Julia Stowe

Measles, mumps, and rubella vaccination and bowel problems or developmental regression in children with autism: population study

Abstract Objectives: To investigate whether measles, mumps, and rubella (MMR) vaccination is associated with bowel problems and developmental regression in children with autism, looking for evidence of a “new variant” form of autism. Design: Population study with case note review linked to independently recorded vaccine data. Setting: Five health districts in north east London. Participants: 278 children with core autism and 195 with atypical autism, mainly identified from computerised disability registers and born between 1979 and 1998. Main outcome measures: Recorded bowel problems lasting at least three months, age of reported regression of the childs development where it was a feature, and relation of these to MMR vaccination. Results: The proportion of children with developmental regression (25% overall) or bowel symptoms (17%) did not change significantly (P value for trend 0.50 and 0.47, respectively) during the 20 years from 1979, a period which included the introduction of MMR vaccination in October 1988. No significant difference was found in rates of bowel problems or regression in children who received the MMR vaccine before their parents became concerned about their development (where MMR might have caused or triggered the autism with regression or bowel problem), compared with those who received it only after such concern and those who had not received the MMR vaccine. A possible association between non-specific bowel problems and regression in children with autism was seen but this was unrelated to MMR vaccination. Conclusions: These findings provide no support for an MMR associated “new variant” form of autism with developmental regression and bowel problems, and further evidence against involvement of MMR vaccine in the initiation of autism. What is already known on this topic A “new variant” form of autism has been hypothesised, associated with developmental regression and bowel problems and caused or triggered by the MMR vaccination This postulated association along with media attention has had a major adverse effect on public confidence in the vaccine Although population studies have shown no association between autism and MMR vaccine it has been further postulated that various environmental or genetic cofactors are required for the effect What this study adds The proportion of children with autism who had developmental regression or bowel problems has not changed over the 20 years from 1979 Neither developmental regression nor bowel problems in children with autism was associated with MMR vaccination No evidence was found for a “new variant” form of autism

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

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-tetanus-whole-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 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 (Coxs 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.

Importance of background rates of disease in assessment of vaccine safety during mass immunisation with pandemic H1N1 influenza vaccines.

Because of the advent of a new influenza A H1N1 strain, many countries have begun mass immunisation programmes. Awareness of the background rates of possible adverse events will be a crucial part of assessment of possible vaccine safety concerns and will help to separate legitimate safety concerns from events that are temporally associated with but not caused by vaccination. We identified background rates of selected medical events for several countries. Rates of disease events varied by age, sex, method of ascertainment, and geography. Highly visible health conditions, such as Guillain-Barré syndrome, spontaneous abortion, or even death, will occur in coincident temporal association with novel influenza vaccination. On the basis of the reviewed data, if a cohort of 10 million individuals was vaccinated in the UK, 21.5 cases of Guillain-Barré syndrome and 5.75 cases of sudden death would be expected to occur within 6 weeks of vaccination as coincident background cases. In female vaccinees in the USA, 86.3 cases of optic neuritis per 10 million population would be expected within 6 weeks of vaccination. 397 per 1 million vaccinated pregnant women would be predicted to have a spontaneous abortion within 1 day of vaccination.

Idiopathic thrombocytopenic purpura and MMR vaccine

A CAUSAL ASSOCIATION BETWEEN MEASLES mumps–rubella (MMR) vaccine and idiopathic thrombocytopenic purpura (ITP) was confirmed using immunisation/hospital admission record linkage. The absolute risk within six weeks of immunisation was 1 in 22 300 doses, with two of every three cases occurring in the six week post-immunisation period being caused by MMR. Children with ITP before MMR had no vaccine associated recurrences.

Investigation of the Temporal Association of Guillain-Barré Syndrome With Influenza Vaccine and Influenzalike Illness Using the United Kingdom General Practice Research Database

In 1976, the national swine influenza vaccination program in the United States was suspended because of an increased risk of Guillain-Barré syndrome. Subsequent studies of seasonal influenza vaccine have given conflicting results. The authors used the self-controlled case series method to investigate the relation of Guillain-Barré syndrome with influenza vaccine and influenzalike illness using cases recorded in the General Practice Research Database from 1990 to 2005 in the United Kingdom. The relative incidence of Guillain-Barré syndrome within 90 days of vaccination was 0.76 (95% confidence interval: 0.41, 1.40). In contrast, the relative incidence of Guillain-Barré syndrome within 90 days of an influenzalike illness was 7.35 (95% confidence interval: 4.36, 12.38), with the greatest relative incidence (16.64, 95% confidence interval: 9.37, 29.54) within 30 days. The relative incidence was similar (0.89, 95% confidence interval: 0.42, 1.89) when the analysis was restricted to a subset of validated cases. The authors found no evidence of an increased risk of Guillain-Barré syndrome after seasonal influenza vaccine. The finding of a greatly increased risk after influenzalike illness is consistent with anecdotal reports of a preceding respiratory illness in Guillain-Barré syndrome and has important implications for the risk/benefit assessment that would be carried out should pandemic vaccines be deployed in the future.

The effect of underlying clinical conditions on the risk of developing invasive pneumococcal disease in England

OBJECTIVE To inform national policy making on the use of the 13-valent pneumococcal vaccine among risk groups we estimated the increased risk of invasive pneumococcal disease (IPD) outcomes among clinical risk groups. Three years of post 7-valent pneumococcal conjugate vaccine (PCV7) data was included to investigate the herd protection effects. METHODS Over 22,000 IPD patients in England (March 2002-March 2009 - aged 2 and over) were linked to their hospitalisation records. The prevalence of risk factors in these patients was compared to the prevalence of risk factors in the general population. RESULTS There was an increased odds ratio (OR) for hospitalisation (OR 11.7 2-15 years; 7.6 16-64; 2.7 65+) and death (OR 2.4 2-15 years, 3.9 16-64, 1.2 65+) from IPD among risk group. The most important risk factors that predict IPD are chronic liver disease, immunosuppression, and chronic respiratory diseases. Herd protection effects due to introduction of the 7-valent vaccine were identical in both patient groups as shown by the similar decline in the proportion of IPD caused by PCV7 serotypes in risk and non-risk groups. CONCLUSIONS There is a marked increased risk of IPD among those with certain clinical conditions, suggesting potential benefit from a targeted vaccination approach. However, the indirect protection from conjugate vaccination of children suggests PCV vaccination of high-risk groups may not provide substantial additional benefit once herd immunity takes effect.

Prevalence of autism and parentally reported triggers in a north east London population

Background: The recorded prevalence of autistic spectrum disorders has risen over recent decades. Measles, mumps and rubella (MMR) vaccine has been blamed, by causing a “new variant” form of “regressive autism” associated with “autistic enterocolitis”. Aims: To estimate the prevalence of autism and to assess any changes in parental perception regarding the onset or causes of autism. Methods and Results: A total of 567 children with autistic spectrum disorder in five districts in north east London were identified, born 1979–98. Reported autism, excluding the 94 cases of Asperger’s syndrome, increased by year of birth until 1992, since when prevalence has plateaued. This flattening off persisted after allowing for expected delay in diagnosis in more recent birth cohorts. The age at diagnosis of autistic spectrum disorder was estimated to have decreased per five year period since 1983, by 8.7% for childhood autism and by 11.0% for atypical autism. There was some evidence that MMR was more likely to be mentioned as a trigger after August 1997 than before. Conclusions: The prevalence of autism, which was apparently rising from 1979 to 1992, reached a plateau from 1992 to 1996 at a rate of some 2.6 per 1000 live births. This levelling off, together with the reducing age at diagnosis, suggests that the earlier recorded rise in prevalence was not a real increase but was likely due to factors such as increased recognition, a greater willingness on the part of educationalists and families to accept the diagnostic label, and better recording systems. The proportion of parents attributing their child’s autism to MMR appears to have increased since August 1997.

Rapid Declines in Age Group–Specific Rotavirus Infection and Acute Gastroenteritis Among Vaccinated and Unvaccinated Individuals Within 1 Year of Rotavirus Vaccine Introduction in England and Wales

BACKGROUND The oral infant rotavirus vaccine, Rotarix, was introduced in England and Wales in July 2013. We estimated the impact on laboratory-confirmed rotavirus infections and hospitalizations for all-cause acute gastroenteritis (AGE) during the first year after introduction. METHODS We extracted data on laboratory-confirmed rotavirus infections (July 2000 through June 2015) and all-cause AGE-associated hospitalizations (July 2007 through June 2014) for all age groups using national databases (LabBase2 and HES). We determined the ratio of the rate during the 2013-2014 rotavirus season to the rate during the prevaccination era. RESULTS In infants, there was a 77% decline (rate ratio [RR], 0.23; 95% confidence interval [CI], .16-.32) in laboratory-confirmed rotavirus infections and a 26% decline (RR, 0.74; 95% CI, .65-.84) in all-cause AGE-associated hospitalizations in 2013-2014, compared with the prevaccination era. Large reductions were also observed in older children, adults, and older adults. We estimated that 10 884 laboratory-confirmed infections and 50 427 all-cause AGE-associated hospital admissions were averted in 2013-2014. Similar reductions have been observed for laboratory-confirmed rotavirus infections during the 2014-2015 season. CONCLUSIONS The rapid declines in rotavirus infection and AGE in vaccinated and unvaccinated age groups within 1 year of introducing an infant rotavirus vaccination program are far greater than expected and than previously reported by other countries.

Bell’s Palsy and Parenteral Inactivated Influenza Vaccine

Concern about a possible increased risk of Bell’s palsy after parenteral inactivated influenza vaccine was raised following the publication in 2004 of a Swiss study in which there was an increased risk following the nasal inactivated formulation of the vaccine. When data from passive reporting systems in the United States and the United Kingdom were examined there was some evidence of increased reporting following the parenteral vaccine. A large population based study using the General Practice Research Database (GPRD) was therefore performed to test the hypothesis that there was an increased risk of Bell’s palsy in the three months following parenteral inactivated influenza vaccine. The risk was also assessed for the same period following pneumococcal vaccine and was stratified into three age groups (

A collaborative approach to investigating the risk of thrombocytopenic purpura after measles–mumps–rubella vaccination in England and Denmark

The assessment of rare adverse events following vaccination may not be possible within a single country due to an insufficiently large denominator population. In 2008 a European consortium (VAESCO) was funded to perform collaborative vaccine safety studies. To help assess the feasibility of multi-country collaboration England and Denmark, who have established vaccine safety research infrastructures, undertook to work to a common protocol and share results and data to estimate the risk of a known true adverse event, thrombocytopenic purpura (TP) following measles-mumps-rubella (MMR) vaccination. TP is a known rare reaction to MMR and therefore provided an opportunity to assess whether two countries would produce similar results when working collaboratively. Despite some initial problems with ensuring data were comparable, the two countries gave very similar estimates of the relative incidence in the 6 weeks after vaccination and a pooled relative incidence estimate of 2.13 (95% confidence interval 1.55-2.94) and attributable risk of 1 in 50,000 doses. Both countries used hospital admissions for TP and the analysis was performed using the self controlled case series method which is particularly suited to collaborative studies because of its implicit control for individual level confounding. The study therefore shows the potential for vaccine safety collaborations across Europe to detect true associations through use of common protocols and sharing of results or data.