The evidence for the safety of thiomersal in newborn and infant vaccines

Abstract

Related Articles in ScienceDirect The evidence for the safety of thiomersal in newborn an... Vaccine The evidence for the safety of thiomersal in newborn and infant vaccines Vaccine, Volume 22, Issues 15-16, 7 May 2004, Pages 1854-1861 C. John Clements Abstract While a number of studies remain to be completed, evidence is mounting that there is no demonstrable risk for infants immunized with vaccines containing thiomersal. Epidemiological studies in the US have shown no developmental or other central nervous system abnormalities resulting from exposure to vaccines containing thiomersal. During the initial evaluation of thiomersal in vaccines during 1999, the toxicological profile of ethyl mercury was unknown and presumed to be the same as that of methyl mercury. Enough evidence has accumulated since then to indicate the profiles of the two compounds are different in crucial aspects. 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Until such time as the scientific evidence is to hand, thiomersal-free presentations of hepatitis B are to be preferred for the birth dose. Given the same levels of exposure, adults are at much lower levels of risk because of increased body mass. It is not possible to prove that thiomersal is completely safe-epidemiology can only quantify a risk, not prove its absence. Purchase PDF (115 K) Maternal exposure to polybrominated and polychlorinated... Chemosphere Maternal exposure to polybrominated and polychlorinated biphenyls: Infant birth weight and gestational age Chemosphere, Volume 69, Issue 8, October 2007, Pages 1295-1304 Marjory L. Givens, Chanley M. Small, Metrecia L. Terrell, Lorraine L. Cameron, Heidi Michels Blanck, Paige E. Tolbert, Carol Rubin, Alden K. 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Obstetrics & Gynecology Season and outdoor ambient temperature: effects on birth weight Obstetrics & Gynecology, Volume 96, Issue 5, Part 1, November 2000, Pages 689-695 L. J. Murray, D. P. J. O’Reilly, N. Betts, C. C. Patterson, G. Davey Smith, A. E. Evans Abstract Objective: To determine the extent to which meteorologic factors explain seasonality in birth weight in a developed country. Methods: Recorded birth weights were collected for all singleton live births after 36 weeks of pregnancy in Northern Ireland between 1971 and 1986. Data on daily maximum and minimum temperatures, rainfall, and hours of bright sunshine were obtained from a local climatologic station for the same period. For each birth, mean daily maximum and minimum temperatures, rainfall, and hours of bright sunshine were calculated for the trimesters of the pregnancy. Linear regression models were constructed with birth weight as the dependent variable and month of birth as a predictor variable. Months of birth were entered in the models as dummy variables. Adjustment was made for year of birth, duration of gestation, maternal age, number of previous pregnancies, sex, and social class of infants at birth and for meteorologic variables relating to each trimester. Results: A clear seasonal pattern in birth weight was observed, with lowest mean birth weight in late spring and summer. Adjusted mean birth weights were 25.5 g, 29.6 g, and 31.6 g lower in May, June, and July, respectively, than in January. This seasonal variation occurred in both sexes, and in female births, it disappeared almost entirely after adjustment for mean daily maximum temperature during the second trimester of pregnancy. Conclusion: Infants born during late spring and summer are lighter than those born in winter, which might be the result of exposure to low winter temperatures during midgestation. Pregnant women should keep themselves warm during midpregnancy. View More Related Articles

Delayed acquisition of neonatal reflexes in newborn primates receiving a thimerosal-containing Hepatitis B vaccine: Influence of gestational age and birth weight

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Laura Hewitson^{a, c, , ,} , Lisa A. Houser^a, Carol Stott^c, Gene Sackett^b, Jaime L. Tomko^a, David Atwood^d, Lisa Blue^d, E. Railey White^d and Andrew J. Wakefield^c

^aDepartment of Obstetrics and Gynecology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, United States

^bWashington National Primate Research Center, University of Washington, Seattle, WA 98195, United States

^cThoughtful House Center for Children, Austin, TX 78746, United States

^dDepartment of Chemistry, University of Kentucky, Lexington, KY 40506, United States

Received 16 June 2009;

accepted 17 September 2009.

Available online 2 October 2009.

Abstract

This study examined whether acquisition of neonatal reflexes and sensorimotor skills in newborn rhesus macaques (Macaca mulatta) is influenced by receipt of the single neonatal dose of Hepatitis B (HB) vaccine containing the preservative thimerosal (Th). HB vaccine containing a standardized weight-adjusted Th dose was administered to male macaques within 24 h of birth (n = 13). Unexposed animals received saline placebo (n = 4) or no injection (n = 3). Infants were raised identically and tested daily for acquisition of 9 survival, motor, and sensorimotor reflexes by a blinded observer. In exposed animals there was a significant delay in the acquisition of three survival reflexes: root, snout and suck, compared with unexposed animals. No neonatal responses were significantly delayed in unexposed animals compared with exposed. Gestational age (GA) and birth weight were not significantly correlated. Cox regression models were used to evaluate the main effects and interactions of exposure with birth weight and GA as independent predictors and time-invariant covariates. Significant main effects remained for exposure on root and suck when controlling for GA and birth weight such that exposed animals were relatively delayed in time-to-criterion. There was a significant effect of GA on visual follow far when controlling for exposure such that increasing GA was associated with shorter time-to-criterion. Interaction models indicated that while there were no main effects of GA or birth weight on root, suck or snout reflexes there were various interactions between exposure, GA, and birth weight such that inclusion of the relevant interaction terms significantly improved model fit. This, in turn, indicated important influences of birth weight and/or GA on the effect of exposure which, in general, operated in a way that lower birth weight and/or lower GA exacerbated the detrimental effect of vaccine exposure. This primate model provides a possible means of assessing adverse neurodevelopmental outcomes from neonatal Th-containing HB vaccine exposure, particularly in infants of lower GA or low birth weight. The mechanism of these effects and the requirements for Th is not known and requires further study.

Keywords: Macaca mulatta; Animal model; Hepatitis B vaccine; Ethyl mercury; Thimerosal; Neurodevelopment; Neurotoxicity

Article Outline

1. Introduction

2. Materials and methods

2.1. Animal assurances

2.2. Subjects

2.3. Housing

2.4. Study design

2.5. Vaccine source, preparation and dosing

2.6. Neurodevelopmental testing

2.7. Statistical analyses

3. Results

3.1. Infant health

3.2. Neonatal development

3.3. Modeling time-to-criterion: main effects models

3.3.1. Exposure and gestational age (GA)

3.3.2. Exposure and birth weight

3.3.3. Modeling all three variables as main effects

3.4. Modeling time-to-criterion: interaction models

3.4.1. Gestational age (GA), birth weight and exposure status

4. Discussion

5. Conclusions

Conflict of interest statement

Acknowledgements

References

Fig. 1. The Kaplan–Meier (K–M) survival curve is a step-function used here to indicate the estimated proportion of animals having reached criterion at various time points from the start of the study period. K–M curves for neonatal reflexes in exposed (green) and unexposed (blue) rhesus macaque infants are presented: reflexes for time-to-criterion were measured daily from birth through Day 14. Significant differences were observed in the mean age (days) at reaching criterion for root (A; p = 0.004), suck (B; p = 0.002) and snout (C; p = 0.03). The value on the y-axis represents the proportion of animals not reaching criterion by the time (in days) represented on the x-axis. Any point on the curve gives the proportion of infants still not having reached criterion at a particular time after the start of the observation period. For example, in A (root) 58% of the unexposed animals remained at Day 1 (meaning that 42% had reached criterion at this stage compared to around 9% of the exposed animals).

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Table 1.

Neonatal reflexes measured, rating categories, and criterion responses.

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Table 2.

Neonatal reflexes: mean time-to-criterion with log-rank statistic and associated p values, for exposed (E) and unexposed (U) groups. Kaplan–Meier survival analysis was used to compare age in days at reaching neonatal basic motor reflexes and sensorimotor responses. The log-rank test identified statistically significant differences (p ≤ 0.05) for the achievement of these milestones between exposed and unexposed groups for three basic motor reflexes (root, suck and snout). There were no statistically significant differences between the groups in time-to-criterion for the remaining neonatal behaviors.

CI, confidence interval; Nr, near.

^a Censored at Day 14 (one infant in the exposed group did not reach criterion during the 14-day testing period for this study).
^b n = 6 for snout (scored as missing data for one infant).

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Table 3.

Main effects models for exposure, gestational age (GA) and birth weight: significant predictors. For each neonatal behavior model, ‘−2LL’ gives the value of the model when all variables are included. Better models have lower values for −2LL. The change from the Omnibus Model (which assumes all effects are 0) to the specified model containing all variables, is represented by the χ² and its associated p value. p <>β) or hazard ratio indicates the rise in risk of outcome (achievement of criterion) associated with a one unit rise in the predictor after controlling for all other terms in the model. Its associated value indicates the probability of an Exp(β) of this magnitude being generated by chance alone. For all analyses, exposure = 0 is the indicator variable. The exposure effect is therefore the effect of being unexposed. In other words for the root reflex, unexposure is associated with a 4.84 risk of meeting criterion for unexposed relative to an exposed animal. Other effects are of a rise in the predictor associated with a rise in risk hazard. Statistically significant p values for Exp(β) shown in bold font.

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Table 4.

Best fit interaction models for root and suck reflexes. For each neonatal behavior model, ‘−2LL’ gives the value of the model when all variables are included. Better models have a lower −2LL. The change from the Omnibus Model (which assumes all effects are 0) to the specified model containing all variables, is represented by the χ² and its associated p value. p <>β) indicates the rise in risk of outcome (achievement of criterion) associated with a one unit rise in the predictor, after controlling for all other terms in the model. Its associated value indicates the probability of an Exp(β) of this magnitude being generated by chance alone. For all analyses, exposure = 0 is the indicator variable. While it is important to include main effects when modeling an interaction term, interpretation of any associated parameter estimates should be avoided when the interaction term is statistically significant. Parameter estimates for main effects are included here for reference and completeness. Statistically significant p values for Exp(β) shown in bold font.

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Corresponding author at: Magee-Women's Research Institute and Foundation, University of Pittsburgh School of Medicine, 204 Craft Avenue, Pittsburgh, PA 15213, United States. Tel.: +1 412 641 2490; fax: +1 412 641 2410.

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