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 µg of thimerosal (25 µg 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.

Key Words: 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 µg/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 µg 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 known morbidity and mortality from vaccine-preventable diseases greatly outweighed any theoretical risk from ethylmercury.⁵

In 2001, the preliminary results of an unpublished US cohort study that screened for associations between various neurodevelopmental and renal disorders and infant thimerosal exposure in vaccines were made available to an Institute of Medicine Immunization Safety Review.⁶ This study used the computerized Vaccine Safety Datalink (VSD) developed by the Centers for Disease Control and Prevention (CDC) in association with 2 health maintenance organizations (HMOs).⁷ The preliminary results suggested a possible trend between the level of ethylmercury exposure in the first few months of life and the following neurodevelopmental diagnoses: tics, attention-deficit disorder (ADD), language/speech delays, unspecified delays, and general neurodevelopmental delays. Although additional analyses were later conducted to control for confounding variables and to include more data, some disorders remained significant. Given the exploratory nature of this study, it was unclear whether these findings were real, a result of chance, or a result of uncontrolled confounding or bias. A subsequent, much smaller study by the CDC using another HMO data set did not confirm the first findings but had inadequate power to identify effects of the size seen in the first study.⁶

After review of the available evidence by the WHO Global Advisory Committee on Vaccine Safety, it was recommended that other studies be conducted to test the hypotheses raised by the VSD study.⁸ The General Practice Research Database (GPRD) in the United Kingdom was identified as 1 of the few databases that were comparable to the HMO databases used in the VSD study.^9,10 In addition, the Avon Longitudinal Study of Pregnancy and Childhood in the United Kingdom was identified as a prospective cohort with information on vaccination and regular assessment of children's developmental progress. This cohort had the advantage of having data on many potential confounding variables, although it was not large enough to assess rare outcome conditions. The results of the analysis of this study are published together with this article.¹¹

The GPRD holds data on all significant patient consultations, referrals, and prescribed medicines, including vaccines from 1988 from 500 general practices in the United Kingdom. Together, these practices provide primary health care for 3.4 million patients (5.7% of the population). Preliminary analyses conducted by staff of the Morbidity and Health Care Team of the Office for National Statistics (which until 1999 managed the GPRD) using the International Classification of Diseases (ICD) codes for the outcomes of interest from the CDC study confirmed that the GPRD had sufficient power to test the hypotheses generated in the CDC study.

In the United Kingdom, the only vaccine that contains thimerosal and has been used routinely in the infant immunization program in the past 2 decades is diphtheria-tetanus-whole-cell pertussis (DTP) vaccine or diphtheria-tetanus (DT) vaccine and any combination vaccine that contains DTP or DT. These vaccines all contain 50 µg of thimerosal (25 µg of Hg) per dose. No other thimerosal-containing vaccines have been given routinely to United Kingdom children, so the cumulative Hg exposure by age can be readily obtained from the number of doses of DTP- or DT-containing vaccines given. Because the United Kingdom changed to an accelerated 2/3/4 month DTP immunization schedule in 1990 (replacing the former 3/5/10 month schedule) and because vaccinations are generally given on time in the United Kingdom, a substantial proportion of children in the GPRD cohort will have had a cumulative Hg exposure of 150 µg of thimerosal (75 µg of Hg) by 4 months of age. This level of Hg exposure, although lower than the maximum of 187.5 µg received in the United States by 6 months of age, is similar to the level received by 3 to 4 months of age in the United States. It is also the same as the amount of thimerosal used by developing countries that follow the expanded immunization schedule.