre- or postnatal methylmercury exposure on the neurologic development of 711 children at 66 months of age. In the Faroe Islands, Grandjean and colleagues7,9,26 found an adverse effect of prenatal exposure to methylmercury on attention, language, and memory at 7 years of age among 917 children. Attention was also found to be inversely related to hair Hg concentrations in Amazonian children aged 7 to 12 years,23 and speech retardation by 24 months was related to maternal hair Hg concentrations in Iraqi children.27
All of these and other studies involved ingested methylmercury, and their relevance to our study of ethylmercury bolus exposure by injection of TCVs is unknown. The magnitudes of Hg exposure in these other studies were also much higher than Hg exposure from vaccines. For example, blood Hg levels after hepatitis B vaccine (HBV) in newborns, as measured by Stajich and colleagues,7,9,22,28,29 although significantly elevated, were far below "no effect" levels as determined by the studies in the Faroe and Seychelles Islands. The results of a recently published study suggest that ethylmercury from thimerosal is metabolized and cleared from children more rapidly than methylmercury.30 The Immunization Safety Review Committee of the Institute of Medicine concluded that although the evidence is indirect and incomplete, the hypothesis that TCVs could be associated with neurodevelopmental disorders is biologically plausible.31
Our use of automated databases has a number of limitations. As most vaccines used in the study population were either thimerosal-free throughout our study period (eg, polio) or thimerosal containing throughout our study period (eg, multidose HBV), our main analyses did not differentiate between the effect of thimerosal and other vaccine components. For example, we did not differentiate potential effects of thimerosal from those of whole-cell pertussis vaccine, which has been associated with an increased risk of encephalopathy. Encephalopathy after pertussis vaccination, however, is rare and unlikely to have had a meaningful impact on our results.32
To try to isolate the effects of thimerosal from other vaccine constituents, we performed a subanalysis comparing risks associated with diphtheria-tetanus-whole cell pertussis vaccine or diphtheria-tetanus-acellular pertussis vaccine and Haemophilus influenzae type b vaccine given separately or combined (Appendix 3). The 2 vaccination regimens included the same vaccine antigens but differed by Hg content (25 µg for the combined vaccine vs a total of 50 µg when the 2 vaccines were given separately). Only at HMO B were both the combined and separate products used. In the analyses of speech and language delay and ADD with cumulative exposure by 3 months, we did not find any statistically significant increased risks associated with increase in Hg exposure when the 2 vaccines were given separately compared with combined.
|
|
For case ascertainment, we used ICD-9 codes at 2 HMOs and Costar codes at the third. The low confirmation rates for ADD illustrate the potentially low positive predictive value of these codes, which could have limited our ability to find an association with this outcome. For other disorders, such as autism, the confirmation rate of the computerized codes was reasonably good. In a subanalysis (not shown), we found consistent results based on computerized codes compared with analyses based on a smaller sample of subjects with autism, ADD, and speech and language disorders whose medical records were reviewed and diagnoses confirmed, suggesting that the reliance on automated data did not introduce appreciable bias.
We were not able to control completely for potentially confounding factors. Clinic identity was unavailable from HMOs A and C and therefore could not be controlled for in the analysis. The variable that denoted which clinic a child attended acted as an appreciable confounder in the analyses at HMO B, and its absence from the other analyses represents a legitimate concern. In terms of the ability for this study to address the effect of other, potentially confounding environmental influences, the HMO databases did not contain information on potential predisposing factors for neurodevelopmental disorders, such as maternal smoking, lead exposure, or fish consumption. However, it is not obvious how these factors would be related to the child’s vaccination status and thus confound the results.
LBW is a particularly important potentially confounding factor because LBW infants (especially those severely premature) are less likely to be vaccinated on time,34 and they are also at increased risk for neurodevelopmental disorders.35 We dealt with this potential bias by excluding LBW infants from the main analysis. Because LBW infants may be especially susceptible to thimerosal exposure as a result of their higher exposure doses relative to weight and their less developed nervous systems, we performed a subanalysis restricted to infants with moderately low birth weights (1500–2499 g). We were able to evaluate ADD and speech or language disorders and did not find significant increased risks associated with increasing thimerosal exposure.
|
CONCLUSIONS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
|---|
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
Reprint requests to (F.D.) Centers for Disease Control and Prevention, 1600 Clifton Rd, NE, MS E-61, Atlanta, GA 30333. E-mail: fxd1{at}cdc.gov
|
REFERENCES |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
|---|
This article has been cited by other articles:
 |
|
 |
|
  R. Schechter and J. K. Grether Continuing Increases in Autism Reported to California's Developmental Services System: Mercury in Retrograde Arch Gen Psychiatry, January 1, 2008; 65(1): 19 - 24. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. G. Dorea AMALGAM STUDY J Am Dent Assoc, December 1, 2007; 138(12): 1536 - 1537. [Full Text] [PDF]
|
|
|
|
 |
|
 W. W. Thompson, C. Price, B. Goodson, D. K. Shay, P. Benson, V. L. Hinrichsen, E. Lewis, E. Eriksen, P. Ray, S. M. Marcy, et al. Early Thimerosal Exposure and Neuropsychological Outcomes at 7 to 10 Years N. Engl. J. Med., September 27, 2007; 357(13): 1281 - 1292. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. J. Monk and D. J. Wiley Will Widespread Human Papillomavirus Prophylactic Vaccination Change Sexual Practices of Adolescent and Young Adult Women in America? Obstet. Gynecol., August 1, 2006; 108(2): 420 - 424. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Fombonne, R. Zakarian, A. Bennett, L. Meng, and D. McLean-Heywood Pervasive Developmental Disorders in Montreal, Quebec, Canada: Prevalence and Links With Immunizations Pediatrics, July 1, 2006; 118(1): e139 - e150. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. A. Offit Why Are Pharmaceutical Companies Gradually Abandoning Vaccines? Health Aff., May 1, 2005; 24(3): 622 - 630. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Heron, J. Golding, and and the ALSPAC Study Team Thimerosal Exposure in Infants and Developmental Disorders: A Prospective Cohort Study in the United Kingdom Does Not Support a Causal Association Pediatrics, September 1, 2004; 114(3): 577 - 583. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Andrews, E. Miller, A. Grant, J. Stowe, V. Osborne, and B. Taylor Thimerosal Exposure in Infants and Developmental Disorders: A Retrospective Cohort Study in the United Kingdom Does Not Support a Causal Association Pediatrics, September 1, 2004; 114(3): 584 - 591. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. K. Parker, B. Schwartz, J. Todd, and L. K. Pickering Thimerosal-Containing Vaccines and Autistic Spectrum Disorder: A Critical Review of Published Original Data Pediatrics, September 1, 2004; 114(3): 793 - 804. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. T. Luman, A. E. Fiore, T. W. Strine, and L. E. Barker Impact of Thimerosal-Related Changes in Hepatitis B Vaccine Birth-Dose Recommendations on Childhood Vaccination Coverage JAMA, May 19, 2004; 291(19): 2351 - 2358. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Verstraeten Thimerosal, the Centers for Disease Control and Prevention, and GlaxoSmithKline Pediatrics, April 1, 2004; 113(4): 932 - 932. [Full Text] [PDF]
|
|
|
|
 |
|
 More Evidence Against Toxicity of Thimerosal Journal Watch Infectious Diseases, December 12, 2003; 2003(1212): 5 - 5. [Full Text]
|
|
|
|
 |
|
 S. S. Ellenberg, M. A. Foulkes, K. Midthun, and K. L. Goldenthal Evaluating the Safety of New Vaccines: Summary of a Workshop Am J Public Health, May 1, 2005; 95(5): 800 - 807. [Abstract] [Full Text] [PDF]
|
|
Read all P3Rs
| ||||||||||||||||||||||||||||||||||||||||||||
