Cohort Study in the United Kingdom Does Not Support a Causal Association Thimerosal Exposure in Infants and Developmental Disorders: A Retrospective

Objective. After concerns about the possible toxicity of thimerosal-containing vaccines in the United States, this study was designed to investigate whether there is a relationship between the amount of thimerosal that an infant receives via diphtheria-tetanuswhole-cell pertussis (DTP) or diphtheria-tetanus (DT) vaccination at a young age and subsequent neurodevelopmental disorders. Methods. A retrospective cohort study was performed using 109 863 children who were born from 1988 to 1997 and were registered in general practices in the United Kingdom that contributed to a research database. The disorders investigated were general developmental disorders, language or speech delay, tics, attention-deficit disorder, autism, unspecified developmental delays, behavior problems, encopresis, and enuresis. Exposure was defined according to the number of DTP/DT doses received by 3 and 4 months of age and also the cumulative age-specific DTP/DT exposure by 6 months. Each DTP/DT dose of vaccine contains 50 g of thimerosal (25 g of ethyl mercury). Hazard ratios (HRs) for the disorders were calculated per dose of DTP/DT vaccine or per unit of cumulative DTP/DT exposure. Results. Only in 1 analysis for tics was there some evidence of a higher risk with increasing doses (Cox’s HR: 1.50 per dose at 4 months; 95% confidence interval [CI]: 1.02–2.20). Statistically significant negative associations with increasing doses at 4 months were found for general developmental disorders (HR: 0.87; 95% CI: 0.81– 0.93), unspecified developmental delay (HR: 0.80; 95% CI: 0.69–0.92), and attention-deficit disorder (HR: 0.79; 95% CI: 0.64–0.98). For the other disorders, there was no evidence of an association with thimerosal exposure. Conclusions. With the possible exception of tics, there was no evidence that thimerosal exposure via DTP/DT vaccines causes neurodevelopmental disorders. Pediatrics 2004;114:584–591; cohort study, neurodevelopment, safety, thimerosal, thiomersal, vaccines. ABBREVIATIONS. Hg, mercury; WHO, World Health Organization; VSD, Vaccine Safety Datalink; CDC, Centers for Disease Control and Prevention; HMO, health maintenance organization; ADD, attention-deficit disorder; GPRD, General Practice Research Database; ICD, International Classification of Diseases; DTP, diphtheria-tetanus-whole-cell pertussis; DT, diphtheria, tetanus; GP, general practitioner; HR, hazard ratio; CI, confidence interval. Inorganic mercury (Hg) poses a potential risk of neurodevelopmental and renal toxicity in young children.1,2 Cumulative exposure to an organic mercury–containing compound, methylmercury, can also produce neurologic or renal damage as it has a long half-life and can cross the blood-brain barrier, where it accumulates and is converted to inorganic mercury. Guidelines to limit cumulative exposure to methylmercury have been drawn up by various agencies and incorporate a wide margin of safety. The maximum daily dose specified by these different agencies varies by nearly 5-fold, the most stringent being the guideline of the Environmental Protection Agency in the United States that specifies a maximum daily exposure to Hg of 0.1 g/kg extrapolated from data on methylmercury exposure. These guidelines are reproduced by Pichichero.2 Ethylmercury, a related organic mercury compound, is a constituent of thimerosal, an antibacterial agent used in certain nonlive vaccines. Ethylmercury has a much shorter half-life than methylmercury, being rapidly excreted via the stools after parenteral administration such that blood levels remain substantially below the safe threshold.2 Nevertheless, the guidelines to limit cumulative methylmercury exposure have been translated to ethylmercury.3 In the United States, increases during the 1990s in the number of childhood vaccines that contained thimerosal, which contains 49.6% Hg by weight, led to questions about safety because the maximum cumulative exposure in some US children was 187.5 g Hg by 6 months of age, which would have exceeded the stringent Environmental Protection Agency limit. Although there is no evidence that this level of Hg exposure via ethylmercury was likely to or had actually caused any harm, a joint statement was issued by the American Academy of Pediatrics and the Public Health Service in 1999 recommending the removal of thimerosal from vaccines as soon as possible, as a precautionary measure.4 Although the World Health Organization (WHO) supported in principle the move toward thimerosal-free vaccines, it nevertheless recommended that vaccines that contain thimerosal continue to be used in the meantime because the From the *Statistics Unit and ‡Immunisation Department, Health Protection Agency, Communicable Disease Surveillance Centre, London, United Kingdom; §Centre for Community Child Health, Royal Free and University College Medical School, Royal Free Campus, London, United Kingdom; and Morbidity and Health Care Team, Office for National Statistics, London, United Kingdom. Accepted for publication Mar 15, 2004. DOI: 10.1542/peds.2003-1177-L Reprint requests to (E.M.) Immunisation Department, Health Protection Agency, Communicable Disease Surveillance Centre, 61 Colindale Ave, London NW9 5EQ, United Kingdom. E-mail: [email protected] PEDIATRICS (ISSN 0031 4005). Copyright © 2004 by the American Acad-