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Keywords:

  • Age Factors;
  • Autistic Disorder [etiology];
  • Clinical Trials as Topic;
  • Crohn Disease [etiology];
  • Epidemiologic Studies;
  • Measles [* prevention & control];
  • Measles-Mumps-Rubella Vaccine [*administration & dosage; *adverse effects];
  • Mumps [*prevention & control];
  • Purpura, Thrombocytopenic [etiology];
  • Rubella [*prevention & control];
  • Seizures, Febrile [etiology];
  • Vaccines, Attenuated [administration & dosage; adverse effects]

Abstract

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Characteristics of studies
  11. Data and analyses
  12. Additional Tables
  13. Appendices
  14. Feedback
  15. What's new
  16. History
  17. Contributions of authors
  18. Declarations of interest
  19. Sources of support
  20. Differences between protocol and review
  21. References

Background

Mumps, measles and rubella (MMR) are serious diseases that can lead to potentially fatal illness, disability and death. However, public debate over the safety of the trivalent MMR vaccine and the resultant drop in vaccination coverage in several countries persists, despite its almost universal use and accepted effectiveness.

Objectives

To assess the effectiveness and adverse effects associated with the MMR vaccine in children up to 15 years of age.

Search methods

For this update we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 2), which includes the Cochrane Acute Respiratory Infections Group's Specialised Register, PubMed (July 2004 to May week 2, 2011) and Embase.com (July 2004 to May 2011).

Selection criteria

We used comparative prospective or retrospective trials assessing the effects of the MMR vaccine compared to placebo, do nothing or a combination of measles, mumps and rubella antigens on healthy individuals up to 15 years of age.

Data collection and analysis

Two review authors independently extracted data and assessed methodological quality of the included studies. One review author arbitrated in case of disagreement.

Main results

We included five randomised controlled trials (RCTs), one controlled clinical trial (CCT), 27 cohort studies, 17 case-control studies, five time-series trials, one case cross-over trial, two ecological studies, six self controlled case series studies involving in all about 14,700,000 children and assessing effectiveness and safety of MMR vaccine. Based on the available evidence, one MMR vaccine dose is at least 95% effective in preventing clinical measles and 92% effective in preventing secondary cases among household contacts.

Effectiveness of at least one dose of MMR in preventing clinical mumps in children is estimated to be between 69% and 81% for the vaccine prepared with Jeryl Lynn mumps strain and between 70% and 75% for the vaccine containing the Urabe strain. Vaccination with MMR containing the Urabe strain has demonstrated to be 73% effective in preventing secondary mumps cases. Effectiveness of Jeryl Lynn containing MMR in preventing laboratory-confirmed mumps cases in children and adolescents was estimated to be between 64% to 66% for one dose and 83% to 88% for two vaccine doses. We did not identify any studies assessing the effectiveness of MMR in preventing rubella.

The highest risk of association with aseptic meningitis was observed within the third week after immunisation with Urabe-containing MMR (risk ratio (RR) 14.28; 95% confidence interval (CI) from 7.93 to 25.71) and within the third (RR 22.5; 95% CI 11.8 to 42.9) or fifth (RR 15.6; 95% CI 10.3 to 24.2) weeks after immunisation with the vaccine prepared with the Leningrad-Zagreb strain. A significant risk of association with febrile seizures and MMR exposure during the two previous weeks (RR 1.10; 95% CI 1.05 to 1.15) was assessed in one large person-time cohort study involving 537,171 children aged between three months and five year of age. Increased risk of febrile seizure has also been observed in children aged between 12 to 23 months (relative incidence (RI) 4.09; 95% CI 3.1 to 5.33) and children aged 12 to 35 months (RI 5.68; 95% CI 2.31 to 13.97) within six to 11 days after exposure to MMR vaccine. An increased risk of thrombocytopenic purpura within six weeks after MMR immunisation in children aged 12 to 23 months was assessed in one case-control study (RR 6.3; 95% CI 1.3 to 30.1) and in one small self controlled case series (incidence rate ratio (IRR) 5.38; 95% CI 2.72 to 10.62). Increased risk of thrombocytopenic purpura within six weeks after MMR exposure was also assessed in one other case-control study involving 2311 children and adolescents between one month and 18 years (odds ratio (OR) 2.4; 95% CI 1.2 to 4.7). Exposure to the MMR vaccine was unlikely to be associated with autism, asthma, leukaemia, hay fever, type 1 diabetes, gait disturbance, Crohn's disease, demyelinating diseases, bacterial or viral infections.

Authors' conclusions

The design and reporting of safety outcomes in MMR vaccine studies, both pre- and post-marketing, are largely inadequate. The evidence of adverse events following immunisation with the MMR vaccine cannot be separated from its role in preventing the target diseases.

Plain language summary

Using the combined vaccine for protection of children against measles, mumps and rubella

Measles, mumps and rubella (MMR) are three very dangerous infectious diseases which cause severe morbidity, disability and death in low-income countries.

Based on the evidence provided by three cohort studies (3104 participants), vaccination with one dose of MMR vaccine is at least 95% effective in preventing clinical measles among preschool children; in schoolchildren and adolescents at least one dose of MMR vaccine was 98% effective in preventing laboratory-confirmed measles cases; one or two MMR doses were respectively 92% and 95% effective in preventing secondary measles cases.

At least one dose of MMR vaccine is effective in preventing clinical mumps among children and adolescents when prepared with Jeryl Lynn strains (vaccine effectiveness = 69% to 81%, one cohort and one case-control study, 1656 participants), as well as when prepared with Urabe strain (vaccine effectiveness = 70% to 75%, one cohort and one case-control study, 1964 participants). Effectiveness against laboratory-confirmed mumps in children and adolescents was estimated to be between 64% to 66% for one and 83% to 88% for two doses of Jeryl Lynn MMR (two case-control studies, 1664 participants) and 87% for Urabe-containing MMR (one cohort study, 48 participants). Vaccination with Urabe MMR confers protection against secondary mumps infection (vaccine effectiveness = 73%, one cohort study, 147 participants).

We identified no studies assessing the effectiveness of MMR vaccine against clinical or laboratory-confirmed rubella.

Results from two very large case series studies involving about 1,500,000 children who were given the MMR vaccine containing Urabe or Leningrad-Zagreb strains show this vaccine to be associated with aseptic meningitis; whereas administration of the vaccine containing Moraten, Jeryl Lynn, Wistar RA, RIT 4385 strains is associated with febrile convulsion in children aged below five years (one person-time cohort study, 537,171 participants; two self controlled case series studies, 1001 participants). The MMR vaccine could also be associated with idiopathic thrombocytopaenic purpura (two case-controls, 2450 participants, one self controlled case series, 63 participants).

We could assess no significant association between MMR immunisation and the following conditions: autism, asthma, leukaemia, hay fever, type 1 diabetes, gait disturbance, Crohn's disease, demyelinating diseases, or bacterial or viral infections. The methodological quality of many of the included studies made it difficult to generalise their results.

The glossary of study designs is available in the full-text review.


Background

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Characteristics of studies
  11. Data and analyses
  12. Additional Tables
  13. Appendices
  14. Feedback
  15. What's new
  16. History
  17. Contributions of authors
  18. Declarations of interest
  19. Sources of support
  20. Differences between protocol and review
  21. References

Description of the condition

Measles, mumps and rubella (MMR) are serious diseases that can lead to potentially fatal illnesses, disabilities and death. MMR are particularly prevalent in low-income countries where vaccination programmes are inconsistent and the mortality rate from disease is high. However, in high-income countries MMR are now rare, due to large-scale vaccination programmes.

Description of the intervention

The single component live attenuated vaccines of MMR have been licensed in the USA since the 1960s (Plotkin 1999a; Plotkin 1999b; Redd 1999). These single vaccines have been shown to be highly effective at reducing the morbidity and mortality rates associated with these childhood illnesses.

At least five MMR vaccines are known.

  • 1.
    Triviraten Berna is a live virus vaccine containing 1000 TCID50 (50% tissue culture infectious doses) of Edmonston-Zagreb (EZ 19) measles strain, 5000 TCID50 of Rubini mumps strain and 1000 TCID50 of Wistar RA 27/3 rubella strain propagated on human diploid cells. The product contains lactose (14 mg), human albumin (8.8 mg), sodium bicarbonate (0.3 mg), medium 199 (5.7 mg) and distilled water as solvent.
  • 2.
    M-M-R by Merck is a live virus vaccine. It is a sterile lyophilised preparation of 1000 TCID50 Enders' attenuated Edmonston measles strain propagated in chick embryo cell culture; mumps 20000 TCID50 Jeryl Lynn strain propagated in chick embryo cell culture; and rubella 1000 TCID50 Wistar RA 27/3 propagated on human diploid lung fibroblasts. The growth medium is medium 199 (5.7 mg) used with neomycin as stabiliser.
  • 3.
    Morupar by Chiron is a live virus vaccine. It contains a sterile lyophilised preparation of 1000 TCID50 of Schwarz measles strain propagated in chick embryo cell culture; 1000 TCID50 Wistar RA 27/3 rubella strain propagated on human diploid lung fibroblasts; and 5000 TCID50 Urabe AM 9 mumps propagated in chick embryo cell culture, with neomycin as stabiliser.
  • 4.
    Priorix vaccine, Glaxo SmithKline Beecham (GSK), is a lyophilised mixed preparation of the attenuated Schwarz measles CCID50 (50% cell culture infective dose) strain; RIT 4385 mumps CCID50 (derived from Jeryl Lynn strain); and CCID50 Wistar RA 27/3 rubella strain of viruses. These are separately obtained by propagation either in chick embryo tissue cultures (mumps and measles) or MRC5 human diploid cells (rubella). The vaccine also contains residual amounts of neomycin (25 µg per dose).
  • 5.
    Trimovax by Pasteur-Merieux Serums and Vaccines contains live viruses: Schwarz measles strain, 1000 TCID50; Urabe Am 9 mumps strain, 5000 TCID50; and Wistar RA 27/3 rubella strain, 1000TCID50.

How the intervention might work

No national health policy recommends that the MMR vaccine be given as three separate vaccines. Combined live attenuated MMR vaccine was introduced in the USA in the 1970s (Redd 1999; Schwarz 1975). MMR is included in the World Health Organization's Expanded Programme on Immunisation and it is used in over 50 European countries, the USA, Canada, Australia and New Zealand; in total, over 90 countries around the world use the MMR vaccine. Accepted recommendations are that the first dose should be administered on or after the first birthday and the second dose of MMR at least 28 days later. In many European countries the second dose is administered at four to 10 years of age. Vaccination with MMR provides significant improvement in the efficiency of paediatric immunisation through the administration of three vaccines in a single injection, which is important in reducing costs while increasing immunisation coverage against the three diseases (Makino 1990). The incidence of MMR worldwide has been significantly reduced by MMR vaccination (WHO 1999).

Single-component measles vaccine (MV) is actually used in nearly all African WHO member states (44 out of 47 states); in the main cases vaccination schedules prescribe a single-dose administration at nine months of age. In only four African countries (Algeria, Lesotho, Republic of South Africa, Swaziland) a second MV dose is administered at 18 months or at six years of age (Algeria) (WHO 2011). The administration of the first dose of measles-containing vaccine at nine months of age is recommended in countries with ongoing transmission and with high risk of measles mortality among infants, in order to ensure adequate protection. The introduction of a second measles-containing vaccine dose to the immunisation schedule is recommended only when a coverage of at least 80% for the first dose of measles-containing vaccine has been reached for three consecutive years. It should be administered at 15 to 18 months of age (WHO 2009). Altogether, besides 44 African WHO member countries, an additional 24 countries have exclusively used MV in their vaccination schedule (among others the Russian Federation). Eleven countries have a single-dose MV administration at nine months of age (Bangladesh, Cambodia, Djibouti, Lao People's Democratic Republic, Malaysia, Nepal, Somalia, Sri Lanka, Timor Leste, Vanuatu and Vietnam).

The capability of MMR mass immunisation to eliminate the targeted disease has been demonstrated in a number of countries. The USA is the largest country to have ended endemic measles transmission (Strebel 2004), with interruption of indigenous transmission in 1993 (Watson 1998). In Finland, a national programme launched in 1982 reached measles elimination in 1996 and in 1999 the country was documented as free of indigenous mumps and rubella (Peltola 2000). These experiences demonstrate the possibility of achieving interruption of transmission in large geographic areas and suggest the feasibility of global eradication of measles. Therefore, it would be ethically unacceptable to conduct placebo-controlled trials to assess vaccine effects. Current research on the effectiveness of MMR vaccines focuses on comparison of vaccine strains and optimising protection by modifying the immunisation schedules; these topics are outside the scope of the present review.

A retrospective study (Kreidl 2003) reported data about MMR vaccination coverage for local areas in South Tyrol (North-East Italy) and reported cases of measles in the same areas. In all areas with complete vaccination coverage below 50%, an incidence of at least 333 cases per 100,000 was observed; whereas a very low incidence of the disease was registered in those areas where the highest immunisation coverage was achieved, despite their higher population density.

After the introduction of MMR vaccine in England in October 1988, the annual incidence of mumps declined sharply. The annual incidence rate fell from 160/100,000 in 1989 to 17/100,000 in 1995 (Gay 1997).

One retrospective observational study, which seemed to show an unexpectedly low clinical effectiveness (Vandermeulen 2004) was carried out on 1825 children aged between 15 months and 11 years. It examined the incidence of mumps in seven kindergartens and primary schools in Belgium during a mumps outbreak. This was assessed using questionnaires completed by parents and following evaluation of the reported data according to the Centers for Disease Control and Prevention (CDC) (CDC 1997) case definition. On average, 91.8% of the children had received at least one dose of MMR vaccine at any time before the outbreak occurred. In this group (N = 1641) mumps was diagnosed in 85 children whereas 20 out of the 139 non-immunised children developed mumps (45 children from both groups were excluded from the analysis because they had a history of mumps prior to the outbreak).

The components of monovalent vaccine containing MMR viruses, and subsequently combined MMR vaccine, are described below (Makino 1990; Plotkin 1999b). Numerous attenuated measles vaccines, mostly derived from the Edmonston strain, are currently produced worldwide. Four vaccines containing non-Edmonston derived strains are also in use, including Leningrad-16, Shanghai-191, CAM-70 and TD97. In most cases the virus is cultured in chick embryo cells. However, a few vaccines are attenuated in human diploid cells. The majority of vaccines contain small doses of antibiotics (for example 25 µg of neomycin per dose) but some do not. Sorbitol and gelatin are used as stabilisers (Schwarz 1975).

More than 10 mumps vaccine strains (Jeryl Lynn, Urabe, Hoshino, Rubini, Leningrad-3, L-Zagreb, Miyahara, Torii, NK M-46, S-12 and RIT 4385) have been used throughout the world (Redd 1999). Most vaccines also contain neomycin (25 µg of per dose). The Jeryl Lynn strain is widely used. Several manufacturers in Japan and Europe produce a live mumps vaccine containing the Urabe Am9 virus strain. Concerns about vaccine-associated meningitis have prompted some countries to stop using MMR with the mumps Urabe strain. Often the viruses are cultured in chick embryo fibroblasts (as with the Jeryl Lynn and Urabe strain-containing vaccines) but quail and human embryo fibroblasts are also used for some vaccines.

Most rubella vaccines used throughout the world contain the RA 27/3 virus strain (Plotkin 1965). The only exceptions are vaccines produced in Japan which use different virus strains: Matsuba, DCRB 19, Takahashi and TO- 336 are all produced using rabbit kidney cells; and Matsuura is produced using quail embryo fibroblasts. The RA 27/3 strain is used most often because of consistent immunogenicity, induction of resistance to re-infection and its low rate of side effects (Plotkin 1973). The live virus produces viraemia and pharyngeal excretion, but both are of low magnitude and are non-communicable (Plotkin 1999a).

Why it is important to do this review

Despite its worldwide use, no systematic reviews studying the effectiveness and safety of MMR vaccines are available.

Objectives

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Characteristics of studies
  11. Data and analyses
  12. Additional Tables
  13. Appendices
  14. Feedback
  15. What's new
  16. History
  17. Contributions of authors
  18. Declarations of interest
  19. Sources of support
  20. Differences between protocol and review
  21. References
  • 1.
    To review the existing evidence on the absolute effectiveness of the MMR vaccine in children (by the effect of the vaccine on the incidence of clinical cases of measles, mumps and rubella).
  • 2.
    To assess the worldwide occurrence of adverse events, including those that are common, rare, short-term and long-term, following exposure to the MMR vaccine in children.

Methods

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Characteristics of studies
  11. Data and analyses
  12. Additional Tables
  13. Appendices
  14. Feedback
  15. What's new
  16. History
  17. Contributions of authors
  18. Declarations of interest
  19. Sources of support
  20. Differences between protocol and review
  21. References

Criteria for considering studies for this review

Types of studies

We included randomised controlled trials (RCTs), controlled clinical trials (CCTs), cohort studies, case-control studies, time-series studies, case cross-over studies, ecological studies, self controlled case series, mixed RCT and time-series (see Appendix 1).

Types of participants

Healthy children up to 15 years of age.

Types of interventions

Vaccination with any combined MMR vaccine given in any dose, preparation or time schedule compared with do nothing or placebo.

Types of outcome measures
Primary outcomes
  • 1.
    Effectiveness: clinical and/or confirmed cases of measles, mumps or rubella.
  • 2.
    Safety: serious systemic adverse events. All those which have been hypothesised so far (thrombocytopenic purpura, parotitis, joint and limb symptoms, Crohn's disease, ulcerative colitis, autism and aseptic meningitis), plus encephalitis/encephalopathy, febrile seizure, asthma, leukaemia, hay fever, type 1 diabetes, gait disturbance, demyelinating diseases, bacterial or viral infection.
Secondary outcomes
  • 1.
    Local reactions (for example, soreness and redness at the site of inoculation) and systemic reactions (for example, fever, rash, vomiting and diarrhoea) following MMR vaccination.

Search methods for identification of studies

Electronic searches
For effectiveness

For this update we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 2), which includes the Cochrane Acute Respiratory Infections Group's Specialised Register, EMBASE (July 2004 to May 2011) and PubMed (July 2004 to May week 2, 2011). We used the following search terms for CENTRAL and PubMed.

# 1 explode 'Vaccines-Combined' / all subheadings

# 2 explode 'Vaccines-Attenuated' / all subheadings

# 3 #1 or #2

# 4 trivalen* or combin* or simultan* or tripl* or trebl*

# 5 vaccin* or immuni* or inoculat*

# 6 # 4 and # 5

# 7 # 3 or # 6

# 8 explode 'Measles-' / all subheadings

# 9 explode 'Mumps-' / all subheadings

# 10 explode 'Rubella-' / all subheadings

# 11 measles and mumps and rubella

# 12 #8 or #9 or #10 or #11

# 13 #7 and #12

# 14 explode 'Measles-Vaccine'

# 15 explode 'Mumps-Vaccine'

# 16 explode 'Rubella-Vaccine'

# 17 explode 'Measles-Mumps-Rubella-Vaccine' / all subheadings

# 18 measles mumps rubella or MMR

# 19 #14 or #15 or #16 or #17 or #18

# 20 #13 or #19

We adapted these subject terms for EMBASE (see Appendix 2). We conducted all searches during the second week of May, 2011. We also considered the Cochrane Database of Systematic Reviews (CDSR) and the NHS Database of Abstracts of Reviews of Effects (DARE) for published reviews. For search strategies used in the previous version of the review see Appendix 3.

For safety

Again, for this update we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 2), which includes the Cochrane Acute Respiratory Infections Group's Specialised Register, EMBASE (July 2004 to May 2011) and PubMed (July 2004 to May week 2 2011). We used the following search terms for CENTRAL and PubMed.

1 Vaccines-Combined [mesh word (mh)]

2 Vaccines-Attenuated

3 ((trivalen*[text word (tw)] or combin* (tw) or simultan* (tw) or tripl* (tw) or trebl* (tw) and (vaccin* (tw) or immuni* (tw) or inoculat* (tw)))

4 or/1-3

5 measles (tw) and mumps (tw) and rubella (tw)

6 4 and 5

7 Measles-Vaccine(mh) and Mumps-Vaccine (mh) and Rubella-Vaccine (mh)

8 MMR [title, abstract (ti,ab)]

9 (measles (tw) and mumps (tw) and rubella (tw) and (vaccin* (tw) or immuni* (tw) or inoculat* (tw))

10 or/6-9

11 adverse events [floating sub-heading (fs)] or chemically induced (fs) or complications (fs) or contraindications (fs) or toxicity (fs) or poisoning (fs) or drug effects (fs)

12 ((adverse (tw) and (effect* (tw) or event* (tw)) or side effect* (tw) or hypersensitiv* (tw) or sensitiv* (tw) or safe* (tw) or pharmacovigil* (tw)

13 explode Product-Surveillance-Postmarketing (mh) or Drug-Monitoring (mh) or Drug-Evaluation (mh) or explode Risk (mh) or Odds-Ratio (mh) or explode Causality (mh)

14 relative risk (tw) or risk (tw) or causation (tw) or causal (tw) or odds ratio (tw) or etiol* (tw) or aetiol* (tw) or etiology (fs) or epidemiology (fs)

15 or/11-14

16 10 and 15

As before, we adapted this filter for searching EMBASE (see Appendix 2).

Searching other resources

For effectiveness trials, we searched bibliographies of all relevant articles obtained and any published reviews for additional studies. We also searched the following sources for unpublished, prospectively registered trials: http://www.clinicaltrials.gov/ and http://www.controlled-trials.com/. In addition, we contacted vaccine manufacturers, companies that market vaccines, the leading or corresponding authors of studies evaluated and researchers or experts in the field, where appropriate, to identify any unpublished studies. We imposed no language restrictions.

For safety trials, we assessed bibliographies of all relevant articles and any published reviews for additional studies. We imposed no language restrictions.

Data collection and analysis

See Appendix 1 for study design definitions (based on: Farrington 2004; Jefferson 1999; Last 2001).

Selection of studies

Two review authors (MGD, CDP) independently applied the inclusion criteria to all identified and retrieved articles. A third review author (VD) arbitrated in case of disagreements about eligibility of a study.

Data extraction and management

Three review authors (AR, MGD, CDP) independently performed data extraction using a data extraction form (Appendix 4). One review author (VD) checked data extractions and arbitrated in case of disagreements.

Assessment of risk of bias in included studies

Three review authors (AR, MGD, CDP) independently assessed the methodological quality of the included studies. We assessed the quality of RCTs and quasi-RCTs using the criteria adapted from the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We assessed the quality of non-RCTs in relation to the presence of potential confounders which could make interpretation of the results difficult. However, because there was insufficient empirical evidence to demonstrate the validity of the non-randomised quality assessment screens, these studies were used for the purposes of qualitative analysis only.

We evaluated the quality of case-control (prospective and retrospective) and cohort studies using the appropriate Newcastle-Ottawa Scales (NOS) (Wells 2000). We applied quality control assessment grids, based on those developed by The University of York, NHS Centre for Reviews and Dissemination (Khan 2001), to historical controlled trials (HCTs), interrupted time-series and case cross-over studies and ecological studies (see Appendix 4). We used a classification and methodological quality checklist (unpublished) for case-only design studies, especially developed by CP Farrington and TO Jefferson and adapted from a paper by CP Farrington (Farrington 2004).

Measures of treatment effect

This is a descriptive review.

Unit of analysis issues

This is a descriptive review.

Dealing with missing data

We did not use any strategies to impute missing outcome data.

Assessment of heterogeneity

We firstly assessed included studies for clinical homogeneity. As we found diversity of exposure, outcomes and length of follow-up, we decided against pooling data and carried out a descriptive review.

Assessment of reporting biases

Not performed.

Data synthesis

We classified and discussed included studies according to the type of outcomes for which they provided evidence, i.e. effectiveness, possible association with harms or local and systemic adverse effects. We illustrated study characteristics, design, population, outcomes definitions, methods used and results in the Effects of interventions section and in the Additional tables.

Subgroup analysis and investigation of heterogeneity

This is a descriptive review.

Sensitivity analysis

This is a descriptive review.

Results

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Characteristics of studies
  11. Data and analyses
  12. Additional Tables
  13. Appendices
  14. Feedback
  15. What's new
  16. History
  17. Contributions of authors
  18. Declarations of interest
  19. Sources of support
  20. Differences between protocol and review
  21. References

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification.

Results of the search

We updated the searches in May 2011 and identified 3371 articles for screening. We identified and retrieved 96 papers after reviewing the titles and abstracts. Out of these, we included 33 in the update. Our original searches identified 4889 articles for screening, a large number of studies because of the deliberately broad search design. After screening, we retrieved 139 studies possibly fulfilling our inclusion criteria; 108 studies did not meet all inclusion criteria and were excluded, while 31 were included in this review. In this 2011 update, we included a total of 64 studies.

Included studies

We included the following studies.

One study (Freeman 1993) had a mixed RCT and time-series design and we classified it as the latter because adverse event data comparison was carried out on outcomes in children before and after vaccination. We classified studies reported as 'field trials' or 'controlled trials' as cohort studies when randomisation was not mentioned.

Twelve studies included effectiveness data against measles or mumps diseases: seven cohorts (Chamot 1998; Lopez Hernandez 2000; Marin 2006; Marolla 1998; Ong 2005; Ong 2007; Schlegel 1999) and five case-control studies (Castilla 2009a; Giovanetti 2002; Goncalves 1998; Harling 2005; Mackenzie 2006).

Seventeen reported on short-term side effects: five RCTs (Bloom 1975; Edees 1991; Lerman 1981; Peltola 1986; Schwarz 1975); one CCT (Ceyhan 2001); 10 cohort studies (Beck 1989; Benjamin 1992; Dunlop 1989; Makino 1990; Miller 1989; Robertson 1988; Sharma 2010; Stokes 1971; Swartz 1974; Weibel 1980) and one time-series study (Freeman 1993).

Important safety harms had been investigated in 35 studies: nine cohort studies (Ahlgren 2009a; DeStefano 2002; Fombonne 2001; Hviid 2004; Hviid 2008; Madsen 2002; McKeever 2004; Uchiyama 2007; Vestergaard 2004); 12 case-control studies (Ahlgren 2009b; Bertuola 2010; Black 1997; Black 2003; Bremner 2005; Bremner 2007; Davis 2001; DeStefano 2004; Ma 2005; Mrozek-Budzyn 2010; Ray 2006; Smeeth 2004); four time-series studies (da Cunha 2002; Dourado 2000; Fombonne 2006; Honda 2005); one case cross-over trial (Park 2004); two ecological studies (Jonville-Bera 1996; Seagroatt 2005) and seven self controlled case series (France 2008; Makela 2002; Miller 2005; Miller 2007; Stowe 2009; Taylor 1999; Ward 2007).

Excluded studies

Out of the 96 papers identified and retrieved for this update, we excluded 50 because they were not comparative, considered vaccines other than MMR, or did not present original data. (See Characteristics of excluded studies table for detailed information regarding reasons for exclusion). We classified a further 13 studies as pending, as some important details were not available in the papers (see Characteristics of studies awaiting classification table).

Risk of bias in included studies

Studies evaluating vaccine effectiveness

Out of the 12 cohorts and case-control studies assessing effectiveness of MMR vaccines in preventing measles or mumps, only three had a moderate bias risk. The remaining nine were characterised by poor methodological quality due to poor reporting or missing information about comparability between exposed or non-exposed groups; the composition of MMR vaccine is sometimes not reported (Table 1, Table 2 and Table 3).

Studies evaluating short-term side effects

Seventeen trials reported on short-term side effects: five RCTs; one CCT; 10 cohort studies and one time-series study (Table 4). We assessed the risk of bias in the RCTs and CCT to be of low risk of bias in two trials (Lerman 1981; Peltola 1986); moderate/unknown risk of bias in two trials (Ceyhan 2001; Edees 1991); and high risk of bias in two trials (Bloom 1975; Schwarz 1975).

Allocation

Out of the five RCTs and one CCT assessing short-term side effects, only two studies (Lerman 1981; Peltola 1986) had adequate concealment.

Blinding

Out of the five RCTs and one CCT assessing short-term side effects, three trials were double-blind (Lerman 1981; Peltola 1986; Schwarz 1975), one single-blind (Edees 1991), whereas the remaining two (Bloom 1975; Ceyhan 2001) were not blinded.

Incomplete outcome data

In the Ceyhan 2001 and Lerman 1981 trials, the selection of paediatric practices involved in the recruitment of children was not explained and the number and assessment of non-responders were not reported. Similarly in the Edees 1991 trial there are few details on the refusal and response rate during the recruitment phase and a lack of demographic information from the two UK areas where the trial was conducted. We considered the Ceyhan 2001 and Edees 1991 trials to have a moderate risk of detection bias affecting the outcomes.

Selective reporting

In the two trials we assessed as being at high risk of reporting bias (Bloom 1975; Schwarz 1975), we reported adverse effects for only 60% and 39% of participants, respectively.

Other potential sources of bias

Not known.

Cohort studies

There was a lack of adequate description of exposure (vaccine content and schedules) in all cohort studies. Another recurring problem was the failure of any study to provide descriptions of all outcomes monitored. A lack of clarity in reporting and systematic bias made comparability across studies and quantitative synthesis of data impossible.

Time-series studies

The only time-series study (Freeman 1993) was evaluated to be affected by a high degree of risk of bias. The number of completed weekly diaries varied over the eight-week study period, with no indication of whether the losses occurred pre or postvaccination. In addition, there was an overall attrition rate of 33%.

Studies evaluating safety harms

The association between MMR and serious harms was investigated in 35 studies (nine cohorts, 12 case-control studies, four time-series studies, one case-cross over, two ecological studies, seven self controlled case series). Results of risk of bias assessment in the following is split by study design.

Cohort studies

In Fombonne 2001 the number and possible impact of bias was so high that interpretation of the results was difficult. The cohort study of Uchiyama 2007 was potentially affected by a different type of bias, considering that the participants were from a private clinic and that definitions of applied Autistic Spectrum Disorders (ASD) diagnosis and of methods used for ASD regression ascertainment were not clearly reported. Estimates from McKeever 2004 (although significant) are strongly affected by ascertainment bias, as children who are not taken to the doctor are less likely to be vaccinated and also have fewer opportunities to have diagnoses of allergic diseases recorded.

Case-control studies

In Black 1997 there was a moderate likelihood of selection bias because of missing cases and their records (up to 27%) but the study and its methods were well reported. Lack of clarity over the vaccine exposure status of the controls made the results of the Black 2003 study difficult to interpret. In Bertuola 2010, cases and controls were apparently not matched. Ascertainment of exposure was performed only with questionnaires to parents. Investigators were probably not blinded to the case or control status of the participants. In Ma 2005, refusal to participate in the study or inability to locate the participants and controls could have introduced a moderate risk of selection bias. Exclusion of participants without completed questionnaires and of those who did not attend the sixth grade at school within the study area could have introduced a relevant selection bias in the Ahlgren 2009b case-control study.

Time-series studies

Limited error could have been introduced by using population data from a prior census (as estimation of the denominator) in Dourado 2000, so as by using the number of doses administered (as opposed to supplied) in the mass vaccination programme. Assessment of Pervasive Development Disorders (PDD) cases in Fombonne 2006 was made on the basis of administrative codes only: diagnosis could have been imprecise and did not allow us to consider PDD subtypes or regression.

Case cross-over studies
  • Low risk of bias: no studies.

  • Moderate/unknown risk of bias in one study (Park 2004).

  • High risk of bias: no studies.

In Park 2004 there was a moderate likelihood of selection bias due to missing cases and their records (up to 27%).

Ecological studies
Self controlled case series studies

The study by Makela 2002 was weakened by the loss of 14% of the original birth cohorts and the effects of the rather long-term follow-up. What the impact of either of these factors was in terms of confounders is open to debate. It should be taken into account that autism does not often involve hospitalisation and data about outpatients visits were not available. The long follow-up for autism could be due to the lack of a properly constructed causal hypothesis. Again, the study of Taylor 1999 demonstrates the difficulties of drawing inferences in the absence of a non-exposed population or a clearly defined causal hypothesis. The exclusive use of discharge diagnoses for identification of cases in Miller 2007 could have introduced a noteworthy selection bias.

Effects of interventions

Studies reporting effectiveness findings

Eight cohorts and five case-control studies investigated effectiveness outcomes.

Measles
Evidence from cohort studies

Effectiveness against measles was investigated in three cohort studies (Marin 2006; Marolla 1998; Ong 2007).

One cohort study (Marolla 1998) evaluated the effectiveness of MMR vaccination in preventing clinical cases of measles in children aged 18 to 90 months from several local health agencies in Rome, Italy (n = 2745). Vaccination was performed with three different commercial MMR vaccines, two containing both Schwarz strain (Pluserix and Morupar) and one other prepared with Edmonston-Zagreb strain (Triviraten). Vaccines effectiveness was calculated by using the following formula [1-(measles incidence among vaccinated/measles incidence among unvaccinated) x 100]. Effectiveness (one dose) was estimated to be 97% (95% confidence interval (CI) 88 to 99) in the Morupar study arm, whereas no measles cases were found among Pluserix recipients. Effectiveness was comparably high (95%; 95% CI 90 to 98) when Triviraten was administered.

One other cohort study (Ong 2007) investigated the effectiveness of MMR immunisation (composition not reported by authors) in children aged between eight and 14 years in preventing measles cases with laboratory confirmation. Two laboratory-confirmed measles cases occurred among the 171 vaccinated children (one dose), whereas seven were observed in the unvaccinated group (n = 13). Vaccine effectiveness (VE = 97%) was calculated in Orenstein 1985, [(attack rate among unvaccinated-attack rate among vaccinated/attack rate among unvaccinated) x 100].

Effectiveness of MMR vaccination in preventing secondary measles cases was assessed in the Marin 2006 study. Vaccination with one or two doses of MMR vaccine (composition unknown) was highly effective in preventing secondary cases among contacts. Estimate VE (Orenstein 1985) was 92% (95% CI 67 to 98) after one dose and 95% (95% CI 82 to 98) after two doses.

Mumps

Effectiveness of the MMR vaccine against clinical mumps disease was assessed in five cohort and five case-control studies.

Evidence from cohort studies

In three cohort studies (Marolla 1998; Ong 2005; Schlegel 1999) occurrence of clinical mumps cases during outbreaks was retrospectively evaluated by comparing the incidence of disease among children who had been immunised with MMR vaccines containing different mumps strains (Jeryl Lynn, Urabe, Rubini) with that observed among non-immunised children.

In Ong 2005, carried out in childcare centres and primary schools in Singapore (n = 5072, aged five to 12) and Schlegel 1999, performed on children (n = 163, aged five to 13 years) from a small rural village in Switzerland, preventive effectiveness for Jeryl Lynn, Urabe or Rubini strains was compared with no immunisation.

Preventive effectiveness estimates (Orenstein 1985) for at least one dose of the Jeryl Lynn strain-containing MMR vaccine were similar in both studies, with statistically relevant significance: VE 80.7%; 95% CI 57.8 to 90.8 (Ong 2005) and 78% (95% CI 64 to 82) (Schlegel 1999).

Effectiveness of MMR Urabe vaccine (at least one dose) has been estimated to be highly effective (VE 87%; 95% CI 76 to 94) in Schlegel 1999, whereas the estimate from the Ong 2005 study did not reach statistical relevance (VE 54%; 95% CI -16.2 to 81.7).

The Rubini strain-containing MMR vaccine was highly ineffective in preventing clinical mumps cases in the Ong 2005 study (VE -55.3%; 95% CI -121.8 to -8.8); the estimate from the Schlegel 1999 study was not statistically relevant (VE -4%; 95% CI 218 to 15).

In Marolla 1998 effectiveness against mumps was similar for both Urabe-containing MMR vaccines (VE 75%; 95% CI 65 to 83 for Pluserix and VE 73%; 95% CI 59 to 82 for Morupar). The Rubini strain was much less effective (VE 23%; 95% CI 6 to 37).

The cohort of Lopez Hernandez 2000 estimated MMR vaccination effectiveness in preventing clinical mumps on male children aged between three and 15 years, attending a scholastic institute in Granada, Spain during an outbreak. Occurrence of clinical mumps cases was compared between children who received at least one dose of MMR vaccine (investigators were not able to determine the vaccine composition) and those who did not receive the MMR vaccine. The effectiveness estimate was 49% (P = 0.047) (Orenstein 1985).

One other cohort study (Chamot 1998) investigated the occurrence of clinical mumps in MMR vaccinated and non-vaccinated household contacts aged up to 16 years (secondary cases) of primary mumps cases (with clinical or laboratory confirmation). Urabe-containing MMR vaccine showed a protective effect against secondary case onset in comparison with no vaccination: vaccine effectiveness as ([1-(attack rate in vaccinated/attack rate in not vaccinated)] x 100) was 73.1%; 95% CI 41.8 to 87.6. Protection afforded by both Jeryl Lynn and Rubini-containing MMR vaccines was instead not statistically relevant (VE 61.6%; 95% CI -0.9 to 85.4 and VE 6.3%; 95% CI -45.9 to 39.8, respectively).

Evidence from case-control studies

Five case-control studies assessed the effectiveness of MMR vaccination against mumps (Castilla 2009a; Giovanetti 2002; Goncalves 1998; Harling 2005; Mackenzie 2006).

One case-control study (Harling 2005) assessed effectiveness of immunisation with one or two doses of Jeryl Lynn-containing MMR vaccine in the prevention of clinical and laboratory-confirmed mumps cases. Cases (n = 156) and controls (n = 175) were children and adolescents (aged one to 18 years) living in a religious community in North-East London, where a mumps outbreak was observed (June 1998 to May 1999). Effectiveness estimates (expressed as VE = [(1-Odds Ratio) x 100] for one or two doses were similar against clinical (VE 69%; 95% CI 41 to 84) and laboratory-confirmed mumps (VE 65%; 95% CI 25 to 84). Two doses were more effective (VE 88%; 95% CI 62 to 96) than one (VE 64%; 95% CI 40 to 78) against clinical mumps.

The following three case-control studies used surveillance systems with the aim of identifying mumps cases in the study population.

Goncalves 1998 assessed the effectiveness of at least one dose of MMR vaccines prepared with either the Urabe or Rubini strain in prevention of clinical mumps cases during an epidemic on a population of children and adolescents (189 cases and 378 controls, aged 15 months to 16 years). Significant protection was conferred by the Urabe strain-containing MMR vaccine (VE= [1-Odds Ratio (OR)] x 100 = 70%; 95% CI 25 to 88), and not by the Rubini strain-containing MMR (VE 1%; 95% CI -108 to 53).

In Giovanetti 2002 field effectiveness of MMR vaccination (at least one dose, unknown composition) in preventing clinical mumps on a population of children and adolescents (139 cases and controls) was 53.7% (95% CI 20.3 to 73.0 ; VE = [1-OR] x 100).

In Castilla 2009a, case definition considers clinical mumps with laboratory or epidemiological confirmation (Table 3), occurring during an outbreak in the Navarre region (Northern Spain) between August 2006 and June 2008 in children and adolescents (241 cases and 1205 matched controls). Vaccine effectiveness of MMR vaccine prepared with Jeryl Lynn mumps strain (VE = [1-OR] x 100), calculated by means of conditional logistic regression analysis, was 72% (95% CI 39% to 87%, P = 0.0013) for any dose, 66% (95% CI 25% to 85%, P = 0.0075) for one dose and 83% (95% CI 54% to 94%, P = 0.0005) for two doses. The authors hypothesised a higher risk of having mumps when the first MMR dose is administered after the 36th month of age (OR 3.11; 95% CI 1.15 to 8.43, P = 0.0254) or when the two MMR doses are administered more than 36 months apart (OR 10.19; 95% CI 1.47 to 70.73, P = 0.0189).

Mackenzie 2006 attempted to estimate effectiveness of MMR vaccination against virological-confirmed mumps on pupils (aged 13 to 17 years) attending a boarding school in Scotland (20 cases and 40 matched controls). The numerical size of the study was not large enough to reach statistical relevance (OR for any MMR dose = 0.66; 95% CI 0.22 to 2.00).

Rubella

We found no studies assessing the effectiveness of MMR vaccine against clinical rubella.

Short-term side effects
CCTs and RCTs

MMR vaccines were compared with monovalent measles vaccine (Ceyhan 2001; Edees 1991; Lerman 1981), two types of monovalent mumps and rubella vaccines (Lerman 1981) or placebo (Bloom 1975; Lerman 1981; Peltola 1986; Schwarz 1975). One trial (Peltola 1986) carried out in twins, reported a possible protective effect of the MMR vaccine with a lower incidence of respiratory symptoms, nausea and vomiting, and no difference in the incidence of other unintended side effects compared with placebo, with the exception of irritability. Another trial concluded that there was no increased clinical reactivity with a MMR vaccine containing two strains of rubella (Lerman 1981).

The trial by Edees concluded that there was no significant difference between the numbers of children developing symptoms after MMR or measles vaccination (Edees 1991). The trials by Bloom and Schwarz concluded that the incidence of raised temperature, rash, lymphadenopathy, coryza, rhinitis, cough, local reactions or limb and joint symptoms were not significantly different from placebo (Bloom 1975; Schwarz 1975).

All RCTs and CCTs reported a wide range of outcomes and used different terms, often with no definition. For example, body temperature higher than 38 °C was measured or reported in 16 ways. When reported, different temperature increments, recording methods, observation periods and incidence made comparisons between trials and pooling of data impossible (Table 5).

Cohort studies

Occurrence of short-term side effects was assessed in 10 cohort studies altogether. They compared the MMR vaccine with single measles vaccine (Dunlop 1989; Makino 1990; Miller 1989; Robertson 1988), mumps-rubella vaccine (Swartz 1974), single mumps vaccine (Makino 1990), single rubella vaccine (Swartz 1974; Weibel 1980), placebo (Beck 1989) or no intervention (Benjamin 1992; Sharma 2010; Stokes 1971).

The study by Benjamin found that the MMR vaccine was associated with an increased risk of episodes of joint and limb symptoms in girls less than five years of age (Benjamin 1992).

There was no difference in the incidence of common outcomes such as fever, rash, cough, lymphadenopathy, arthralgia, myalgia and anorexia between the MMR vaccine and rubella vaccine (Makino 1990; Swartz 1974; Weibel 1980), mumps-rubella vaccine (Swartz 1974), single mumps vaccine (Makino 1990) or measles vaccine (Dunlop 1989; Makino 1990). Two studies (Miller 1989; Robertson 1988) found that symptoms were similar following MMR and measles vaccination except for a higher incidence of parotitis following MMR vaccination (Miller 1989). Makino reported a higher incidence of diarrhoea in the MMR vaccines arm compared to the single measles or rubella vaccines arms (Makino 1990). The studies by Beck and Stokes reported no difference in the incidence of rash and lymphadenopathy between MMR vaccination and placebo (Beck 1989) or do nothing (Stokes 1971). However, Stokes 1971 reported an increase in the incidence of fever in the period Day 5 to Day 12 postvaccination but Beck 1989 reported no difference.

Considering the cohort of Sharma 2010 only within the subgroup of younger children (16 to 24 months of age), fever during the 42 days postvaccination had been reported more frequently among individuals immunised with MMR than among unvaccinated individuals. This trend appeared to be different when the older population was considered; fever had been reported with slightly higher frequency among unvaccinated children.

Time-series

In the Freeman 1993 study, conducted by 22 family physicians, occurrence of common symptoms following MMR immunisation (type not described) was assessed by means of weekly diaries in participants immunised at 13 and 15 months of age, comparing their incidence during the four weeks before with that observed four weeks after immunisation. The incidence of rash, lymphadenopathy and nasal discharge was found to be higher after exposure to MMR immunisation.

Severe harms

Possible association of MMR immunisation with severe harms has been tested in several observational studies.

Neurological diseases
1. Encephalitis - encephalopathy

Association between MMR immunisation and occurrence of encephalopathies was investigated in three studies: one case-control study (Ray 2006) and two self controlled case series studies (Makela 2002; Ward 2007).

The case-control study of Ray 2006 tested if hospitalisations due to encephalopathy, Reyes syndrome or encephalitis (Table 6) occurring in children aged zero to six years could be linked to MMR vaccine administration. Different time intervals between MMR exposure and date of hospitalisation have been considered: seven to 14 days, zero to 14 days, zero to 30 days, zero to 60 days and zero to 90 days. Four hundred and fifty-two cases together with their 1280 matched controls were included in the analysis. In none of the considered time intervals was exposure to the MMR vaccine statistically different among the cases and controls.

Makela 2002 was based on a surveillance study by the National Public Health Institute that began after the introduction of MMR vaccination in Finland for children aged 14 to 18 months and six years (1982). Participants aged one to seven years (n = 535,544) who received the MMR II vaccine between November 1982 and June 1986 were considered in the study (this population corresponds to 86% of all children scheduled for MMR vaccination in Finland). Risk association was evaluated by comparing the number of hospitalisations for encephalitis or encephalopathy (see Table 6 for outcome definition) within three months after vaccination with those occurring during the subsequent seven three-month intervals. Out of the 199 hospitalisations for encephalitis or encephalopathy, nine occurred within three months after MMR vaccination, 110 occurred more than three months after vaccination (88 in an interval between three and 24 months), whereas 80 occurred before the vaccine was administered. Trial authors stated that no hospitalisation excess for encephalitis or encephalopathy was observed during the three months post-immunisation (P = 0.28).

In Ward 2007, in order to evaluate the association between encephalitis (see Table 6 for case definitions) and MMR vaccination, cases (n = 107) diagnosed at the age of 12 to 35 months were considered (children aged 12 to 15 months were scheduled for MMR vaccination in Britain and Ireland). The risk period for encephalitis was considered to be the time between 15 and 35 days following MMR immunisation. The incidence of disease within the risk period was compared with that outside it (the control period). The incidence of encephalitis in the risk period (15 to 35 days) was not statistically different from that of the control period (relative incidence = 1.34 ; 95% CI 0.52 to 3.47). This estimate does not change in the presence or absence of primary HHV-6 or HHV-7 infections.

2. Aseptic meningitis

The association of the MMR vaccine with aseptic meningitis was evaluated in the following studies.

Case-control studies

In Black 1997, MMR vaccination within defined intervals before the index date (zero to 14 days, zero to 30 days, eight to 14 days) was assessed in cases and controls to assess its association with aseptic meningitis (see Table 7 for outcome definitions). Exposure to the MMR vaccine was not statistically different between cases and controls in any of the considered time intervals.

Cross-over studies

In Park 2004 the risk association of MMR vaccination with aseptic meningitis (see Table 7 for outcome definitions) has been evaluated by means of a cross-over design. Thirty-nine participants aged 13 to 29 months of both sexes were included. Risk estimation was calculated considering whether MMR vaccine exposure occurred during a time window of 42 days before disease onset or before (from 43 to 365 days before): 11 out of the 39 participants received MMR vaccination during the risk period and 28 outside of it. Mantel-Haenszel OR estimate indicates a positive association (3.0; 95% CI 1.5 to 6.1).

Self-controlled case-series study

In the study of Makela 2002, the risk association of MMR II vaccine (Enders-Edmonston, Jeryl Lynn ,Wistar RA 27/3) exposure was assessed as for encephalitis, by comparing the number of hospitalisations within three months after vaccination with those occurring during the subsequent seven three-month intervals. Ten hospitalisations for aseptic meningitis occurred within three months after MMR immunisation, whereas there were 110 thereafter (54 between three and 24 months) and 41 were vaccinated after hospitalisation. No significant increase in aseptic meningitis was observed during the three months following immunisation (P = 0.57).

Time-series studies

Dourado 2000 compared the incidence of aseptic meningitis hospitalisation (see Table 7 for definitions) before and after a mass immunisation campaign (Pluserix) carried out in Salvador city (State of Bahia, NE Brazil, population about 2.2 million in 1996) and having as target population children aged one to 11 years (452,334 based on the 1996 census). The incidence of aseptic meningitis hospitalisation was significantly higher during the third (18 cases risk ratio (RR) 14.28; 95% CI 7.93 to 25.71), fourth (15 cases RR 11.90; 95% CI 6.38 to 22.19), fifth (nine cases, RR 7.14; 95% CI 3.38 to 15.08) and sixth (four cases, RR 3.17; 95% CI 1.12 to 9.02) weeks following the start of the immunisation campaign when compared with that observed during the 23 pre-immunisation weeks (reference period). Risk association was moreover estimated by case series method, including in analysis only the 37 aseptic meningitis cases with known vaccination status and date occurring during the epidemiological weeks 36 to 39 (about 15 to 35 days after immunisation). Authors attributed 32 of the 37 cases to be due to Urabe-containing MMR vaccine Pluserix (one in about 14,000 doses).

The study of da Cunha 2002 had an analogous design and was carried out in two other Brazilian states, Mato Grosso (MT) and Mato Grosso do Sul (MS). As before, the target population were children aged one to 11 years (estimated 580,587 in MS and 473,718 in MT). The incidence of aseptic meningitis in MS became significantly higher than in the pre-immunisation time from two weeks after the start of the campaign (four cases, RR 5.6; 95% CI 1.3 to 14.1), which peaked at three weeks (16 cases, RR 22.5; 95% CI 11.8 to 42.9) and four weeks after the start of the campaign (15 cases, RR 21.1; 95% CI 11.0 to 40.7) and returned to the average after week 39. A similar trend was observed in MT, where the incidence of cases became significantly higher during the third week (40) after the start of the campaign (five cases, RR 2.6; 95% CI 1.1 to 6.5) which peaked in week 42 (30 cases, RR 15.6; 95% CI 10.3 to 24.2) and week 43 (23 cases, RR 12.0; 95% CI 7.6 to 19.4) and returned to the average from week 46 onwards.

3. Febrile seizure

Person-time cohort studies

The study of Vestergaard 2004 is a person-time cohort assessing the risk of febrile seizure (Table 8) after the introduction of routine MMR vaccination in Denmark in 1987. The study population consisted of the birth cohorts 1991 to 1998 (n = 537,171). Globally, the risk of febrile seizure was significantly higher among the vaccinated (RR 1.10; 95% CI 1.05 to 1.15). When different time frames after vaccination are considered, the RR was at the highest point within two weeks after immunisation (RR 2.75; 95% CI 2.55 to 2.97), did not differ significantly in weeks three to six and became slightly less than one in weeks seven, eight, nine to 26 and 27 to 52. The RR was not different to the unvaccinated after week 53. For evaluation of long-term prognosis, the number of recurrent episodes of febrile seizure and the cases of epilepsy observed in children who received MMR vaccination within 14 days before their first febrile seizure episode and in those who were vaccinated more than 14 days before their first febrile seizure episode, were compared with those who were not vaccinated at the time of their first febrile seizure episode. A significant risk association was found only for recurrent febrile seizure episodes in children who were immunised with MMR within 14 days before the first episode (RR 1.19; 95% CI 1.10 to 1.41, adjusted for age, calendar period, age at first febrile seizure and current vaccination status).

Self controlled case series study

In Ward 2007 (already described in the section 'Encephalitis – encephalopathy'), the risk of severe illness with fever and convulsion following MMR immunisation was also investigated. The considered risk period was the time between six and 11 days following immunisation. As before, disease incidence within the risk period was compared with that outside it (the control period). Episodes of severe illness with fever and convulsion were more frequent within six to 11 days after MMR immunisation (relative incidence (RI) 5.68; 95% CI 2.31 to 13.97).

In Miller 2007 children aged 12 to 23 months (n = 894) with a discharge diagnosis of febrile convulsion (Table 8) and who received one MMR vaccine dose were included in the analysis. The incidence of disease during two "at risk" periods (between six to 11 and 15 to 35 days after immunisation) was compared with that determined for the background period. During the time between six and 11 days following MMR vaccination (of all types) a significantly higher relative incidence (RI) of febrile convulsion had been observed (RI 4.09; 95% CI 3.1 to 5.33). On the contrary, RI of febrile convulsions did not differ significantly from the background period during the 15 to 35 days following MMR immunisation (RI 1.13; 95% CI 0.87 to 1.48). The risk incidence of febrile convulsion was also analysed considering a “more specific” definition (Table 9). Considering all MMR vaccine types, the risk incidence remains higher in the six to 11 days following vaccination (RI 4.27; 95% CI 3.17 to 5.76), whereas the time between 15 to 35 days following vaccination it remains of borderline significance (RI 1.33; 95% CI 1.00 to 1.77).

Thrombocytopaenic purpura
Case-control studies

In Black 2003 cases (n = 23) and matched controls (n = 116) were selected within data contained in the General Practice Research Database (GPRD). Relative risk of developing idiopathic thrombocytopaenic purpura (ITP) (see Table 10) within six weeks after MMR immunisation was estimated to be 6.3 (95% CI 1.3 to 30.1) with an estimate attributable risk of 1 case/25,000 doses. Risk would be not statistically different from reference groups for the time between 7 and 26 weeks after vaccination.

Also Bertuola 2010 tested the association between acute immune thrombocytopaenia (AIT) and MMR vaccination by means of a case-control design in children and adolescents (aged one month to 18 years). The risk estimate was calculated considering the exposure to the MMR vaccine (strain composition not reported) during the six weeks preceding hospitalisation in cases and controls (see definitions Table 10). Fourteen out of the 387 cases and 27 out of the 1924 controls received the MMR vaccine within six weeks before hospitalisation (OR 2.4; 95% CI 1.2 to 4.7, adjusted for age and use of drugs by multiple logistic regression).

Self controlled case series and risk interval studies

The study by France 2008 is based on data contained in the Vaccines Safety Datalink project for the years 1991 to 2000, covering eight managed care organisations (MCO) across the USA. By consulting the database, 63 cases aged 12 to 23 months who met the definition (Table 10) could be identified. The 42 days following immunisation was considered as the exposed period, whereas the time before and after this was considered the not exposed period, with the exclusion of a six-week time interval before vaccination. Twenty cases had been classified as exposed and 43 as not exposed. The incidence rate ratio (IRR) between the exposed and unexposed time was calculated by using two different analytical methods: the self controlled case series (SCCS) and the "risk interval" (i.e. person-time cohort) method. By the SCCS method, conditional Poisson regression was used to calculate the IRR, controlled by age and excluding fixed covariate from the model (gender, MCO, MMR dose number). By the "risk interval" method, the Poisson regression model controlled for age, MMR dose number, MCO site and gender was used to calculate IRR. Estimates were respectively 5.38 (95% CI 2.72 to 10.62) and 3.94 (95% CI 2.01 to 7.69). Considering the analysis included only children aged 12 to 15 months (the age at which about 80% of MMR vaccinations were administered), the IRR estimates were 7.06 (95% CI 1.95 to 25.88) and 7.10 (95% CI 2.03 to 25.03) for SCCS and "risk time", respectively. The attributable risk was estimated to be about 1 ITP case per 40,000 administered MMR doses.

Ecological studies

The evidence of association between MMR, or any of its component vaccines, and the onset of thrombocytopenic purpura (TP) was also assessed in one ecological study (Jonville-Bera 1996). The study concluded that the evidence favoured an association but in all cases TP appeared to be a benign, self limiting condition not distinguishable from its idiopathic counterpart or from TP occurring after natural infection with measles, mumps or rubella. The study discussed the weakness of relying on the passive reporting system for the identification of cases and acknowledged a possible under-reporting of cases of TP.

Autism
Cohort studies

Three retrospective cohort studies investigated the risk of autism and pervasive development disorders (PDD) following MMR immunisation (Fombonne 2001; Madsen 2002; Uchiyama 2007) (Table 9).

The study by Madsen 2002 was conducted in Denmark and included all Danish children born between January 1991 and December 1998. The authors linked vaccination data reported in the National Board of Health with a diagnosis of autism (Table 9) from the Danish Psychiatric Central Register. After adjustment for confounders, the RR for autism is 0.92 (95% CI 0.68 to 1.24) and 0.83 (95% CI 0.65 to 1.07) for other autistic spectrum disorders. No association between age at vaccination, time since vaccination or date of vaccination and development of autism was found.

The retrospective cohort study by Fombonne 2001 tested several causal hypotheses and mechanisms of association between exposure to MMR vaccination and pervasive development disorders (PDDs, Table 9). The population was made up of three cohorts of participants; one was of older children acting as the control (pre-MMR vaccination introduction). The authors concluded that there was no evidence that PDDs had become more frequent, the mean age at parental concern had not moved closer to the date of exposure to MMR vaccination, there was no evidence that regression with autism had become more common, parents of autistic children with regression did not become concerned about their child in a different time frame from that of children without regression and children with regressive autism did not have different profiles or severity to those in the control group. Nor was there evidence that regressive autism was associated with inflammatory bowel disorders.

The retrospective cohort study by Uchiyama 2007 assessed the association between exposure to MMR vaccination and regression in autistic spectrum disorders (ASD). Participants were children with an ASD diagnosis (Table 9) from a private paediatric psychiatric clinic located in Yokohama city, Japan (Yokohama Psycho-Developmental Clinic, YPCD), that has become recognised as a centre for ASD. For study purposes, cases of ASD in patients born between 1976 and 1999 were considered (n = 904). They were classified according to the chance of having received the MMR vaccine as follows.

  • 1.
    Pre-MMR vaccine generation: born between January 1976 and December 1984, n = 113.
  • 2.
    MMR vaccine generation: born between January 1985 and December 1991, n = 292.
  • 3.
    Post–MMR vaccine generation with an age of one to three years old after 1993 when the MMR vaccination programme was terminated, n = 499.

For 325 out of the 904 identified ASD cases, a regression in ASD could be assessed. Data were analysed in different ways.

Within the MMR vaccine generation group, OR estimates were calculated considering the cases of deterioration observed in children who received the MMR vaccine from the MCH handbook (15/54) and the number of regression observed among participants who did not receive the MMR vaccine (45/132), after exclusion of those with unknown vaccination status (89). Authors reported an OR of 0.74 (95% CI 0.35 to 1.52, P = 0.49) in patients who received the MMR vaccine versus no MMR vaccination in the MMR period.

Furthermore, the OR estimate was calculated considering as the control group (not MMR vaccinated) also both pre- and post-MMR generation groups. Estimates were again not significant (OR 0.626; 95% CI 0.323 to 1.200). Comparison of regression cases observed within the MMR generation group (independent from documented vaccination status) with that observed in pre-MMR, post-MMR and pre- plus post-MMR groups did not provide statistically significant OR estimates.

Case-control studies

The risk of an association between the MMR vaccine and autism was investigated in three case-control studies (DeStefano 2004; Mrozek-Budzyn 2010; Smeeth 2004).

The study by Smeeth 2004 assessed the association between exposure to the MMR vaccine and the onset of autism and other PDDs (Table 9). The study was based on data from the UK's General Practice Research Database (GPRD) which was set up on 1 June 1987. The authors concluded that their study added to the evidence that MMR vaccination was not associated with an increased risk of PDDs. The OR for the association between MMR vaccination and PDDs was 0.78 (95% CI 0.62 to 0.97) for the non-practice matched control group and 0.86 (95% CI 0.68 to 1.09) for the practice matched control group. The findings were similar when analysis was restricted to children with a diagnosis of autism only, to MMR vaccination before their third birthday, or to the period prior to media coverage of the hypothesis linking MMR vaccination with autism.

DeStefano 2004 compared the distribution of ages at first MMR vaccination in children with autism (cases, Table 9) and controls, divided into three age strata: up to 18, 24 and 36 months. The authors concluded that there was no significant difference between cases and controls in the age at first vaccination up to 18 months (adjusted OR 0.94; 95% CI 0.65 to 1.38) and 24 months (adjusted OR 1.01; 95% CI 0.61 to 1.67); but more cases received MMR vaccination before 36 months (adjusted OR 1.23; 95% CI 0.64 to 2.36; unadjusted OR 1.49; 95% CI 1.04 to 2.14), possibly reflecting the immunisation needs of children in a surveillance programme.

In the study by Mrozek-Budzyn 2010 cases of autism in children aged between two and 15 years were identified by means of general practitioners' records from Małopolska Province in southern Poland (Table 9). For each case, two controls matching for birth year, gender and practice were selected. A total of 92 cases with childhood or atypical autism and 192 matched controls were included. Estimate OR were calculated considering vaccine exposure (MMR or monovalent measles) before autism diagnosis or before symptoms onset separately in univariate and multivariate analysis (this latter balanced for mother age ≥ 35 years, gestation time ≤ 38 weeks, medication during pregnancy, perinatal injuries and five-minute Apgar score). In multivariate analysis, administration of MMR vaccine before the diagnosis was associated with a relevant reduced risk of autism (OR 0.17; 95% CI 0.06 to 0.52; P = 0.002); this association was not confirmed when exposure before symptom onset was considered (OR 0.42; 95% CI 0.15 to 1.16). Risk of autism was significantly lower for MMR vaccinated children when compared with children immunised with single component measles vaccine, both before diagnosis (OR 0.47; 95% CI 0.22 to 0.99) and symptom onset (OR 0.44; 95% CI 0.22 to 0.91).

Time-series studies

Fombonne 2006 analysed the trend of pervasive developmental disorders (PDDs) prevalence in cohorts born from 1987 to 1998 attending a school board in the south and west parts of Montreal (n = 27,749 on 1 October 2003). The relationship between PDD prevalence trends and MMR vaccination coverage through each birth cohort was assessed. Children with PDDs (n = 180) were identified from a special list that was filled with data of children identified by code 51 (autism) and by code 50 (autism spectrum disorder) to allow the schools to receive incremental funding. The authors reported that while a significant trend toward a decrease in MMR uptake through birth cohorts from 1988 to 1998 (X2 for trend = 80.7; df = 1; P < 0.001) could be assessed, a significant increase in rates of PDDs from 1987 to 1998 was found (OR 1.10; 95% CI 1.05 to 1.16; P < 0.001). By comparing the rate of increase in PDDs prevalence between the one-dose and two-dose period, no statistically significant differences were detected.

A Japanese study (Honda 2005) assessed the trend of autistic spectrum disorders (ASDs) incidence among birth cohorts from 1988 to 1996 (Yokohama city, Central Japan) up to seven years of age, in relation to the decline of MMR vaccination coverage in the same birth cohorts, i.e. before and after termination of MMR vaccination programmes in children (1993). Through examination of risk factor analysis with conditional regression, a significant increase in cumulative incidence of all ASDs through birth cohorts from 1988 to 1996 has been observed (χ2 = 45.17, df = 8, P < 0.0001). This trend was different before and after the 1992 birth cohort: considering the 1996 birth cohort as a reference, incidence of all ASDs was significantly lower until 1992 and was not different after 1993. A significant increased incidence could be assessed also when outcomes definition of childhood autism (χ2 = 31.86, df = 8, P < 0.0001) or other ASD (χ2 = 19.25, df = 8, P = 0.01) were considered. The authors concluded that causal hypothesis involving the MMR vaccine as a risk factor was not supported by the evidence because the ASD incidence continued to increase even if the MMR vaccination programme was terminated.

Self controlled case series

In the study by Makela 2002, already described in the section relative to neurological diseases (see above), an attempt to evaluate the association between MMR vaccination and hospitalisation for autism was made (Table 9). Unlike encephalitis and aseptic meningitis, instead of a risk period, changes in the overall number of hospitalisations for autism after MMR vaccination, including only the first hospital visit during the study period, were considered. Times between immunisation and hospitalisation observed among the 309 hospitalisations for autism following MMR immunisation were very wide (range three days to 12 years and five months), their numbers remained relatively steady during the first three years and then decreased gradually. No cluster intervals from vaccination could be identified. Authors concluded that there was no evidence of association, but did not report statistical data supporting this conclusion.

One other self controlled case series study (Taylor 1999) assessed clustering of cases of autism by post-exposure periods in a cohort of 498 (with 293 confirmed cases) children. The authors reported a significant increase in onset of parental concern at six months post-vaccination, but no significant clustering of interval to diagnosis or regression was found within any of the considered time periods (two, four, six, 12, 24 months).

Asthma
Cohort studies

The cohort study by McKeever 2004 used an historical birth cohort of children (1988 to 1999) consisting of 29,238 children of both sexes aged between 0 and 11 years and identified through the West Midlands General Practice Research Database (GPRD), to investigate the association between MMR and diphtheria, polio, pertussis and tetanus (DPPT) vaccination and asthma or eczema (Table 11). Incident diagnoses of asthma/wheeze and eczema (Table 11) were identified using the relevant Oxford Medical Information System (OMIS, derived from ICD-8) and Read codes (a hierarchical code used in GP practices in England). Association with MMR vaccine exposure and risk of asthma and eczema has been assessed by univariate analysis. Correspondent crude hazard ratios (HR) were 3.51 (95% CI 2.42 to 5.11) and 4.61 (95% CI 3.15 to 6.74) for asthma and eczema, respectively. Stratifying for GP consultation frequency in the first 18 months, HR estimates remain significant only for the subgroup with lower consulting frequency (zero to six times in the first 18 months) and not for the other subgroups (seven to 10 times, 11 to 16 times and more than 16 times): HR 7.18 (95% CI 2.95 to 17.49) for association between MMR vaccination and asthma; HR 10.4 (95% CI 4.61 to 23.29) for association between MMR vaccination and eczema, respectively.

One other cohort study (DeStefano 2002) used data from the Vaccine Safety Datalink (VSD) project in order to detect a possible association between asthma and some infant vaccines, among which was MMR (Table 11). For the study, a population of children who were enrolled in four Health Maintenance Organisations (HMOs) from birth until at least 18 months of age (to a maximum of six years) between 1991 and 1997 was considered (n = 167,240). Asthma cases (n = 18,407) were identified by reviewing computerised databases maintained at each HMO (see Table 11 for case definition). Ascertainment of vaccine exposure was performed by using computerised immunisation tracking systems maintained by each of the HMOs. Out of the 167,240 included participants 12,426 were not immunised with the MMR vaccine. Proportional hazard regression does not show a significant association between asthma and MMR vaccination (RR 0.97; 95% CI 0.91 to 1.04).

Person-time cohort studies

Association between asthma hospitalisation, anti-asthma medications (Table 11) and MMR vaccine exposure was tested on Danish birth cohorts from 1991 to 2003 in the Hviid 2008 study, by using the Danish Civil Registration System. Each participant recorded in the register had an identification number, that allowed a link to data contained in other national registers (Danish National Hospital Register, Danish Prescription Drug Database and National Board of Health). MMR vaccination status was considered as a time-varying variable and individuals could contribute to person-time as both unvaccinated and vaccinated participants. MMR vaccination is protective against all asthma hospitalisation (RR 0.75; 95% CI 0.73 to 0.78); the protective effect of vaccination was greater in younger children (no more significant when the vaccine was administered after 18 months of age), in those with the longest time spent at the hospital (18 days to one year), in girls, in low birth-weight children, in children with one older sibling and in those living in rural areas. The vaccination was also protective against hospitalisation for severe asthma (RR 0.63; 95% CI 0.49 to 0.82), even if estimates were not significant within the following stratifications: age three or four years; fully immunised children; low hospitalisation propensity; male sex; birth weight below 2499 g or above 4000 g; birth order >/= three; birth in the capital or in a rural area. Total use of anti-asthma medications was less frequent among participants immunised with MMR (RR 0.92; 95% CI 0.91 to 0.92). No reduction in use (all medications) was observed for participants vaccinated at ages between 23 and 26 months (RR 1.00; 95% CI 0.98 to 1.01) or at 27 months or later (RR 1.01; 95% CI 0.99 to 1.03). Considering single classes of medication in the unstratified study population, these data were confirmed with the exception for systemic b2-agonists, for which reduction in use could not be observed (RR 1.02; 95% CI 1.01 to 1.02). Considering only the first use of any anti-asthma medication in the unstratified population, the RR was 0.93; 95% CI 0.92 to 0.94.

Leukaemia

The case-control study of Ma 2005 was realised within the Northern California Childhood Leukaemia Study (NCCLS) and assessed whether vaccination with MMR (and other vaccines) plays a role in the aetiology of leukaemia. In NCCLS (active since 1995) incident cases of newly diagnosed leukaemia in children aged between 0 and 14 years and ascertained from major paediatric clinical centres within 72 hours after diagnosis were collected (Table 12). Analyses had been carried out for both total leukaemia cases and control (323 and 409, respectively) and for acute lymphoblastic leukaemia (ALL) subset (282 cases and 360 controls). Considering leukaemia as case definition, OR estimates for any MMR dose before the reference date in all populations was 1.06 (95% CI 0.69 to 1.63). Considering ALL as case definition the OR estimate for any MMR dose before the reference date in all populations was 0.87 (95% CI 0.55 to 1.37).

Hay fever

Two case-control studies (Bremner 2005; Bremner 2007) investigated the risk of hay fever in MMR-vaccinated children in the UK (using the same data source).

Bremner 2005 focused particular attention on the timing of MMR vaccination to identify a critical period for MMR immunisation and hay fever risk (see Table 13 for definition). The nested case-control study was conducted within two large databases, the General Practice Database (GPRD) and Doctors' Independent Network (DIN) and involved 7098 hay fever cases and controls. After performing a conditional logistic regression the authors reported that infants who received MMR vaccination did not have a greater or lesser risk of developing hay fever than unvaccinated children. MMR unvaccinated children compared with vaccinated in month 14 (base group) had an OR of 0.79 (95% CI 0.78 to 1.08). A reduced risk of hay fever was noted after completing MMR after two years of age (OR 0.62; 95% CI 0.48 to 0.80).

Bremner 2007 specifically investigated if exposure to MMR vaccination during the first grass pollen season of life influences the risk of hay fever more than any other time of the year. The study was conducted within GPRD and DIN Databases and involved 7098 hay fever cases matched with controls. The risk of later hay fever following exposure to MMR vaccine within the first grass pollen season of life was not statistically different from that observed when MMR administration occurred outside of it (OR 1.05; 95% CI 0.94 to 1.18; P = 0.38).

Type 1 diabetes

Hviid 2004 was a retrospective cohort study carried out in Denmark aiming to evaluate if there was an association between childhood vaccinations and the onset of type 1 diabetes. A cohort of children born from 1 January 1990 to 31 December 2000 from the Danish Civil Registration System was individuated. The Danish Civil Registration System identified with a unique number all people living in Denmark. This number made it possible to obtain linked information on vaccination, diagnosis of type 1 diabetes (Table 14), the presence or absence of siblings with type 1 diabetes and potential confounding factors. The vaccination data were obtained from the National Board of Health, where the General Practitioners reported data. The results of this study do not sustain the hypothesis that there is a link between vaccinations and type 1 diabetes (measles, mumps and rubella (all children): rate ratio 1.14; 95% CI 0.90 to 1.45).

Gait disturbance

Association between MMR vaccination and gait disturbance was assessed by means of a self controlled case series study (Miller 2005) and considered as cases hospital admissions or general practice consultations in children within the Thames regions of England. Hospital admission cases were obtained from hospital computerised records for the period April 1995 to June 2001, considered those relative to children aged 12 to 24 months with ICD-10 diagnoses related to acute gait disorder (G111, G112, G25, R26, R27, R29, H55 and F984). Cases were validated by reviewing hospital case notes and grouped into five categories (Table 15). Vaccination history of cases was obtained from immunisation records. In all, 127 cases with available immunisation status were identified. Out of these, 65 belonged to category 4 (i.e. non-ataxic, non-viral origin) and were excluded from analysis. No cases corresponding to category 1 definition were found. Relative incidence (RI) within and outside post-vaccination time risk (0 to 30 and 31 to 60 days) was calculated after age stratification in one-month intervals. RI estimates for pooled two, three and five categories were not statistically relevant (RI 0.83; 95% CI 0.24 to 2.84 for 0 to 30 days risk time and RI 0.20; 95% CI 0.03 to 1.47 for 31 to 60 days risk time).

As gait disturbance does not require hospitalisation, authors carried out a further analysis based on cases observed in General Practices using the General Practice Research Database (GPRD) as the source, and considered children aged 12 to 24 months, born between 1988 and 1997. Read and OXMIS codes indicating a possible consult for gait disturbance were identified in GPRD by mapping ICD-9 codes and by searching keywords 'ataxia', 'gait', 'co-ordination', 'mobility' and 'movement'. Diagnoses were grouped into six categories (Table 15). Vaccination history was obtained from prescription records. In all, 1398 children with diagnoses A-F and known immunisation history were included. Since, in the authors' opinion, a vaccine-specific effect would appear one week after immunisation (an excess of B and C diagnoses was observed on vaccination day) the risk period zero to day five was separately considered. In any other considered risk periods (six to 30, 31 to 60 and six to 60 days after MMR immunisation) RI did not have a statistically relevant increased incidence. Early administration of thiomersal-containing DTP/DT vaccine did not influence this estimate.

Crohn's disease and inflammatory bowel disease

Two studies (Davis 2001; Seagroatt 2005) considered the hypothesis of an association between MMR vaccination and Crohn's disease (CD) or inflammatory bowel disease and ulcerative colitis (Table 16).

One case-control study (Davis 2001) was conducted in the United States using data from the Vaccine Safety Datalink (VSD) to evaluate if MMR and measles-containing vaccines increased the risk for inflammatory bowel disease (IBD). Medical records were reviewed and cases were classified according to the type of disease (CD, ulcerative colitis/proctitis or IBD). The authors concluded that exposure to the MMR vaccine was not associated with an increase risk of CD (OR 0.4; 95% CI 0.08 to 2.0), ulcerative colitis (OR 0.80; 95% CI 0.18 to 3.56) and all IBD (OR 0.59; 95% CI 0.21 to 1.69).

One ecological study (Seagroatt 2005) investigated a possible association between the MMR vaccine and CD. Using English national data on emergency admissions, the authors compared admissions for CD in populations with a vaccination coverage of ≥ 84% with populations with a MMR vaccination coverage of ≥ 7%. The estimated rate ratio for the MMR vaccination programme was 0.95 (95% CI 0.84 to 1.08). Even if age-specific rates of emergency admission for CD increased during the time considered in the study (April 1991 to March 2003), this trend seems not to have been influenced by the introduction of the MMR vaccine. The introduction of the MMR vaccination programme in England did not increase the risk of CD.

Demyelinating diseases

The possible association between the MMR vaccine and demyelinating diseases was assessed in two studies, using the same population data set.

Ahlgren 2009a is a cohort study carried out in the Gothenburg area (Swedish west coast, 731,592 residents on 31 December 2000). Cases of multiple sclerosis (MS) and clinically isolated syndrome (CIS) in participants born between 1959 and 1990 with onset at ages between 10 and 39 years before July 1984 among Gothenburg residents were considered, corresponding to a total of 5.9 million person-years of observation (Table 17). The incidence of probable or definite MS (Poser criteria) and CIS (372 and 162 cases, respectively) was analysed in corresponding measles, mumps and rubella vaccination programmes, by selecting four birth cohorts corresponding to the first years of a specific vaccination programme.

  • Birth cohorts 1962 to 1966 (102 MS cases): administration of the monovalent rubella vaccine to 12-year old girls in 1974.

  • Birth cohorts 1970 to 1973 (62 MS cases): administration of the MMR vaccine at 12 years of age (1982).

  • Birth cohorts 1974 to 1978 (37 MS cases): administration of monovalent measles vaccine in pre-school children. (It was already introduced in 1971, thus adequate coverage was reached only for those born in 1974 and onwards). About 90% of subjects from these birth cohorts received the MMR vaccine at 12 years of age.

  • Born between July 1981 and June 1984 (five MS cases): administration of the MMR vaccine at 18 months and at 12 years of age.

The incidence of MS and CIS within each birth cohort was compared to that calculated for the preceding ones, including that of 1959 to 1961, corresponding to the pre-vaccine era. No significant changes in age and gender-specific incidence of MS between selected and preceding selected cohorts has been observed.

Authors use the same population incidence data in order to assess an association between MMR exposure and MS onset by means of a case-control design (Ahlgren 2009b). Similar to the cohort study, case definitions included MS or CIS according to Poser's criteria, residence in Gothenburg, birth date between 1959 and 1986, and disease onset from the age of 10 years onwards. For analysis of vaccine exposure, only cases and controls who attended the sixth grade in school (12 years) within the study area, for whom CHSH records were available (206 cases and 888 controls) were included. Estimates (OR) were calculated by using a logistic model including sex and year of birth, using MMR vaccine exposure as a dependent variable. Exposure to the MMR vaccine (in all) was not statistically different among cases and controls (OR 1.13; 95% CI 0.62 to 2.05).

Bacterial and viral infections

The incidence of viral and bacterial infection following MMR administration was investigated by means of a self controlled case series design by Stowe 2009. Episodes of hospitalisation for bacterial or viral infections occurring in children aged between 12 and 23 months, were identified by consultation of computerised hospital admission records from North, East and South London, Essex, East Anglia, Sussex and Kent using ICD-9 or ICD-10 codes and covering the time between 1 April 1995 and 1 May 2005 (2077 admission in 2025 children).

Bacterial infections were characterised as lobar pneumonia or invasive bacterial infection, whereas those of viral aetiology were encephalitis/meningitis, herpes, pneumonia, varicella zoster or miscellaneous virus (Table 18). Admissions were linked to date of MMR (and meningococcal) immunisation resulting from records held on child health systems. 'At risk' time periods were considered the intervals of 0 to 30, 31 to 60 and 61 to 90 days after immunisation. Admissions for lobar pneumonia were less frequent in the time between 0 and 30 days after MMR immunisation (RI 0.65; 95% CI 0.48 to 0.86) or during the 90 days following immunisation (RI 0.77; 95% CI 0.64 to 0.93). No significant differences were found comparing incidence of invasive bacterial diseases in risk periods with that of background period. Regarding viral infections, a significantly lower incidence of varicella zoster was assessed within 30 days after MMR immunisation (RI 0.58; 95% CI 0.34 to 0.99). However, RI estimates were not statistically relevant for the 31 to 60, 61 to 90 and the whole 0 to 90 days risk periods. On the contrary, the risk of hospitalisation due to herpes infection was higher in the risk time interval between 31 and 60 days after MMR vaccine administration (RI 1.69; 95% CI 1.06 to 2.70) but this risk was not significant considering the other risk periods. Hospitalisation risk for encephalitis/meningitis, viral pneumonia and miscellaneous viral infections, did not reach statistical significance in any of the considered risk time intervals. No significant risk of both bacterial and viral infection has been detected following concomitant administration of MMR and meningococcal C vaccine.

Discussion

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Characteristics of studies
  11. Data and analyses
  12. Additional Tables
  13. Appendices
  14. Feedback
  15. What's new
  16. History
  17. Contributions of authors
  18. Declarations of interest
  19. Sources of support
  20. Differences between protocol and review
  21. References

Summary of main results

MMR vaccination would be highly effective (≥ 95%) in preventing clinical measles cases in preschool children and estimates were similar for each of the two measles strains with which participants had been immunised (Schwarz or Edmonston-Zagreb, one cohort study, n = 2745). The MMR vaccine (unspecified composition) is also about 98% effective in preventing laboratory-confirmed cases in children and adolescents (one cohort study, n = 184). Effectiveness in preventing secondary measles cases among household contacts was 92% for one and 95% for two vaccine doses (one cohort study, n = 175).

Effectiveness of at least one dose of a Jeryl Lynn-containing MMR vaccine in preventing clinical mumps cases in children and adolescents has been estimated between 69% and 81% (one cohort and one case-control study, n = 1656). Effectiveness of Jeryl Lynn containing MMR in preventing laboratory-confirmed mumps cases in children and adolescents was estimated to be between 64% to 66% for one and 83% to 88% for two vaccine doses (two case-control studies, n = 1664). At least one dose of Urabe strain-containing MMR is 70% to 75% effective in preventing clinical mumps (one cohort and one case-control study, n = 1964) and 87% effective against laboratory-confirmed mumps (this last estimate was provided from only one small cohort study with high bias risk, n = 48). Vaccination with MMR prepared with Urabe strain has demonstrated to be 73% effective in preventing secondary mumps cases (one cohort study, n = 147). In any case, there was an acceptably high effectiveness of the vaccine prepared only with Urabe or Jeryl Lynn strain but not so for that containing Rubini strain.

We found no studies assessing effectiveness of MMR against rubella.

Association with aseptic meningitis is confirmed for MMR vaccines containing Urabe and Leningrad-Zagreb mumps strains on the basis of two very large time-series studies with moderate risk of bias and carried out on about 1,500,000 children aged one to 11 years, assessing a significant increased risk in the time between one and 10 weeks after immunisation, peaking within the third or fifth week. Association was not significant for vaccines prepared with mumps Jeryl Lynn strains, as it results from one cohort and one self controlled case series studies.

Due to the results of a well conducted, very large person-time cohort study involving 537,171 children between three months and five year of age, febrile seizure (as first or as recurrent episode) has been found to be associated with MMR vaccine (prepared with Moraten, Jeryl Lynn and Wistar RA) within two weeks after administration in preschool Danish children.

In children aged 12 to 23 months, association with febrile convulsion six to 11 days after immunisation, would have been assessed for MMR containing both Jeryl Lynn or RIT 4385 mumps strains in a self controlled case series study with moderate bias risk (n = 894).

Increased risk of severe illness with fever and convulsions in children aged 12 to 35 months within six to 11 days after MMR exposure was assessed in one further self controlled case series study in which the vaccine strain composition was not reported (n = 107).

Association with acute or idiopathic thrombocytopaenic purpura within six weeks from immunisation was assessed in four studies (two case-controls, n = 2450, one self controlled case series, n = 63) but vaccine composition was not described in any of the studies.

Based on the identified studies, no significant association could be assessed between MMR immunisation and the following conditions: autism, asthma, leukaemia, hay fever, type 1 diabetes, gait disturbance, Crohn's disease, demyelinating diseases, bacterial or viral infections.

Overall completeness and applicability of evidence

External validity of included studies was also low. Descriptions of the study populations, response rates (particularly in non-randomised studies), vaccine content and exposure (all important indicators of generalisability) were poorly and inconsistently reported. In addition, inadequate and inconsistent descriptions of reported outcomes (a well-known problem (Kohl 2001)), variable observation periods and selective reporting of results contributed to our decision not to attempt pooling data by study design.

Quality of the evidence

We found problematic internal validity in some included studies and the biases present in the studies (selection, performance, attrition, detection and reporting) influenced our confidence in their findings. The most common type of bias was selection bias. We analysed reasons presented by the papers to justify missing data. Despite accepting as 'adequate' explanations such as 'non-response to questionnaire' and 'medical records unavailable', not all reports offered adequate explanations for missing data.

Potential biases in the review process

There are some weaknesses in our review. The age limit of participants, although substantially justified by public health concerns about the effects of vaccination on the developing child, did lead us to exclude some studies only on this basis. Additionally, the methodological quality tools used to assess the ecological, time-series and case-only designs have not to our knowledge been empirically tested. We believe this to have had minimal impact on our findings given the size and nature of the biases present in the design and reporting of the included studies.

The range of differing study designs used by authors is partly a reflection on the lack of control children not exposed to MMR, due to the population nature of vaccination programmes. As MMR vaccine is universally recommended, recent studies are constrained by the lack of a non-exposed control group. This is a methodologically difficulty which is likely to be encountered in all comparative studies of established childhood vaccines. We were unable to include a majority of the retrieved studies because a comparable, clearly-defined control group or risk period was not available. The exclusion may be a limitation of our review or may reflect a more fundamental methodological dilemma: how to carry out meaningful studies in the absence of a representative population not exposed to a vaccine that is universally used in public health programmes. Whichever view is chosen, we believe that meaningful inferences from individual studies lacking a non-exposed control group are difficult to make.

The hypothesis that secondary vaccine failure (waning immunity) could occur and increase over the years after the last immunisation, has been considered in some studies but it needs to be better elucidated. Two studies (Briss 1994; Hersh 1991) carried out in the USA during mumps epidemics on high school student populations having high vaccination coverage (over 97% received at least one mumps-containing vaccine dose before the outbreak), showed that risk of acquiring mumps was higher in participants who were vaccinated at least three (Briss 1994) or five years (Hersh 1991) before the outbreak, than in those who were more recently vaccinated, thus this estimate was not statistically relevant. Linear regression analysis demonstrated no significant trend for increasing mumps attack rates by years, since last vaccination neither after one nor after two mumps-containing vaccine doses (Schaffzin 2007). A Belgian study carried out on pupils from seven kindergartens and primary schools in Bruges city (age range three to 12 years) during a mumps epidemic in 1995 to 1996 (Vandermeulen 2004) estimated that odds of developing mumps increased 27% per one-year increase, from one year after the last MMR immunisation onwards. A case-cohort study (Cortese 2008) carried out at a University in Kansas (USA) during the 2006 outbreak showed that case patients were more likely than their roommates without mumps to have received the second MMR dose more than 10 years before (odds ratio (OR) 2.50; 95% confidence interval (CI) 1.28 to 5.00). Waning immunity may be secondary to a lack of natural exposure (Cortese 2008; Dayan 2008a). The group with the highest mumps incidence during the 2006 outbreak in the USA were college-age youths (18 to 24 years) born during the 1980s, when the spread of mumps was so low that many of them were never exposed to the disease. They probably received a second dose in the early 1990s, when opportunities for booster shots against exposure to wild viruses became increasingly rare (Dayan 2008a). Moreover, the risk of the contracting mumps virus from abroad should be considered, because in several countries, mumps vaccination was not routinely administered (Cohen 2007; Dayan 2008a). Apart from waning immunity it must be taken in account that mumps strains used in vaccine preparation differed phylogenically from those isolated during recent mumps outbreaks (Dayan 2008a; Dayan 2008b). These facts could explain, at least in part, the vaccine failure observed during some mumps outbreaks.

Agreements and disagreements with other studies or reviews

Currently, this is the only review covering both effectiveness and safety issues of MMR vaccines. In agreement with results from other studies and reviews a significant association between autism and MMR exposure was not found. The study of Wakefield (Wakefield 1998), linking MMR vaccination with autism, has been recently fully retracted (The Editors of The Lancet 2010) as Dr. Wakefield has been found guilty of ethical, medical and scientific misconduct in the publication of the paper; many other authors have moreover demonstrated that his data were fraudulent (Flaherty 2011). A formal retraction of the interpretation that there was a causal link between MMR vaccine and autism has already been issued in year 2004 by 10 out of the 12 original co-authors (Murch 2004). At that time (1998) an excessive and unjustified media coverage of this small study had disastrous consequences (Flaherty 2011; Hilton 2007; Offit 2003; Smith 2008), such as distrust of public health vaccination programmes, suspicion about vaccine safety, with a consequential significant decrease in MMR-vaccine coverage and re-emergence of measles in the UK.

Authors' conclusions

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Characteristics of studies
  11. Data and analyses
  12. Additional Tables
  13. Appendices
  14. Feedback
  15. What's new
  16. History
  17. Contributions of authors
  18. Declarations of interest
  19. Sources of support
  20. Differences between protocol and review
  21. References

Implications for practice

Existing evidence on the safety and effectiveness of MMR vaccine supports current policies of mass immunisation aimed at global measles eradication and in order to reduce morbidity and mortality associated with mumps and rubella.

Implications for research

The design and reporting of safety outcomes in MMR vaccine studies, both pre and post-marketing, need to be improved and standardised definitions of adverse events should be adopted. More evidence assessing whether the protective effect of MMR could wane with the time since immunisation should be addressed.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Characteristics of studies
  11. Data and analyses
  12. Additional Tables
  13. Appendices
  14. Feedback
  15. What's new
  16. History
  17. Contributions of authors
  18. Declarations of interest
  19. Sources of support
  20. Differences between protocol and review
  21. References

The review authors gratefully acknowledge the help received from Shelley Deeks, Sulachni Chandwani, Janet Wale, Sree Nair and Peter Morris for their contribution to this 2011 draft updated review. We wish to thank the following for commenting on the previous review draft: Drs Harald Hejbel, Paddy Farrington, Ms Sally Hopewell, Melanie Rudin, Anne Lusher, Letizia Sampaolo and Valeria Wenzel, Bruce Arroll, Lize van der Merwe, Janet Wale and Leonard Leibovici. The original review was funded by the European Union and by the Italian Istituto Superiore di Sanità. This 2011 update was unfunded. The review authors wish to acknowledge Tom Jefferson and Deirdre Price as previous authors.

Characteristics of studies

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Characteristics of studies
  11. Data and analyses
  12. Additional Tables
  13. Appendices
  14. Feedback
  15. What's new
  16. History
  17. Contributions of authors
  18. Declarations of interest
  19. Sources of support
  20. Differences between protocol and review
  21. References

Characteristics of included studies [ordered by study ID]

Ahlgren 2009a
MethodsCohort study
ParticipantsParticipants residents in the great Gothenburg area (Sweden) born between 1959 and 1990
InterventionsDifferent vaccination programmes carried out from 1971 with different vaccines (single-component measle, mumps and rubella vaccine so as with MMR vaccine) having as target population children of different ages
OutcomesIncidence of multiple sclerosis (MS, 4 Poser's criteria) and Clinically Isolated Syndrome (CIS) with onset between 10 and 39 years of age was assessed in birth cohorts immunised within 4 vaccination programmes
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Ahlgren 2009b
MethodsCase-control study
Participants

Cases: participants with multiple sclerosis (MS) or clinically isolated syndrome (CIS) born between 1959 and 1986 and disease onset at age ≥10 years, resident in Gothenburg area (Sweden)

Cases: participants from the same area as the cases (randomly selected from General Population Register) born in the same year as cases

InterventionsMMR vaccination (vaccination with single-component vaccines has been also considered)
OutcomesRisk of MS associated with MMR exposure
NotesSame population as for Ahlgren 2009a
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Beck 1989
MethodsProspective cohort
Participants196 children aged 12 to 14 months
Interventions

MMR containing 4.1 TCID50 of mumps strain L -Zagreb (information about measles and rubella employed strains not reported, n = 103)

versus

Placebo (composition unknown, n = 93)

No information about doses given and route of immunisation

Outcomes

- Local reactions (redness, swelling, tenderness, 30 days follow-up)

- Temperature > 37.5 °C

- Catarrhal symptoms

- Parotid swelling

NotesThe study is reported with minimal details (no population description, no details given on how the groups are selected, how they are assigned, the total population, how measurements are made)
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Benjamin 1992
MethodsRetrospective cohort comparing incidence of joint and limb symptoms in MMR vaccinated children versus non-vaccinated
Participants5017 children between 1 and 5 years
Interventions

MMR vaccine (strains and doses not specified, 1588 participants included in analysis)

versus

No treatment (1242 participants included in analysis)

Outcomes

- Joint complaints, all episodes (arthralgia, possible/probable arthritis)

- Joint complaints 1st ever episodes (arthralgia, arthritis possible or probable, joint total first ever, limb/joint complaint episodes, hospital admission, GP consultation, sore eyes, convulsion, coryza, parotitis, temperature, rash)

Within 6 weeks after immunisation. Data based on a 6-week parental recall questionnaire and clinician home visit

NotesLow response rate in non-immunised group
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Bertuola 2010
MethodsCase-control study
Participants

Cases (n = 387): children aged between 1 month and 18 years of age with acute immune thrombocytopaenia (AIT, defined as platelets count < 100,000/l at admission) recorded between November 1999 and September 2007

Controls (n = 1924): children of the same age, hospitalised during the same period as cases with acute neurological disorders and endoscopically confirmed gastroduodenal lesions were considered as controls

InterventionsMMR vaccine exposure (strain composition not reported)
OutcomesRisk of AIT during the 6 weeks following MMR immunisation
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Black 1997
MethodsCase-control study
Participants

Children 12 to 23 months old from the Vaccine Safety Datalink project. Cases: children with confirmed aseptic meningitis (hospital record, discharge diagnosis and cerebrospinal fluid white blood cell count, n = 59)

Controls: children matching cases by age, sex, HMO membership status (n = 188)

InterventionsVaccination with MMR (Jeryl Lynn strain only), data from medical records
OutcomesRisk of AM within 14 days, 30 days, 8 to 14 days of vaccination
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Black 2003
MethodsRetrospective case-control
Participants

Cases: children enrolled in the General Practice Research Database (GPRD), aged less than 6 years with idiopathic thrombocytopaenic purpura (ITP) (n = 23)

Cases: children matched with controls by age at index date, practice and sex

InterventionsMMR vaccine (from GPRD records)
OutcomesExposure to MMR within 6 weeks or 7 to 26 weeks
NotesControls are not described very well (for example, we do not know from which population they are drawn)
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Bloom 1975
MethodsRCT, double-blind
Participants282 children
Interventions

Three lots of MMR vaccine (lot 1, 2, 3 prepared from Schwarz live attenuated measles virus, Jeryl Lynn live attenuated measles virus, and Cenedehill live attenuated measles virus)

versus

Placebo

Vaccines contained at least 1000 TCID50 for measles and rubella and 5000 for mumps

Outcomes

Observations for intercurrent illness and vaccine reactions made approximately 3 times/child between 7 to 21 days post

- Temperature elevation above normal 1.5 °F

- Rash

- Lymphadenopathy

- Coryza

- Rhinitis

- Cough

- Other

- Local reaction

- Limb and joint symptoms

NotesThe study does not say if all children were observed at least once
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationUnclear riskUnclear
Allocation concealmentUnclear riskUnknown but decoding and tabulation done by computer

Blinding

All outcomes

Unclear riskNot mentioned

Incomplete outcome data addressed

All outcomes

High risk16% of possible total observations missing
Free of selective reportingHigh riskNo explanation for excluding symptom reports are missing
Bremner 2005
MethodsNested case-control studies carried out in United Kingdom (England, Wales, Scotland, Northern Ireland) using 2 large databases of primary care consultations
Participants

Case Certain (Definition I): a child with hay fever diagnosis before 24 months of age, and a second diagnosis of hay fever or a relevant therapy in a subsequent years and with a 3rd diagnosis or a relevant therapy in a further year

Case Certain (Definition II):a child without first diagnosis before 24 months of age, but with a second diagnosis of hay fever or a relevant therapy in subsequent year

Case Less certain (Definition I): a child as a case certain (Definition I) without 3rd diagnosis of hay fever or a relevant therapy in a further year

Case Less certain (Definition II): a child with at least a hay fever diagnosis, even if there are not a second diagnosis or a relevant therapy in a subsequent year

For GPRD Database 2115 Cases Certain and 2271 Cases Less Certain were selected. After exclusion of cases without a suitable control left (2.025 Cases certain and 2171 Cases Less Certain)

For DIN Database 1480 Cases Certain and 1477 Cases Less Certain were selected. After exclusion of cases without a suitable control left 1459 Cases certain and 1443 Cases Less Certain.

Only codex synonymous with “allergic rhinitis” with seasonal variation in recording were permitted

Description of controls: the controls were the children that had not allergic rhinitis or hay fever diagnosis. A suitable control matched a case (1:1) with a practice ID, age , sex and index date (date of a first diagnosis in a 'Less certain' case, or date of confirmatory diagnosis or therapy if a certain case)

Interventions

MMR II (first entries). The time categories for MMR immunisation were: 1st to 13th month, 14th, 15th, 16th, 17th, 18th-24th, 25th month or later

The study considers also association with DTP and BCG vaccines

OutcomesRisk of hay fever at different immunisation ages, using administration at 14 months of age as reference value
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Bremner 2007
MethodsCase-control study
ParticipantsCase of hay fever were children with diagnostic codes and/or treatment for hay fever (see Bremner 2005), after 2 years of age. Control was child that matched for general practice, sex, birth month and follow-up of control "to at least date of diagnosis case"
InterventionsMMR II
OutcomesIncidence of hay fever following MMR exposure was compared inside versus outside the grass pollen season
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Castilla 2009a
MethodsCase-control study
Participants

Cases (n = 241): children aged 1 to 10 years with confirmed (laboratory or epidemiologically) mumps with symptoms of disease between August 2006 and June 2008

Controls (n = 1205): children matched for sex, municipality, district of residence and paediatrician

InterventionsMMR vaccine prepared with Jeryl Lynn mumps strain
OutcomesExposure to MMR vaccine at least 30 days before mumps onset
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Ceyhan 2001
MethodsCCT
Participants1000 infants aged 38 to 40 months from 5 maternity and child health centres in Ankara, Turkey
Interventions

Measles vaccine (Rouvax, Schwarz measles strain, 1000 TCID50) administered at 9 months plus MMR administered at month 15

versus

MMR (Trimovax, Schwarz measles strain, 1000 TCID50; AM 9 mumps strain, 5000 TCID50; Wistar RA/27/3 rubella strain, 1000 TCID 50) administered at months 12 only

Outcomes

- Fever 39.4 °C

- Runny nose

- Cough

- Rash

- Diarrhoea

- Redness

- Swelling

Even if visits by midwife 7, 14, 28 days after vaccination to collect adverse reactions records from parents and every 3 months for 60 months phone call/visit for standard questionnaire were carried out, the time of observation for adverse events is not specified

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskSemi-randomised
Allocation concealmentUnclear riskNot used

Blinding

All outcomes

High riskNot blinded

Incomplete outcome data addressed

All outcomes

Unclear risk10% (50/500) excluded from arm 2 because immunised with different vaccine batch
Free of selective reportingUnclear riskAdverse reactions does not specify the time of observations (7, 14 days) if cumulative, number of events or number of children
Chamot 1998
MethodsRetrospective cohort study
ParticipantsFamily contacts (n = 265) aged up to 16 years of primary confirmed (n = 223) or probable (n = 60) mumps cases notified at Health Service Cantonal of Geneva from 01 February 1994 to 30 April 1996
Interventions

Immunisation with MMR containing different mumps strains:

- MMR-II®, Merck Sharp & Dohme used in Switzerland since 1971 prepared with Jeryl Lynn B mumps strain

- Pluserix®, SmithKline Beecham or Trimovax®, Mérieux, used in Switzerland since 1983 prepared with Urabe Am 9 mumps strain

- Triviraten ®, Berna used in Switzerland since 1986 and prepared with Rubini mumps strain

Unvaccinated contact acted as control group. The vaccination status was obtained from vaccination books

Outcomes

Clinical mumps cases among contacts:

Secondary cases were those diagnosed from 10 to 30 days maximum after a index case

Tertiary cases were those diagnosed from 10 to 30 days maximum after a secondary case

NotesBy participants recruiting paediatricians included the serious cases and excluded household with difficult access to Health Service
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
da Cunha 2002
MethodsBefore/after study to see if there is increased risk of acute aseptic meningitis and mumps in children aged 1 to 11 years in 2 regions of Brazil, Mato Grosso do Sul and Mato Grosso (MS and MT)
ParticipantsAbout 845,000 children aged between 1 and 11 years
InterventionsMMR vaccine containing Leningrad-Zagreb mumps strain (Serum Institute of India Ltd)
OutcomesAseptic meningitis (clinical diagnosis or notification form). 31 (in MT) or 37 (in MS) weeks before and 10 weeks after vaccination campaign
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Davis 2001
MethodsCase-control study
Participants

Vaccine Safety Datalink Project (VSDP), children enrolled from the 6th month

Cases: cases of definite IDB (VSDP, n = 142)

Controls: children matched for sex, HMO and birth year (n = 432)

InterventionsExposure to MMR or other measles containing vaccines (MCV)
OutcomesExposure to MMR or MCV considering any time, within 2 to 4 months, within 6 months
NotesThere are no details of vaccine type - manufacturer, strains, dosage etc
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
DeStefano 2002
MethodsRetrospective cohort (from the Vaccine Safety Datalink Project)
Participants167,240 children between 18 months and 6 years
InterventionsExposure to MMR vaccine (and other vaccines)
Outcomes- Asthma (ICD -9 code 493)
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
DeStefano 2004
MethodsRetrospective case-control
Participants

Cases: children with autism through the Metropolitan Atlanta Developmental Disabilities Surveillance Program (MADDSP, n = 624)

Controls: children matched with cases for age, gender and school attendance (n = 1824)

InterventionsExposure to MMR vaccine (no better defined)
OutcomesMMR exposure in cases and controls stratified for age groups
NotesProbable bias in the enrolment in MADDSP and cases may not be representative of the rest of the autistic population of the city
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Dourado 2000
MethodsBefore/after. Retrospective study of aseptic meningitis. Pre-mass vaccination campaign versus post cases are compared to determine the incidence of aseptic meningitis
Participants452,344 children aged 1 to 11 years (from census)
InterventionsImmunisation with MMR vaccine Pluserix (Smith Klein Beecham, containing mumps strain Urabe)
OutcomesAseptic meningitis periods of 23 weeks pre-vaccination and 10 weeks post were compared
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Dunlop 1989
MethodsProspective cohort
Participants335 healthy children aged about 15 months
Interventions

MMR vaccine Trimovax (Mérieux, containing measles strain Schwarz 1000 TCID50, rubella RA 27/3 1000 TCID50, mumps Urabe Am/9 5000 TCID50)

versus

Measles vaccine Rouvax (Mérieux, containing measles strain Schwarz, 1000 TCID50)

Single dose IM or sc administered

Outcomes

- Rash

- Temperature

- Cough

- Pallor

- Diarrhoea

- Rash nappy

- Injection site bruise

- Earache

- Parotitis

- Lymphadenopathy

- Hospitalisation

Parental daily diary for 3 weeks and weekly for 3 more weeks

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Edees 1991
MethodsRCT, single-blind
Participants420 healthy children aged between 12 and 18 months
Interventions

MMR vaccine Trimovax (Schwarz measles strain, 1000 TCID50 ; Urabe AM/9 mumps strain, 5000 TCID50 ; RA/27/3 rubella strain, 1000 TCID 50)

versus

Measles vaccine Rouvax (Schwarz 100 TCID50)

Administered both in upper arm or leg

Outcomes

- Local symptoms: erythema, induration, pain

- General - specific symptoms: rash, parotitis, conjunctivitis, testicular swelling, arthralgia, arthritis, convulsions

- General non-specific symptoms: temperature, adenopathy, nasopharyngeal disorders, gastrointestinal disorders, restlessness.

Diary completed by parents daily for 3 weeks with a further 3 weekly observations

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationUnclear riskNo description
Allocation concealmentUnclear riskNot used

Blinding

All outcomes

High riskSingle-blind

Incomplete outcome data addressed

All outcomes

Low risk 
Fombonne 2001
MethodsRetrospective cohort
Participants283 children from 3 cohorts of children with pervasive development disorders (PDD)
InterventionsTesting several causal hypothesis between exposure to MMR and developing of PDD
OutcomesAll cases were accurately assessed by a multidisciplinary team and in most cases data were summarised and extracted on standard forms
NotesThe number and possible impact of biases in this study is so high that interpretation of the results is impossible
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Fombonne 2006
MethodsTime-series study
ParticipantsBirth cohorts 1988 to 1998 attending a school board in the south and west parts of Montreal area (N = 27,749 on October 1st, 2003), age 5 to 16
InterventionsMMR vaccination
OutcomesPrevalence trend of Pervasive Development Disorders (PDD) was analysed in relation to MMR vaccination status
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
France 2008
MethodsStudy based on Vaccine Safety Datalink (VSD) investigating association of immune thrombocytopaenic purpura (ITP) and MMR within 42 days after immunisation and assessing association risk by means of both self controlled case series and risk intervals (person-time cohort) methods
ParticipantsChildren aged 12 to 23 months with ITP identified from VSD database for the years 1991 to 2000
InterventionsExposure to MMR vaccine (composition not provided in the study report)
OutcomesITP diagnoses within 42 days from immunisation
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Freeman 1993
MethodsBefore/after. Children due to receive MMR (over a 1-year period) were assigned to receive the vaccine (MMR II) at either 13 or 15 months, depending on the random assignment of their family physician
ParticipantsChildren receiving MMR
InterventionsMMR - MMRII (Merck Sharp & Dohme) administered at either 13 or 15 months
Outcomes

- Cough

- Temperature

- Rash

- Eyes runny

- Nose runny

- Lymphadenopathy

- Hospital admission

Assessed by daily diaries (from 4 weeks before to 4 weeks post vaccination)

NotesOnly ˜67% of the participants (253 out of 376) completed the study. It is not explained how delays in vaccination, for some participants, effect the 8-week diary
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Giovanetti 2002
MethodsCase-control study
Participants

Children and adolescent aged 14 months to 15 years from an Italian Local Health Agency with 12,880 residents of this age group

Cases (n = 139): clinical mumps cases identified by national infectious diseases surveillance system within study area

Controls (n = 139): randomly selected from immunisation registry, matched for birth year and address

InterventionsMMR vaccine exposure at least 30 days before disease onset (registry and phone interviews)
OutcomesAssociation between MMR vaccine exposure and clinical measles within 30 days
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Goncalves 1998
MethodsCase-control study
Participants

Children and adolescents (15 months to 16 years) from Oporto city (Portugal)

Before 1 November 1992 (immunisation with Urabe mumps strain):

Cases (n = 73): clinical mumps cases reported by GPs or hospital doctors during the 1995 to 1996 mumps outbreak

Controls (n = 169): 2 consecutive vaccination records of the same sex, month and birth year as the case, were selected

After 1 November 1992 (immunisation with Rubini mumps strain):

Cases (n = 133): clinical mumps cases reported by GPs or hospital doctors during the 1995 to 1996 mumps outbreak

Controls (n = 236): 2 consecutive vaccination records of the same sex, month and birth year as the case, were selected

InterventionsMMR vaccination. As in vaccination records strain was not reported, authors assume that until 1 November 1992 Urabe strain has been administered, whereas Rubini strain thereafter
OutcomesAssociation between MMR vaccine exposure and clinical measles
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Harling 2005
MethodsCase-control study carried out on children from a religious community in North East London, as a measles outbreak occurred (June 1998 to May 1999). The community was located in a quite small area, with own schools and amenities and was served by 2 GPs. MMR vaccination coverage in the community ranged between 67% and 86%
Participants

Cases (n = 161): clinical or laboratory mumps diagnoses with onset date between 18 June 1998 to 2 May 1999 observed in children aged from 1 to 18 years who belonged to the community, identified through mumps notification from the 2 GPs to the local Consultant Communicable Disease Control (CCDC), searching of the electronic practice list for diagnoses made using the terms “mumps” and successive checking, or verbal reports by community members. For notified cases, laboratory testing (oral fluid for IgM antibody and mumps RNA was made available (at the Enteric, Respiratory and Neurological Virus Laboratory, ERNVL). Altogether 161 mumps cases with onset during the outbreak were observed (142 notified by GPs, 12 through search in the electronic practice list, and 7 reported by parents). One case had no date of onset specified, but illness occurred in the outbreak period. Out of the 142 notified cases, 43 had also laboratory-confirm of infection by IgM radioimmuno assay, PCR detection of mumps RNA or both

Controls (n = 192): controls were selected from children in the community registered with the 2 practices. They were chooses by random samples from electronic practices lists in order to match age and sex profile of the cases. Community membership was ascertained as by cases

Interventions

Vaccination status of cases and controls (together with clinical details of cases) was obtained from practice records and cross-checked with child health immunisation database of the local health authority. Laboratory records were obtained from ERNVL

As vaccination status was available for 156 cases and 175 controls data analysis was carried out on this population. 79 cases and 134 controls received at least 1 dose of MMR vaccine at least 1 month before disease onset

Even if authors did not report any descriptions of the MMR vaccine used for immunisation, it is assumed that mumps component was Jeryl Lynn strain, as it is in use in the UK at study time

Outcomes

Association between measles (clinical defined) and receiving of any doses, 1 or 2 doses of MMR vaccine at least 1 month before disease onset

Association between laboratory-confirmed measles cases and receiving of any doses of MMR vaccine at least 1 month before disease onset

Notes

Composition and description of the administered vaccine was not provided, although it is stated that in UK at study time, MMR vaccine was prepared by using Jeryl Lynn strain

Authors notes that the presence of controls who have had in the past mumps infection (i.e. could have developed immunity without vaccination) and the longer exposition to the outbreak for the cases, could have lead to underestimation of vaccine effectiveness. Other factors other than sex, age, and practices, could moreover have influenced the risk of infection and vaccination status of both cases and controls (e.g. if they were drawn from different residential areas or from groups with different levels of herd immunity and different behaviours)

Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Honda 2005
MethodsTime-series study
ParticipantsBirth cohorts from 1988 to 1996 (Yokohama city, Central Japan) up to 7 years of age (N = 31,426)
InterventionsMMR vaccine exposure
OutcomesAutistic Spectrum Disorders (ASD) incidence before and after termination of MMR vaccination programme in children (1993)
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Hviid 2004
MethodsPerson-time cohort study
ParticipantsDanish birth cohorts 1990 to 2000
InterventionsVaccination with MMR and other vaccines (data from the National Board of Health)
OutcomesType 1 diabetes
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Hviid 2008
MethodsBy using data from the Civil Registration System and considering all children born in Denmark between January 1st, 1991 and December 31st, 2003, the present study investigates the association between MMR immunisation and hospitalisation with asthma diagnosis and use of anti-asthma medication with a person-time cohort design
Participants

For the analysis of association between MMR vaccination and asthma hospitalisation all born in Denmark between 1 January 1991 and 31 December 2003, aged between 1 and 5 years, has been considered within the time period from 1 January 1992 and 31 December 2004 (N = 871,234). Children contributed to person-time follow-up from 1 year of age until age of 5, or until 31 December 2004, death or disappearance/emigration. Follow-up resulted in 2,926,406 person-years. In consequence of several reasons, 15,914 children terminated their follow-up prematurely (5455 because of death, 10,159 emigrated and 300 disappeared)

Follow-up length for the analysis of use of anti-asthma medication reached from 1 January 1996 to 31 December 2004 as data about medical prescription were available only from 1996. A total of 600,938 children contributed to follow-up, corresponding to 1,858,199 person-years. Follow-up was prematurely terminated for 12,552 children (for 4681 because of death, 7710 because of emigration, whereas 161 disappeared).

InterventionsDates of MMR vaccination were obtained from the National Board of Health, NBH (in Denmark routine childhood vaccination could be administered by GPs only, who have to report them to the NBH). Used preparation contains strain Moraten measles strain, Jeryl Lynn mumps strain and Wistar RA 27/3 rubella strain. Authors report that 85% of the 871,234 subjects in the cohort for asthma hospitalisation and 84% of those considered for anti-asthma medication (n = 600,938) received MMR before follow-up end. MMR vaccination status was considered as time-varying variable and individuals could contribute to person-time as both unvaccinated and vaccinated subjects
Outcomes

Asthma hospitalisation (from the Danish National Hospital Register)

Anti-asthma medication (from the Danish Prescription Drug Database)

NotesThere is no information about the time considered between vaccination and disease onset or use of medication (i.e. authors do not provide a definition of MMR vaccinated and not vaccinated status)
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Jonville-Bera 1996
MethodsEcological study to assess the association between MMR and the onset of thrombocytopenic purpura (TP)
ParticipantsData from the French passive survey between 1984 and June 30th 1992. The 60 cases with outcome (TP) were mainly toddlers
InterventionsImmunisation with MMR (n = 4,396,645), measles (n = 860,938), mumps (n = 172,535), rubella DTP and ingle rubella (n = 2,295,307), measles/rubella (n = 1,480,058)
OutcomesCases of thrombocytopenic purpura diagnosed at one of the 30 survey centres after. All case within 45 days from vaccination. Over 8-year period of immunisation
NotesThe denominator is determined by the number of doses distributed
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Lerman 1981
MethodsRCT, double-blind
Participants502 healthy children aged between 15 months and 5 years
Interventions

MMR vaccine (Merck Sharp & Dohme) with HPV - 77: DE - 5 rubella strain

versus

MMR vaccine (MMRII) with Wistar RA 27/3 rubella strain

versus

Measles vaccine (Merck Sharp & Dohme)

VS

Mumps vaccine (Merck Sharp & Dohme)

versus

Rubella vaccine HPV 77: CE - 5

evrsus

Rubella vaccine Wistar RA 27/3

versus

Placebo (vaccine diluent)

One dose subcutaneously

Outcomes

- Local reactions (pain, redness or swelling at the injection site within 4 days after immunisation)

- Temperature > 38 °C at 6 weeks

- Respiratory symptoms (6 weeks)

- Rash (6 weeks)

- Lymphadenopathy (6 weeks)

- Sore eyes (6 weeks)

- Joint symptoms (6 weeks)

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationLow riskAdequate
Allocation concealmentLow riskAdequate

Blinding

All outcomes

Low riskDouble-blind
Lopez Hernandez 2000
MethodsRetrospective cohort study assessing effectiveness of MMR vaccination against clinical mumps on preschool and school children during an outbreak (March-November 1997)
ParticipantsMale children aged between 3 and 15 years attending one scholastic institute in the district of Cartuja y Almanjàyar (n = 775), that had the highest mumps attack rate in the district
InterventionsMMR immunisation (school, vaccination or register by the local Health Centre). Composition and strains not reported
OutcomesParotitis. Clinical defined by surveillance (case definition: unilateral or bilateral swelling of parotids or salivary glands, sensible to tasting, lasting more than 2 days, that appears without apparent cause or without contact with affected subjects)
NotesIt was not possible to assess mumps strain types administered to study population (in Spain Urabe Am 9 strain was used till 1993, it was replaced by Jeryl Lynn and Rubini after that year. Even if cases are those identified by surveillance, there is no description in the report of how it has been performed (e.g. active or passive surveillance ?). In any case, in the paragraph of case definition, authors declare that included cases are only those identified by surveillance and that real cases are unknown (underestimated)
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Ma 2005
MethodsCase-control study
Participants

Cases (n = 323): newly diagnosed leukaemia in children aged between 0 and 14 years and ascertained from major paediatric clinical centres within 72 after diagnosis

Controls (n = 409): for each case 1/2 controls matched for date of birth, gender, Hispanic status (either parent Hispanic), maternal race (white, African American, or other) and maternal county of residence

InterventionsMMR immunisation (no vaccine description) before index date
OutcomesAssociation between MMR exposure and onset of leukaemia or acute lymphoblastic leukaemia (ALL)
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Mackenzie 2006
MethodsCase-control study carried out in a private school in Lothian (Scotland) to evaluate effectiveness of 1 or 2 doses of MMR vaccine
Participants

Cases (n = 20): virologically confirmed mumps cases

Controls (n = 40): participants matched to cases for age, sex, residential status and country source (UK or other)

InterventionsMMR immunisation with 1 or 2 vaccine doses (no description of composition)
OutcomesProtective effectiveness of MMR immunisation against virological confirmed mumps
NotesThe size sample of cases employed was to small for reaching statistical significance, the poor accuracy in reporting vaccination status by parents of some children, the fact that controls had not virological test, the absolute lack information about vaccine composition (e.g. strain employed), the narration done by authors to have matched cases and controls for age, sex, residential status, country source without description of these variables in 2 groups make this study at high risk of bias
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Madsen 2002
MethodsRetrospective cohort
ParticipantsAll Danish children born between January 1991 and December 1998: 537,303
Interventions

MMR vaccine (containing measles strain Moraten, mumps Jeryl Lynn, rubella Wistar RA 27/3)

versus

Pre-vaccination or non-vaccinated person-years

Outcomes

- Autism (ICD-10 code F84.0, DSM-IV code 299.00)

- Autistic-spectrum disorder (ICD-10 codes F84.1 - F84.9, DSM-IV codes 299.10 - 299.80)

NotesThe follow-up of diagnostic records ends one year (31 Dec 1999) after the last day of admission to the cohort. Because of the length of time from birth to diagnosis, it becomes increasingly unlikely that those born later in the cohort could have a diagnosis
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Makela 2002
MethodsPerson-time cohort study
Participants561,089 children aged between 1 and 7 years at the time of vaccination
InterventionsImmunisation with MMR 2 vaccine (Merck, containing measles strain Enders Edmonston, mumps Jeryl Lynn and rubella Wistar RA 27) during a national immunisation campaign
Outcomes

- Encephalitis

- Aseptic meningitis

- Autism

NotesIncidence of outcomes during the first 3 months after immunisation was compared with that in the following period (from 3 to 24 months after immunisation)
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Makino 1990
MethodsProspective cohort
Participants1638 healthy children
Interventions

MMR vaccine MPR (Kitasato Institute, Japan containing measles AIK-C 5000 TCID50 , mumps Hoshino 15000 TCID50 and rubella Takahashi 32000 TCID50)

versus

Measles vaccine (Kitasato Institute, containing measles AIK-C 25000 TCID50)

versus

Mumps vaccine (Kitasato Institute, containing mumps Hoshino 10000 TCID50)

Outcomes

- Temperature, axillary (up to 37.5 °C or up to 39.0 °C)

- Rash (mild, moderate or severe)

- Lymphadenopathy

- Parotitis

- Cough

- Vomiting

- Diarrhoea

Within 28 days after vaccination

NotesInadequate description of the cohorts
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Marin 2006
MethodsRetrospective cohort study carried out in Republic of the Marshall Islands (South Pacific) after a measles outbreak in 2003 to evaluate MMR vaccine effectiveness in contacts aged 6 months to 14 years with household secondary attack rate (SAR) method
Participants72 households (a total of 857 participants) were selected by convenience sampling of measle cases reported in Majuro from 13 July to 7 November 2003. Contacts of these 72 primary cases aged between 6 months and 14 years with available MMR vaccination status were considered for effectiveness analysis (n = 219)
Interventions

MMR vaccine (composition not reported) in 1, 2, 3 or more doses administered

A contact was considered vaccinated if documented record of measles vaccine administration > 4 days before the rash onset of primary case was available. An unvaccinated contact was a person without record of measles vaccination according to criteria in written or electronic records in a centralised electronic database. A person with unknown vaccination status had not immunisation card and his name was not in immunisation record (excluded from analysis)

Outcomes

Measles case defined as a subject who:

1) met the WHO clinical definition for measles (fever, generalised maculopapular rash and cough, coryza or conjunctivitis)

or

2) had a positive test for measles IgM antibody by any serologic assay with the absence of vaccination 6 to 45 days before testing

Primary case: first case of measles in household

Secondary case: a contact (person that resided in household for at least 1 day through the infectious period of primary case - from 4 days before rash to 4 days after) with measles rash onset 7 to 18 days after primary case's rash onset

Non-case: a contact with no clinically apparent disease within 18 days after primary case's rash onset

Data were collected by a “standardized questionnaire” and interviews were conducted at home with household member

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Marolla 1998
MethodsRetrospective cohort study
ParticipantsParticipants were children born between 1 January 1989 and 31 December 1994, whose parents requested an ambulatory visits by their family paediatricians between 15 May and 30 June 1996. 3050 were enrolled, corresponding to about 40% of the children population in the same age range in care by the 20 paediatricians who participated in the study
Interventions

During the time between 15 May and 30 June 1996 (period in which the visits has been performed) the 20 family paediatricians together with children's parents and by considering the content of medical records filled in a schedule, in which following information were collected: personal data, study titre of both parents, type of trivalent MMR vaccine, date of immunisation, practitioner who administered vaccine, onset of measles or mumps disease, eventual hospital admission, diagnostic criteria used and the practitioner who diagnosed the disease. For the cases when vaccination status could not be immediately assessed, parents were required to communicate as soon as possible the data contained in vaccination records

During study time paediatricians received a questionnaire on vaccination modality and on how to store and administer it correctly

Out of the 3050 initially enrolled children, 2099 were vaccinated with 1 of 3 MMR commercial preparations whereas 646 were not vaccinated. A total of 2745 were included in the effectiveness analysis

The remaining 305 participants were excluded because of receiving monovalent vaccine (167), because schedule was compiled with insufficient detail (124), received vaccine after disease onset (6), or contracted measles or mumps before the 15th month of age

Out of the 2099 vaccinated, 1023 received Pluserix ®SKB, 747 Morupar® Biocine, and 329 Triviraten® Berna

Outcomes

Diseases under investigation has been defined as following:

Measles: exanthema lasting for at least 3 days, with fever and/or coryza, and/or conjunctivitis, diagnosed at least 30 days after vaccine administration

Mumps: parotid swelling lasting for at least 2 days diagnosed by a practitioner at least 30 days after vaccine administration

Even if not described, paediatricians who conducted the study, considered as cases those corresponding to these definition from schedule data

Altogether 124 measles cases (10 among vaccinated) and 457 mumps cases (251 among vaccinated) has been observed. 92 (74.2%) measles and 386 mumps cases (84.5%) occurred in the years 1995 to 1996

Notes

Diagnosis of measles and mumps disease was made only on clinical parameters and on the basis of data sampled during interviews and of those present in the medical records by paediatricians

Results have been managed by paediatricians themselves, who were not blind to vaccination status of the children

Mean age at enrolment was not statistical different between not vaccinated and pooled vaccinated groups (about 52 months), but authors do not provide these data (or age stratification) within each vaccine arm (considering age interval and visit time, follow-up time considered could range from 3 to 75 months). Administered vaccine types varied during the time considered for investigation: Pluserix (Schwarz/Urabe AM9) has been more used in the years between 1990 and 1991 and was withdrawn from the mark in 1992. Triviraten (Edmonston-Zagreb/Rubini) was of prevalent use in the years 1992, 1993 and 1994, Morupar (Schwarz/Urabe AM9) in 1995 and 1996. Exposition to disease and time since vaccination could be very different among subjects and this is not taken in account by evaluating effectiveness

Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
McKeever 2004
MethodsCohort study assessing association between MMR and diphtheria, polio, pertussis and tetanus vaccination (DPPT) and asthma or eczema
ParticipantsBirth cohorts 1988 to 1999 identified through the West Midlands General Practice Research Database (GPRD; n = 16,470, aged from 20 months to 11 years, accounting for 69,602 person-years)
InterventionsMMR vaccination (data from GPRD; also data about other vaccination has been considered)
OutcomesIncident diagnoses of asthma/wheeze and eczema were identified using the relevant Oxford Medical Information System (OXMIS, derived from ICD-8) and Read codes
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Miller 1989
MethodsProspective cohort
Participants12023 healthy children aged 1 to 2 years
Interventions

MMR vaccine (Immrawa or Pluserix, both containing measle strain Schwarz, rubella RA 27/3, mumps Urabe 9)

versus

Measles vaccine (not described)

Single dose

Outcomes

- Temperature (2 or more days over 21 days)

- Rash (2 or more days over 21 days)

- Anorexia (2 or more days over 21 days)

- Number of symptoms for 1 day only

(Daily diary completed by parents)

NotesThe study reports that 84% of diaries/questionnaires completed but only analysed 65%
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Miller 2005
MethodsSelf controlled case series
Participants

Children hospitalised with gait disturbance between April 1995 and June 2001 (n = 127, age 12 to 24 months)

Children with gait disturbance resulting from general practice visit (GPRD archive), born between 1988 and 1997 (n = 1398, age 12 to 24 months)

InterventionsMMR immunisation
OutcomesRelative incidence of gait disturbance after MMR immunisation (considered risk periods 0 to 30 to 31 60 days)
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Miller 2007
MethodsSelf controlled case series
ParticipantsChildren aged 12 to 23 months (894) with discharge diagnosis of febrile convulsion (ICD-10 codes R560 or R568)
InterventionsMMR vaccination dose when on age of 12 to 23 months (immunisation records)
OutcomesIncidence of disease during two at risk periods (between 6 to 11 and 15 to 35 days after immunisation)
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Mrozek-Budzyn 2010
MethodsCase-control study
Participants

Cases: 96 children with childhood or atypical autism diagnosis aged between 2 and 15 years from Małopolska Province (southern Poland)

Controls: 192 children matched for birth year, gender and practice to the cases

InterventionsMMR vaccine and monovalent measles
OutcomesAssociation between vaccine exposure before diagnosis or symptoms onset
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Ong 2005
MethodsRetrospective cohort study carried out on children aged between about 5 and 12 years in order to state protection conferred from MMR immunisation (containing different mumps strains) against clinical defined mumps during an outbreak in Singapore in 1999
ParticipantsChildren from childcare centres (n = 2533) and primary schools (n = 2539)
InterventionsMMR vaccination status of each child (MMR or nothing) was obtained from health booklet (updated in Singapore when a child receives vaccination in accordance with the immunisation schedule). The specific strain type (Rubini, Jeryl Lynn, Urabe, or unknown mumps strain) has been identified by matching the batch number of vaccine in health booklet with the record of the vaccine in polyclinic or family doctor's clinic. Even if the number of administered doses was not indicated, we can suppose that only older children could have received a 2nd MMR dose, as it was routinely introduced in January 1998
OutcomesMumps: clinically defined as fever associated with unilateral or bilateral swelling and tenderness of one or more salivary glands, usually the parotid gland. Diagnosed by physician. Serological confirmation was not carried out
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Ong 2007
MethodsRetrospective cohort study carried out in Singapore during a measles outbreak in April to May 2004 in primary 3 and 6 school to evaluate the MMR vaccine effectiveness
ParticipantsStudents (n = 184, age 8 to 14 years) from 5 classes of primary school in Singapore
Interventions

MMR vaccine (no description). Only 1 dose administered. Data about vaccination (date and type vaccine administered) were noted in health booklet of each child and confirmed with the National Immunisation Registry (NIR)

Control: do nothing

OutcomesMeasles cases laboratory-confirmed, defined following the World Health Organization criteria (WHO 2001)
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Park 2004
MethodsCase cross-over. The design divides the study period (1 year of 365 days) into a hazard period (42 days after MMR - or before meningitis as defined by the authors) and a control period of 323 days
ParticipantsChildren aged 13 to 29 months
InterventionsImmunisation with MMR
OutcomesCases of aseptic meningitis before and after immunisation
NotesThere is a likelihood of selection bias which the authors dismiss as they say that moving (probable cause of wrong phone numbers) is not associated with MMR exposure. The missing 27% of hospital records is also worrying
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Peltola 1986
MethodsRCT, double-blind
Participants6086 pairs of twins aged between 14 months and 6 years
Interventions

MMR vaccine (Vivirac, Merck Sharp & Dohme)

versus

Placebo

One 0.5 ml dose subcutaneously administered

Outcomes

- Temperature (< 38.5 °C; 38.6 to 39.5 °C; > 39.5 °C) rectal

- Irritability

- Drowsiness

- Willingness to stay in bed

- Rash generalised

- Conjunctivitis

- Arthropathy

- Tremor peripheral

- Cough and/or coryza

- Nausea or vomiting

- Diarrhoea

Measured by parental completed questionnaire for 21 days - parents given a thermometer

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationUnclear riskUnclear
Allocation concealmentLow riskAdequate

Blinding

All outcomes

Low riskDouble-blind

Incomplete outcome data addressed

All outcomes

Low riskAdequate
Ray 2006
MethodsCase-control study investigating possible relationship between MMR and DTP immunisation and hospital admission for encephalopathy within 60 days. Data from 4 health maintenance organisations (Group Health Cooperative, Washington, Northern and Southern California Kaiser Permanente, Northwest Kaiser Permanente, Oregon and Washington), involving children aged 0 to 6 years, who were hospitalised for encephalopathy or related conditions between 1 January 1981 and 31 December 1995 (from 1 August 1998 for Southern California Kaiser Permanente) were reviewed
Participants

Cases (n = 452): children (aged 0 to 6 years) with encephalopathy, Reye syndrome or encephalitis defined accordingly to definition (see Table 8)

Controls (n = about 1280): for each case up to 3 controls were selected, matching for health maintenance organisation location, age within 7 days, sex and length of enrolment in health plan

InterventionsVaccination status concerning MMR and DTP vaccines exposure of both cases and controls was assessed by vaccination records. Only the neurologist who made the final case diagnosis was blind to vaccination status, not so the abstracter. Exposure to both vaccines was stratified in the results on the basis of the time elapsed between vaccination and hospital admission (0 to 90 days, 0 to 60 days, 0 to 30 days, 0 to 14 days, 7 to 14 days, 0 to 7 days)
OutcomesObserved cases (encephalopathy, Reye syndrome or encephalitis) were further classified considering disease aetiology: known, unknown or suspected but unconfirmed (this latter includes cases in which a diagnosis such a meningitis has not been confirmed by specific laboratory test)
NotesAuthors did not indicate formally how many controls have been included in the analysis. Controls included in each stratification could be calculated from percentages in tables 2, 3, 4. Regarding vaccine exposure, we know only that it has been assessed by means of vaccination record, but any further informations (e.g. vaccine type and composition, number of administered doses) is absent in the report. This is would be an important information, as it would permit to test association with diseases and single vaccine strains: cases were enrolled between 1981 and 1995, during this time different vaccines formulation have been in use
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Robertson 1988
MethodsProspective cohort
Participants319 children aged 13 months
Interventions

MMR vaccine (Mérieux, containing measles strain Schwarz, mumps Urabe AM/9 and rubella Wistar RA 27/3)

versus

Measles vaccine (Schwarz strain)

Allocation by parental choice

Outcomes

- Irritability

- Rash

- Coryza

- Temperature (parental touch)

- Cough

- Lethargy

- Diarrhoea

- Vomiting

- Anorexia

- Conjunctivitis

- Lymphadenopathy

- Parotitis

- Local reactions

- No symptoms

- Paracetamol use

- Seen by GP

- Convulsion

Parental completed diaries of symptoms. 3-week follow-up

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Schlegel 1999
MethodsRetrospective cohort study carried out on children aged between 5 and 13 years in order to assess protective effectiveness of MMR vaccine prepared with different mumps strains (Rubini, Jeryl Lynn, Urabe) during a mumps epidemic in comparison with no vaccination
ParticipantsParticipants were children aged 5 to 13 years from a small village in Switzerland (n = 165). Vaccination coverage in this population was high (95%)
InterventionsImmunisation with MMR vaccine prepared with different mumps strain. 79 children were immunised with Rubini-containing MMR vaccine, 36 with Jeryl Lynn containing MMR vaccine, and 40 with Urabe-containing MMR vaccine. 8 participants were not MMR vaccinated. Vaccine strain was not known for 2 children without mumps, who were excluded from study. Vaccination status was ascertained by study investigators from vaccination certificates. All children received immunisation within 2 years of age
OutcomesA mumps case was defined by viral isolation of mumps virus in a culture, doctor's confirm of diagnosis or if the presence of the typical clinical picture was described in a sibling of a patient with confirmed disease. Investigators who ascertained mumps cases were blind to vaccination status
NotesMany study details are described with insufficient detail present in this brief report (e.g. mumps case definition, onset and duration of the outbreak, methods of cases ascertainment)
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Schwarz 1975
MethodsMulticentre RCT, double-blind
ParticipantsAltogether 1481 healthy children from different countries in North and South America were allocated
Interventions

Three lots of MMR vaccine (Liutrin, Do Chemical containing live attenuated measles strain Schwarz, at least 1000 TCID50; mumps live strain Jeryl Lynn, at least 5000 TCID50; live rubella Cenedehill strain, at least 1000 TCID50)

versus

Placebo

One dose subcutaneously administered

OutcomesAxillary and rectal temperature, rash, lymphadenopathy, conjunctivitis, otitis media, coryza, rhinitis, pharyngitis, cough, headache, parotitis, orchitis, arthralgia, paraesthesia, site adverse events, hypersensitivity. Children were observed for adverse events approximately 3 times each between 7 to 21 days
Notes

- Age restriction (1 to 4 years) was not enforced

- A large number of patients were missing from all observations

Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationUnclear riskNot described
Allocation concealmentHigh riskInadequate

Blinding

All outcomes

Low riskDouble-blind

Incomplete outcome data addressed

All outcomes

High risk 
Seagroatt 2005
MethodsEcological study
ParticipantsEngland population aged between 4 and 18 years between April 1991 and March 2003 (about 11.6 million)
InterventionsIntroduction of MMR vaccination (1988)
OutcomesEmergency hospitalisation for Crohn's disease (CD). Age specific ranges were calculated so as rates in population with at least 84% coverage and that in population with coverage below 7% were compared
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Sharma 2010
MethodsCohort study carried out in Egypt, assessing reaction observed after immunisation with MMR in occasion of compulsory vaccinations
ParticipantsChildren aged 16 to 24 months (n = 73,745) from 9 Egyptian governorates and aged 5 to 7 years (n = 371,184) from 8 Egyptian governorates
Interventions

Immunisation with MMR vaccine containing Leningrad-Zagreb mumps strain (Tresivac, Serum Institute of India)

It contains 1000 CCID50 live attenuated measles Edmonston-Zagreb strains, 5000 CCID50 of mumps strain Leningrad-Zagreb, 1000 CCID50 of rubella strain Wistar RA 27/3 in each 0.5 ml dose. Partially hydrolysed gelatin (2.5%), sorbitol (5%), neomycin (≤ 15μg) and water as diluent belong also to vaccine composition. 24 different lots (EU 615V, EU 618V - EU 640V) were used in the study. Younger children were immunised in the thigh, older in the deltoid

OutcomesPain, redness, swelling, fever, rash, parotitis, arthralgia, lymphadenopathy. Data collected by means of a structured questionnaires for the time within 42 days after vaccination
NotesOne of the main study purpose was to investigate the association between MMR and aseptic meningitis. No disease cases have been identified
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Smeeth 2004
MethodsRetrospective case-control study
Participants

All person born in 1973 or later registered in the General Practice Research Database (GPRD)

Cases: participants with diagnosis of pervasive developmental disorders

Controls: individuals matched to cases by year of birth or by practice registration

InterventionsExposure to MMR vaccination from birth to index date (date of the first diagnosis with PDD)
OutcomesNumber of MMR vaccination among cases and controls prior to PDD diagnosis and prior PDD diagnosis and 3rd birthday
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Stokes 1971
MethodsProspective cohort
ParticipantsAltogether 966 children (334 in the US and 632 in Cost Rica)
Interventions

MMR vaccine (Merck Sharp & Dohme containing measles strain Moraten 1000 TCID50, mumps strain Jeryl Lynn 5000 TCID50, rubella strains HPV - 77 1000 TCID50) 1 dose subcutaneous

versus

No treatment

Outcomes

- Temperature (> 38 °C in US, no range given in Costa Rica)

- Conjunctivitis

- Upper respiratory tract illness

- Lymphadenopathy

- Gastroenteritis

- Fretfulness

- Malaise and anorexia

- Measles-like rash

- Arthralgia (only in Costa Rica)

Follow-up 28 days

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Stowe 2009
MethodsSelf controlled case series
ParticipantsChildren aged 12 to 23 months with hospitalisation for bacterial or viral infections identified from hospital admission records by reviewing ICD-9 or -10 codes (n = 2025)
InterventionsMMR vaccination
Outcomes

- Bacterial infections: lobar pneumonia or invasive bacterial infection

- Viral infections: encephalitis/meningitis, herpes, pneumonia, varicella Zoster, or miscellaneous virus

Relative incidence (RI) of each disease was assessed within specified time risk intervals (0 to 30, 31 to 60, 61 to 90 or 0 to 90 days) after MMR immunisation

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Swartz 1974
MethodsProspective cohort
Participants59 children aged 1 to 6 years (mean about 2 years)
Interventions

MMR vaccine (Merck Institute for Therapeutic Research)

versus

Mumps - rubella vaccine (Merck Institute for Therapeutic Research)

versus

Rubella vaccine (Merck - Meruvax HPV 77-DE5

No information about doses and schedule

Outcomes

- Temperature (37.2 to 38.2; 38.3 to 39.3; over 39.4 °C)

- Lymphadenopathy

- Enanthema

- Conjunctivitis

- Rash

Complaints - any (up to 60 days)

Follow-up 7 to 15 days

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Taylor 1999
MethodsCase-coverage comparing incidence of autistic disorders in 8 health districts in UK
Participants498 children with autism
InterventionsMMR vaccine and, in some cases, measles or MR vaccines identified through a computerised register
OutcomesTypical and atypical autism and Asperger's syndrome. No definition given, but identification of some of the cases was made through ICD 10 codes
NotesThe absence of unvaccinated controls limits the inductive statements that can be made from this study
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Uchiyama 2007
MethodsRetrospective cohort study conducted in Japan, employing data from patients of a private child psychiatric clinic in Yokohama to evaluate association between MMR vaccination and regression in autism spectrum disorders (ASD) and to evaluate the “change over time” in proportion of children who presented regressive symptoms during the pre-MMR (before MMR vaccine programme), MMR (during MMR vaccine programme) and post MMR era (when the programme ceased).
ParticipantsChildren born between 1976 and 1999 with clinical diagnosis of ASD assessed at the Yokohama Psycho-Developmental Clinic (YPDC, n = 904)
InterventionsMMR vaccine containing AIK-C (measles), Urabe AM9 (mumps) and To-336 (rubella) strains
OutcomesASD regression
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Vestergaard 2004
MethodsPerson-time cohort study
Participants537,171 Danish children
InterventionsExposure to MMR vaccine (containing measles strain Moraten, Mumps Jeryl Lynn and rubella Wistar)
OutcomesFebrile seizure (ICD definition) in children aged 3 months to 5 years: cases occurred within 2 weeks after vaccination and cases occurred after this time
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Ward 2007
MethodsSelf controlled case series study carried out to assess whether exposure to MMR and other vaccines (DTP/Hib, MenC) was associated with onset of serious neurological diseases
Participants155 children aged between 2 and 35 months from Republic of Ireland and Britain with serial neurological disease (see outcome definition) and documented vaccination history. Data about cases were collected between October 1998 and September 2001
InterventionsImmunisation with MMR or DTP vaccine. Data were obtained from child's GP by Immunisation Department and Center for Infection. Vaccination history should cover 1 year after disease onset. Authors consider as at risk period the time between 0 and 3 days or 0 and 7 days following DTP, Hib and MenC vaccinations and the time between 6 and 11 days or 15 and 35 days following MMR vaccination
Outcomes

- Severe illness with fever and convulsion

- Encephalitis

(see Table 8 for detailed definition)

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable
Weibel 1980
  1. AIT = acute immune thrombocytopaenia

  2. AM = aseptic meningitis

  3. BCG = Bacillus Calmette-Guérin

  4. DIN = Doctors' Independent Network

  5. DPT = diphtheria, pertussis and tetanus

  6. GPRD = General Practice Database

  7. HMO = Health Maintenance Organisation

  8. IM = intra-muscular

  9. MMR = measles, mumps, rubella

  10. MS = multiple sclerosis

  11. n = number

  12. PCR = polymerase chain reaction

  13. sc = subcutaneous

  14. wks = weeks

MethodsProspective cohort
Participants135 children
Interventions

MMR vaccine (Merck, containing measles strain Moraten, mumps Jeryl Lynn, rubella RA 27/3)

versus

Rubella vaccine (strain RA 27/3)

One dose subcutaneous

Outcomes

- Temperature > 38 °C

- Rash

- Lymphadenopathy

- Arthralgia

- Myalgia

- Anorexia

Follow-up 42 days

NotesNo information given on how the children were distributed between the 3 arms. Sparse detail on safety data collection procedures
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generationHigh riskNot applicable
Allocation concealmentHigh riskNot applicable

Blinding

All outcomes

High riskNot applicable

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. CCT = controlled clinical trial

  2. DTP = diphtheria, pertussis and tetanus

  3. ITP = idiopathic thrombocytopaenic purpura

  4. KD = Kawasaki disease

  5. MMR = measles, mumps, rubella

  6. MS = multiple sclerosis

  7. OPV = trivalent oral poliovirus

Akobeng 1999No original research - review
Andre 1984No direct data on MMR; only observation that it may interfere with varicella vaccine
Anonymous 1982Non-comparative
Anonymous 1997No original data
Anonymous 1999Not original research - review
Anonymous 2004Abstract of Hviid 2004 (included study)
Aozasa 1982Not MMR vaccine
Asaria 2008Review
Autret 1996Epidemiological survey comparing onset of ITP following vaccination with MMR compared to M, M and R
Bakker 2001Authors attribute school mumps outbreak to bad attenuated MMR vaccine lots; uncertain data about relationship between MMR exposure and symptoms onset
Balraj 1995Review on mumps vaccine
Beck 1991Assesses safety of MMR vaccination in children allergic to eggs
Bedford 2010Editorial
Beeler 1996Case series
Benjamin 1991No new research review
Berger 1988aSerology outcomes only
Berger 1988bSerology (seroconversion) outcomes only
Berlin 1983Surveillance data
Bernsen 2008No outcomes
Bhargava 1995Non-comparative
Bonanni 2005Non-comparative
Borchardt 2007Not comparative
Borgono 1973Insufficient data presented
Boxall 2008Non-comparative
Brockhoff 2010Non-comparative
Bruno 1997Compares 2 types of MMR
Buntain 1976Case report
Buynak 1969Several studies - non-comparative
Cardenosa 2006Non-comparative
Castilla 2009bSame study as Castilla 2009a (included study)
Chang 1982No adverse effect data
Chen 1991Individuals over 15 years
Chen 2000Review
Cherian 2010No data
Chiodo 1992Non-comparative
Cinquetti 1994Compares 2 types of MMR
Contardi 1989Non-comparative
Contardi 1992Compares 3 types of MMR
Coplan 2000Does not compare against a single component or do nothing
Coronado 2006Case-fatality rate study
Cox 2009Letter
Curtale 2010Non-comparative
Czajka 2009No comparison: MMR-v versus MMR+V
D'Argenio 1998No safety data
D'Souza 2000Non-comparative
Dales 2001Non-comparative
Dallaire 2009Non-comparative
Dankova 1995No adverse event data
Dashefsky 1990MMR not given independently
Davis 1997MMR not given independently
Dayan 2008aNon-comparative
De Laval 2010Seroprevalence study
Deforest 1986MMR given with DTP and OPV in different schedules
Deforest 1988DTP/OPV plus or minus MMR versus placebo or without MMR
DeStefano 2000Duplicate data
Diaz-Ortega 2010No comparison: MMR versus MMR versus MMR
Dobrosavljevic 1999Case report
Dominguez 2008Surveillance study
Dos Santos 2002MMR versus MMR versus MMR
Doshi 2009Effectiveness of measles-containing vaccines has been assessed, not specifically MMR
Dyer 2010aCommentary
Dyer 2010bCommentary
Ehrenkranz 1975Duplicate data Schwarz 1975
Elphinstone 2000Data free
Englund 1989MMR not given independently
Farrington 1996Non-comparative
Farrington 2001No new data
Fitzpatrick 2007Commentary
Fletcher 2001No data
Garrido L 1992Non-comparative
Geier 2004Uncertain MMR focus, mixed with thimerosal
Gerber 2009Review
Goodson 2010Monovalent measles vaccine
Griffin 1991Non-comparative
Grilli 1992Comparison of different types of measles in MMR
Hilton 2009Content analysis
Hindiyeh 2009No outcomes of interest
Hornig 2008Subjects affected by gastrointestinal disturbance
Hu 2007Non-comparative
Hua 2009Association with KD tested for vaccines other than MMR
Huang 1990No safety data
Ipp 2003Head-to-head of 2 types of MMR
Jiang 2009Non-comparative
Jones 1991Non-comparative
Just 1985Comparison of different types of MMR; CCT with serological outcomes
Just 1986MMR not given independently - comparison of MMR plus or minus varicella vaccine
Just 1987aNot given independently - comparison of MMR plus or minus OPV
Just 1987bComparison of MMR plus or minus DTP
Kaaber 1990Comparison of MMR with or without other vaccine versus other vaccines (DTP and OPV)
Karim 2002Case report
Kaye 2001Non-comparative
Kazarian 1978Case report
Khalil 2005Cross-sectional study
Kiepiela 1991RCT of 2 types of measles vaccine
Kulkarni 2005Review
Kurtzke 1997Case-control of exposure to anything/measles vaccine and MS
Lee 1998Data free
Lee 2007Retrospective analysis of medical records
Lucena 2002No comparator
Maekawa 1991Non-comparative - non-inferential
Maguire 1991Non-comparative
Mantadakis 2010Review
Matter 1995Non-comparative
Matter 1997Seroprevalence study
Meissner 2004Review
Menniti-Ippolito 2007Previous report of Bertuola 2010 (included study)
Miller 1983Non-comparative; egg allergy
Miller 1993Non-comparative
Miller 2001Non-comparative
Miller 2002No new data
Min 1991Compares 2 types of MMR
Minekawa 1974Non-comparative
Mommers 2004MMR and all other childhood vaccines, indistinguishable comparison
Mupere 2006No MMR vaccine
Nalin 1999No data
Nicoll 1998No data
Noble 2003Follow-up of the Madsen et al study with some data about resurgence of measles in Japan after vaccination became optional
O'Brien 1998No data presented
Ong 2006Review
Patja 2000Non-comparative
Patja 2001Non-comparative
Pekmezovic 2004Not about MMR
Peltola 1998Non-comparative case series
Peltola 2007Review
Puvvada 1993Non-comparative case series
Rajantie 2007Non-comparative (unclear study design)
Ramos-Alvarez 1976Duplicate publication of Schwarz 1975
Roost 2004Cross-sectional study
Sabra 1998Data free
Saraswathy 2009Seroprevalence study
Scarpa 1990Non-comparative
Schaffzin 2007Differences between the 2 subpopulations in the study were not taken into account. Partially outside age. Effectiveness was calculated cumulatively for campers (n = 368, age 7 to 15 years, mean 12 years, 366/368 previously immunised with 2 doses of mumps containing vaccine, only 2/368 with one dose) and staff members (n = 139, age 14 to 65 years, mean 21 years, of whom 74, 44, and 21 received respectively 2, 1 or no doses of a mumps-containing vaccine)
Schettini 1989No safety data
Schettini 1990Non-comparative
Schmid 2008Non-comparative
Schwarz 2010No treatment: measles + MMR vaccine
Schwarzer 1998Compares 2 types of MMR
Seagroatt 2003Assesses measles vaccine
Sharma 2004Non-comparative
Shinefield 2002MMR not given independently
Spitzer 2001No data
Stetler 1985DTP vaccine
Stokes 1967No safety data
Stratton 1994Review
Sugiura 1982Data not reported by arm
Ueda 1995Compares 2 types of MMR
Vesikari 1979No new data to review
Vesikari 1984Compares 2 types of MMR
Wakefield 1998Case series
Wakefield 1999aNo comparative data
Wakefield 1999bNo data
Wakefield 2000No comparative data
Walters 1975Redundant publication: Schwarz 1975
Wilson 2003Systematic review
Woyciechowska 1985Not MMR
Yamashiro 1998Children past age limit
Yu 2007Non-comparative

Characteristics of studies awaiting assessment [ordered by study ID]

Arenz 2005
MethodsCohort study
ParticipantsChild household contacts in families with at least 1 mumps case
InterventionsVaccination with measles-containing vaccine
OutcomesMeasles secondary cases
NotesInsufficient information about vaccine composition (if MMR or bivalent) for household contact study. Screening method was used for vaccine effectiveness assessment in Coburg school population aged above 5 years. Many important details are missing
Barlow 2001
MethodsCohort study
ParticipantsChildren (n = 137,457) from 4 Health Maintenance Organisations in USA
InterventionsImmunisation with MMR vaccine
OutcomesRisk of febrile seizure within 0 to 7, 8 to 14, 15 to 30 days after immunisation
Notes 
Barrabeig 2011
MethodsCohort study
ParticipantsSchool children (n = 166)
InterventionsPost-exposure prophylaxis with MMR vaccine
OutcomesMeasles
Notes 
Benke 2004
MethodsRetrospective cohort
ParticipantsYoung adults aged between 22 and 44 years
InterventionsImmunisation with MMR and other vaccines
OutcomesPossible association between vaccination and asthma was tested
NotesOutside of age range
Cohen 2007
MethodsScreening method
ParticipantsChildren (n = 312) with confirmed mumps in England
InterventionsImmunisation with MMR vaccine
OutcomesEffectiveness against mumps diseases
NotesScreening method design (effectiveness is estimated considering the proportion of vaccinated among cases and in the general population)
da Silveira 2002
MethodsSurveillance study carried out in Rio Grande do Sul (Brazil) following an immunisation campaign with MMR vaccine containing Leningrad-Zagreb mumps strain
ParticipantsChildren between 1 and 11 with aseptic meningitis
InterventionsImmunisation with Leningrad-Zagreb MMR vaccine
OutcomesRisk association with aseptic meningitis
Notes 
Dominguez 2010
MethodsScreening method
ParticipantsChildren and adults (n = 381) measles cases
InterventionsImmunisation with MMR vaccine
OutcomesEffectiveness against measles diseases
NotesScreening method (effectiveness is estimated considering the proportion of vaccinated among cases and in the general population)
Huang 2009
MethodsCase-control study
Participants

Cases = 126 undergraduate students with mumps

Controls = 147 controls matched for age, sex, dormitory

InterventionsCase and controls with adequate MMR immunisation (at least 2 doses) were compared in univariate and multivariate analysis
OutcomesRisk factor for developing mumps
NotesOutside of age range
Jick 2010
MethodsCase-control study carried out in England
Participants

Cases = measles cases diagnosed in 1994, age 1 to 19 years, born from 1982 onwards (n = 1261)

Controls = no prior measles, matched to each case on year of birth, gender, general practice attended, index date (n = 4996)

Interventions 
Outcomes 
NotesUnclear MMR or MR exposure. Author was asked about. Further review of the study is needed
Mallol-Mesnard 2007
MethodsCase-control study
ParticipantsCases of acute leukaemia in subjects aged < 15 years residing in France (ESCALE study)
InterventionsVaccination with MMR and other vaccines (diphtheria, tetanus, poliomyelitis, pertussis and others)
OutcomesAssociation of vaccine exposure with acute leukaemia
NotesEffect of exposure to several vaccination (i.e. not MMR only) was evaluated in this study. As data about MMR vaccine were not available from study report, we made an attempt to contact trial authors in order to obtain this information, but no answer was received
Marin 2008
MethodsCohort study
ParticipantsStudent population from 2 colleges in Iowa, USA (n = 2363)
InterventionsImmunisation with MMR vaccine
OutcomesMumps cases following an outbreak
NotesStudy population outside of review's age range
Schultz 2008
MethodsCase-control study
Participants

Cases = 83 children with autistic disorders

Controls = 80 children

InterventionsMMR vaccine administration with or without acetaminophen
OutcomesAssociation of intervention exposure with autistic disorders
NotesThe study evaluated association between acetaminophen and MMR or MMR alone with autistic disorders
Sheppeard 2009
MethodsScreening method
ParticipantsNotified measles cases in children from New South Wales, Australia during 2006 (n = 56)
InterventionsMMR immunisation
OutcomesEffectiveness against measles diseases
NotesScreening method design (effectiveness is estimated considering the proportion of vaccinated among cases and in the general population)
So 2008
MethodsRetrospective cohort study performed following a measles outbreak
ParticipantsPreschool students (n = 152) in Incheon, Korea
InterventionsImmunisation with measles-containing vaccine
OutcomesMeasles cases
NotesArticle in Korean. No translation available
Svanstrom 2010
MethodsPerson-time cohort
ParticipantsChildren born in Denmark from 1995 to 2007 (n = 918,831)
InterventionsMMR vaccination Enders-Edmonston (measles), Jeryl Lynn (mumps) and Wistar RA 27/3 (rubella)
OutcomesPossible association between vaccine exposure and febrile convulsion, idiopathic thrombocytopenic purpura, lymphadenopathy and rash was tested
NotesUnclear design
Wichmann 2007
MethodsRetrospective cohort study
ParticipantsStudents between 10 and 21 years of age (Duisburg, Germany)
InterventionsImmunisation with measles-containing vaccine
OutcomesEffectiveness of vaccination in preventing measles during an outbreak
NotesUnclear if all study population was immunised with MMR or single component vaccines

Additional Tables

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Characteristics of studies
  11. Data and analyses
  12. Additional Tables
  13. Appendices
  14. Feedback
  15. What's new
  16. History
  17. Contributions of authors
  18. Declarations of interest
  19. Sources of support
  20. Differences between protocol and review
  21. References
Table 1. Effectiveness against measles: summary findings from cohort studies
StudyPopulation characteristicsCase definition/findingMMR strain/exposureControlNumber of events/number of exposed Effectiveness estimate VE% (95% CI)Evaluation of bias riskGeneralisability
  1. IgM: immunoglobulin M

  2. MMR: measles, mumps, rubella vaccine

  3. n: number of participants in intervention and control arm

  4. VE: vaccine effectiveness

  5. WHO: World Health Organization

Marolla 1998Children (19 to 67 months) whose parent required a paediatrician visit during a measles outbreak peak

Clinical diagnosis

Patients record and parents interview

Schwarz

n = 329 (Pluserix)

n = 747 (Morupar)

1 dose

Vaccination records

n = 646

not vaccinated

- No measles cases observed among 'Pluserix' recipients (0/19,836 person-months)

- Morupar = 2 cases /12,906 person-months

- Control 114 cases/22,188 person-months

VE = 97% (88% to 99%) for 1 Morupar dose

HighLow
Marolla 1998See above

Clinical diagnosis

Patients record and parents interview

Edmonston-Zagreb (Triviraten)

n = 1023

Vaccination records

n = 646

not vaccinated

- Triviraten = 8 cases/31,329 person-months

- Control 114/22,188 person-months

VE = 95% (90-98) for 1 Triviraten dose

HighLow
Ong 2007Children from primary school in Singapore (aged 8 to 14 years) during a measles outbreak

Clinical with laboratory-confirmation.

Active survey and serological confirmation

Not reported

n = 171

1 dose

Health booklets

n = 13

not vaccinated

- 2 cases/171 vaccinated

- 7 cases/13 unvaccinated controls

VE = 97.8% for 1 dose

HighLow
Marin 2006Household contacts (6 months to 14 years) of primary measle cases

Clinical (WHO definition) or IgM positive antibody of secondary cases

Standardised questionnaires

Not reported

n = 48 (1 MMR dose)

n = 106 (2 MMR doses)

Vaccination records

n = 21

not vaccinated

- 2 secondary cases/48 contacts vaccinated with 1 MMR dose

- 3 secondary cases/106 contacts vaccinated with 2 MMR doses

- 11 secondary cases/21 unvaccinated contacts

VE = 92% (67 to 98) from 1 MMR dose

VE = 95% (82 to 98) for 2 MMR doses

HighLow
Table 2. Effectiveness against mumps: summary findings from cohort studies
  1. MMR: measles, mumps, rubella vaccine

  2. n: number of participants in intervention and control arm

  3. VE: vaccine effectiveness

StudyPopulation characteristicsCase definition/findingMMR-strain/exposureControl

Number of events/number of exposed

Effectiveness estimate VE% (95% CI)

Evaluation of bias riskGeneralisability
Ong 2005Children from childcare centres and primary schools in Singapore, aged 5 to 12 yearsClinical diagnosis. Standard questionnaire filled by trained public health officer or physician diagnoses

Jeryl Lynn

n = 711

1 or 2 MMR doses (health booklet)

n = 614

no vaccination

- Jeryl Lynn = 8 cases/711 vaccinated

- Control = 35 cases/614 unvaccinated

VE = 80.7% (57.8 to 90.8) for at least 1 dose

HighLow
Ong 2005See aboveSee above

Urabe

n = 190

1 or 2 MMR doses (health booklet)

n = 614

no vaccination

- Urabe = 5 cases/190 vaccinated

- Control = 35 cases 614 unvaccinated

VE = 54.4% (from -16.2 to 81.7) for at least 1 dose

HighLow
Ong 2005See aboveSee above

Rubini

n = 1694

1 or 2 MMR doses (health booklet)

n = 614

no vaccination

- Rubini = 150 cases 1694 vaccinated

- Control = 35 cases/614 unvaccinated

VE = -55.3% (from -121.8% to -8.8%) for at least 1 dose

HighLow
Schlegel 1999Children aged 5 to 13 years from a small village in Switzerland

Clinical confirmation after virus isolation or clinical picture observed in sibling of confirmed cases

Parents interview and evaluation by study investigators

Urabe

n = 40

vaccination records

n = 8

not vaccinated

- Urabe = 3 cases/40 vaccinated

- Control = 5 cases/8 unvaccinated

VE = 87% (76 to 94) for at least 1 dose

HighLow
Schlegel 1999See aboveSee above

Jeryl Lynn

n = 36

Vaccination records

n = 8

not vaccinated

- Jeryl Lynn = 5 cases/36 vaccinated

- Control = 5 cases/8 unvaccinated

VE = 78% (64 to 82) for at least 1 dose

HighLow
Schlegel 1999See aboveSee above

Rubini

n = 79

vaccination records

n = 8

not vaccinated

- Rubini = 53 cases/79 vaccinated

- Control = 5 cases/8 unvaccinated

VE = -4% (-218 to 15) for at least 1 dose

HighLow
Marolla 1998Children (19 to 67 months) whose parent required a paediatrician visit during a measles outbreak peak

Clinical diagnosis

Patients record and parents interview

Urabe

n = 329 (Pluserix)

n = 747 (Morupar)

1 dose

vaccination records

n = 646

not vaccinated

- Pluserix = 38 cases/19,433 person-months

- Morupar = 28 cases/12,785 person-months

- Control = 206 cases/25,816 person-months

VE = 75% (65% to 83%) for 1 dose Pluserix

VE = 73% (59 to 82) for 1 dose Morupar

HighLow
Marolla 1998See aboveSee above

Rubini (Triviraten)

n = 1023

One dose

Vaccination records

n = 646

Not vaccinated

- Triviraten = 185 cases/29,974 person-months

VE = 23% (6 to 37) for 1 dose Triviraten

HighLow
Lopez Hernandez 2000Male children aged between 3 and 15 years attending a scholastic institute during a mumps outbreak (March to November 1997)Clinical diagnosis. Cases notified by the Andalusian survey system

Not known

n = 685

vaccination record

n = 38

not vaccinated

- 73 cases/685 vaccinated

- 8 cases/38 unvaccinated controls

VE = 49% (Chi2 test = 3.91, P = 0.047) for at least 1 dose

HighLow
Chamot 1998Children aged up to 16 years from Ginevra were household contacts of primary confirmed mumps cases (clinical or with laboratory confirmation notified by a paediatrician)

Clinical diagnosis of secondary cases

Phone interview

Urabe

n = 75

vaccination records

n = 72

no vaccination

- Urabe = 7 cases/75 vaccinated contacts

- Control = 25 cases/72 unvaccinated contacts

VE = 73.1% (41.8 to 87.6)

Number of doses not specified

ModerateLow
Chamot 1998See aboveSee above

Jeryl Lynn

N = 30

vaccination records

n = 72

no vaccination

- Jeryl Lynn = 4 cases/30 vaccinated contacts

- Control = 25 cases/72 unvaccinated contacts

VE = 61.6 % (-0.9 to 85.4)

Number of doses not specified

ModerateLow
Chamot 1998See aboveSee above

Rubini

n = 83

vaccination records

n = 72

no vaccination

- Rubini = 27 cases/83 vaccinated contacts

- Control = 25 cases/72 unvaccinated contacts

VE = 6. 3% (-45.9 to 39.8)

Number of doses not specified

ModerateLow
Table 3. Effectiveness against mumps: summary findings from case-control studies
  1. CCDC: Consultant in Communicable Disease Control

  2. IgM: immunoglobulin M

  3. MMR: measles, mumps, rubella vaccine

  4. n: number of cases or control participants

  5. PCR: polymerase chain reaction

  6. VE: vaccine effectiveness

StudyPopulation characteristicsCase definition/findingControls/selectionMMR strain/exposure

Number of vaccinated in cases/controls

Effectiveness estimate VE % (95% CI)

Evaluation of bias riskGeneralisability
Harling 2005Children and adolescents aged between 1 and 18 years from religious community in NE London. Mumps outbreak

Clinical diagnosis

n = 156

(GP notification to the local CCDC, mumps diagnoses from electronic practice list, verbal reports by community members)

n = 175 randomly selected and stratified for age and sex from practice listJeryl Lynn 1 or 2 MMR doses received at least 1 month before index date

79/156 cases and 134/175 controls received at least 1 MMR dose

VE = 69% (41 to 84) for at least 1 dose, adjusted for age, sex, practice

ModerateMedium
Harling 2005See above

Laboratory-confirmation of clinical diagnosis

n = 43

- GP notification to the local CCDC

To notified cases, IgM and mumps RNA testing was offered

See aboveSee above

- VE for at least 1 dose = 65% (25 to 84)

- VE for 1 dose = 64% (40 to 78)

- VE for 2 doses = 88% (62 to 96)

All adjusted for age, sex, practice

Proportion of vaccinated in cases and controls not provided

ModerateMedium
Goncalves 1998Children and adolescents (15 months to 16 years) from Oporto (Portugal)

Clinical diagnosis n = 73

Cases reported by GPs or hospital doctors, occurred during the 1995 to 1996 mumps outbreak

n = 169, 2 consecutive vaccination records of the same sex, month and birth year as the case, were selected

Urabe vaccination records

(assuming that before 1 November 1992 MMR mumps Urabe strain was administered)

56/73 cases and 142/169 controls received at least 1 MMR dose

VE = 70% (25 to 88) for at least 1 dose

HighLow
Goncalves 1998See above

Clinical diagnosis n = 133

Cases reported by GPs or hospital doctors, occurred during the 1995 to 1996 mumps outbreak

n = 236 see aboveRubini vaccination records (assuming that after 1 November 1992 MMR mumps Rubini strain was administered)

116/133 cases and 209/236 controls received at least 1 MMR dose

VE = 1% (from -108 to 53) for at least 1 dose

HighLow
Giovanetti 2002Children and adolescent aged from 14 months to 15 years from urban area of Alba and Bra and 10 rural towns (12,880 residents from 0 to 15 years). During 2000 to 2001 epidemic

Clinical diagnosis (cases notified by national infectious diseases surveillance system)

n = 139

- Notified mumps cases

n = 139 randomly selected from immunisation registry, matched for birth year and address

Not specified

Vaccination registry and phone interviews, immunisation should have been received at least 30 days before disease onset

90/139 cases and 111/139 controls received at least 1 MMR dose

VE = 53.7% (20.4 to 73.0) for at least 1 dose

HighLow
Castilla 2009aChildren aged between 15 months and 10 years from Navarre region (Northern Spain) at the time when a mumps outbreak occurred (between August 2006 and June 2008)

Laboratory or epidemiological confirmation of clinical cases: swelling of 1 of more salivary glands for at least 2 days with either laboratory (PCR or IgM positive) or epidemiological confirmation (i.e. epidemiological relation with other laboratory-confirmed or clinical mumps cases)

Obtained from cases notified to the regional health authority n = 241

n = 1205 matched for sex, municipality, district of residence and paediatricianJeryl Lynn 1 or 2 MMR doses received at least 30 days before symptom disease onset. Blinded review of primary care vaccination registry

- 169/241 cases and 852/1205 matched controls were immunised with 1 MMR dose

- 59/241 cases and matched 330/1205 controls were immunised with 2 MMR doses

VE for any doses = 72% (95% CI from 39% to 87% , P = 0.0013)

VE for 1 dose = 66% (95% CI 25% to 85%, P = 0.0075)

VE for 2 doses = 83% (95% CI 54% to 94%, P = 0.0005)

ModerateMedium
Mackenzie 2006About 600 pupils attending a boarding schools in Scotland during a mumps outbreak that peaked between October and November 2004

Virological confirmation of clinical diagnosis

n = 20 (age 13 to 17 years)

Cases notified to consultant in public health medicine. Acute cases with virological positive test

n = 40 matched for age, sex, residential status, UK or international studentsNot specified Pre-outbreak vaccination status obtained by medical notes held in the school, communication with parents and from Scottish Immunisation Recall System

- 9/20 cases and 20/40 controls received 1 MMR dose

- 2/20 cases and 6/40 controls received 2 MMR doses

- VE (at least 1 versus unvaccinated) = 34% (from -100 to 88)

- VE (For 2 doses versus unvaccinated) = 48% (from -216 to 91)

VE (1 versus 2 doses) = 26% (from -340 to 88)

HighLow
Table 4. Salient characteristics of studies evaluating short-term side effects
StudyStudy designPopulation enrolledRisk of biasLikely biasGeneralisability
Bloom 1975RCT282HighReportingLow
Ceyhan 2001CCT1000ModerateDetectionMedium
Edees 1991RCT420ModerateDetectionMedium
Lerman 1981RCT502LowDetectionMedium
Peltola 1986RCT686LowDetectionHigh
Schwarz 1975RCT1481HighReportingLow
Beck 1989Cohort196 *HighSelectionLow
Benjamin 1992Cohort5017ModerateDetectionMedium
Dunlop 1989Cohort335HighSelectionLow
Makino 1990Cohort1638HighSelectionLow
Miller 1989Cohort12185HighReportingLow
Robertson 1988Cohort319ModerateSelectionMedium
Sharma 2010Cohort453,119HighReportingLow
Stokes 1971Cohort966HighSelectionLow
Swartz 1974Cohort59HighSelectionLow
Weibel 1980Cohort135HighSelectionLow
Freeman 1993Time-series375HighAttritionLow
  * The number enrolled is unclear   
Table 5. Reporting of temperature in RCTs (MMR versus single components/placebo/do nothing)
Temperature increment (°C)Measurement siteReporting frequencyObservation periodReference
38.0 to 38.4AxillaAll episodes21Schwarz 1975
38.0 to 38.4RectalAll episodes21Schwarz 1975
38.5 to 38.9AxillaAll episodes21Schwarz 1975
38.5 to 38.9RectalAll episodes21Schwarz 1975
38.6 to 39.5Not reportedMean number of episodes21Peltola 1986
39.0 to 39.4AxillaAll episodes21Schwarz 1975
39.0 to 39.4RectalAll episodes21Schwarz 1975
39.5 to 39.9AxillaAll episodes21Schwarz 1975
39.5 to 39.9RectalAll episodes21Schwarz 1975
40.0 to 40.4RectalAll episodes21Schwarz 1975
Up to 38.5Not reportedMean number of episodes21Peltola 1986
> 1 C above normalNot reportedFirst episode21Bloom 1975
> 38Not reportedAll episodes42Lerman 1981
Not reportedNot reportedFirst episode21Edees 1991
Up to 39.5Not reportedMean number of episodes21Peltola 1986
Table 6. MMR and encephalitis/encephalopathy
  1. CI: confidence interval

  2. CSF: cerebro-spinal fluid

  3. DTP: diphtheria, tetanus, pertussis vaccine

  4. Hib: Haemophilus influenzae b vaccine

  5. MenC: meningococcus C vaccine

  6. MMR: measles, mumps, rubella vaccine

  7. n: number of participants

  8. OR: odds ratio

Study and designOutcomePopulationOutcome definitionFindingsMMR typeRisk timeResultsRisk of biasGeneralisability

Case-control

Encephalopathy, Reyes syndrome or encephalitis

Cases (n = 452): children aged 0 to 6 years with outcome of interest.

Controls (n = 1280): matching for health maintenance Organisation location, age within 7 days, sex and length of enrolment in health plan

1. Encephalopathy: acute generalised disturbance of brain function requiring hospitalisation and consisting of coma or stupor that cannot be attributed to medication or postictal state. Such cases must have altered consciousness, delirium, obtundation and/or confusion.

2. Reyes syndrome: clinical symptoms of acute encephalopathy with altered level of consciousness as well as:

a. Absence of inflammatory changes in cerebrospinal fluid as indicated by 5 white blood cells/mm3 or brain histology showing cerebral oedema without perivascular or meningeal inflammation, plus

b. Evidence of hepatitis or liver failure documented by a 3-fold or greater elevation in serum glutamic oxaloacetic transaminase, serum glutamate pyruvate transaminase or serum ammonia or fatty changes of hepatocytes on liver biopsy or autopsy, plus

c. Absence of other aetiologies for cerebral or hepatic abnormalities

3. Encephalitis/encephalomyelitis: evidence of acute neurologic disease presenting with nonspecific signs such as fever, seizures, altered consciousness, headache, vomiting, meningismus or anorexia. We required multifocal involvement of the central nervous system and evidence of cerebrospinal fluid inflammation (7 white blood cells/mm3)

Disease with other known etiologies were excluded.

For data analysis all cases were stratified on the basis of their aetiology: known, unknown, suspected but unconfirmed (this last when a diagnosis was not confirmed by a diagnostic test)

Hospitalisation cases for encephalopathy, Reyes syndrome or encephalitis (primary or secondary diagnosis) in children aged 0 to 6 years, members of the health plan of 4 Health Maintenance Organisations in the USA and occurred between 1 January 1981 and 31 December 1995, were considered as possible cases. Hospital charts were reviewed by abstracter (not blind to vaccination status of the cases) who included in first instance encephalitis diagnoses by a neurologist with clear aetiology and excluded all cases with a condition other than encephalopathy. All other neurologic cases were reviewed by a neurologist (blind to vaccination status of the cases) an included as cases if they met case definition (see column on the right).

Not reported.

Vaccination status of both cases and controls was ascertained from medical records

7 to 14, 0 to 14, 0 to 30, 0 to 60 and 0 to 90 days

Not significant

- OR 7 to 14 days 0.40 (95% CI from 0.05 to 3.46)

- OR 0 to 14 days 0.35 (95% CI from 0.04 to 2.95)

- OR 0 to 30 days 0.85 (95% CI from 0.27 to 2.68)

- OR 0 to 60 days 0.64 (95% CI from 0.27 to 1.50)

- OR 0 to 90 days 0.98 (95% CI from 0.47 to 2.01)

ModerateMedium

Self controlled case series

Encephalitis/encephalopathyChildren immunised between 1 and 7 years of age between November 1982 and June 1986 (535,544) with outcome of interest (n = 199)

Encephalitis: acute or subacute onset of neurologic symptoms. Presence of neurologic symptoms or findings (clinical or laboratory, for example microbiological, electroencephalographic, computed tomographic) indicative of involvement of the brain parenchyma, such as coma, seizures, focal neurologic findings, or mental function impairment. Absence of evidence of other diagnoses, including non-inflammatory conditions and no microbiological or other laboratory findings suggestive of a nonviral infection. When pleocytosis in CSF is present, the term encephalitis is used, implying an inflammatory response within the brain. The presence of normal CSF findings does not preclude the diagnosis if the other criteria are satisfied.

Encephalopathy: clinically resembles encephalitis but no inflammatory response is evident. Chronic encephalopathy: persistence of acute findings usually over several months

The National Hospital Discharge Register was consulted by using the following ICD-8 codes: 065.99, 066.01, 066.02, 072.01, 292.20, 292.38, 292.39, 323.00, 323.01, 323.08, 323.09, 781.70, 999, 999.10

Medical records of hospitalised subjects were reviewed (in order to evaluate possible other causes of the event) and their correspondence to diagnostic criteria (see column on the right) examined

MMR II

Enders-Edmonston (measles)

Jeryl Lynn (mumps)

Wistar RA 27/3 (rubella)

Vaccination data were assessed through vaccination register

3 months after immunisationNot significant excess of hospitalisation within 3 months of vaccination (P = 0.28)ModerateMedium

Self controlled case series

EncephalitisChildren aged 12 to 35 months, (immunised with MMR; NK) with outcome of interest diagnosed between October 98 and September 2001 (n = 106)

Encephalitis:

(i) Encephalopathy for at least 24 hours and at least 2 of the following: fever, convulsions, focal neurologic findings (≥ 24 hrs), pleocytosis (> 5 leukocytes per μL CSF), characteristic abnormal results of neuroimaging (computerised tomography or MRI), herpes simplex virus nucleic acid (or nucleic acid of any other virus proven to cause encephalitis) in CSF; or

(ii) postmortem histologic evidence of encephalitis

Exclude:

(i) viral (aseptic) meningitis without encephalopathy

(ii) the following confirmed causes were excluded: hypoxic/ischaemic; vascular; toxic; metabolic, neoplastic, traumatic and pyogenic infections

(iii) uncomplicated convulsions or a series of convulsions lasting < 30 minutes

(iv) immunocompromised children

Cases of suspected encephalitis and/or severe illness with fever and convulsion occurring in children aged between 2 and 35 months through Britain and Ireland, were identified by consultant paediatricians taking part in a survey (October 1998 to September 2001) and notified to the British Paediatric Surveillance Unit. Details about neurologic illnesses were collected by reporting paediatricians by means of a detailed questionnaires. For diagnostic purposes saliva, blood and cerebrospinal samples were also collected. Questionnaires were reviewed by study investigators in order to assess whether reported cases corresponded to an analytical case definition taking in account severe illness with fever and convulsion and encephalitis (see column on the right)

Not reported.

Immunisation history of cases was obtained by the Immunisation Department of the Health Protection Agency (other than MMR vaccine the study considers also DTP, Hib and MenC vaccines). Only cases with known vaccination history were included in the analysis

15 to 35 days after immunisationThe incidence of encephalitis was not statistically different between "at risk" and control period: relative incidence 1.34 (95% CI from 0.52 to 3.47)LowHigh
Table 7. MMR and aseptic meningitis
  1. AM: aseptic meningitis

  2. CI: confidence interval

  3. HMO: Health Maintenance Organisation

  4. ICD: international classification of diseases

  5. MS: multiple sclerosis

  6. MT: Mato Grosso do Sul

  7. n: number of participants

  8. RR: risk ratio

Study and designOutcomePopulationDefinitionFindingsMMR typeRisk timeResultsRisk of biasGeneralisability
Black 1997 Case-controlAseptic meningitis59 cases and 118 matched controls (age 12 to 23 months at the time of discharge diagnosis, between 1984 and 1993). For each ascertained case (n = 59), 2 controls matched for age, sex, HMO and HMO membership status were selectedNo evidence of prior underlying meningitis or underlying disease caused by toxoplasmosis, syphilis, cytomegalovirus, neonatal herpes simplex or human immunodeficiency virus. (The same exclusion criteria were also used for controls.) In addition bacterial, mycobacterial and fungal cultures of the cerebrospinal fluid must have been negative, and the patient must have had a cerebrospinal fluid white blood cell count of >= 10 cells/mm3Potential cases of aseptic meningitis were identified by computerised hospitalisation at 4 Health Maintenance Organisations (HMO) that participated in the Vaccine Safety Datalink project. They were children aged 12 to 23 months with ICD-9 discharge diagnoses 045.2, 047.*, 048, 072.1, 321.2 or 322.* between 1984 and 1993. Medical records of potential cases were reviewed and included as cases when correspond to a validation criteria (see column on the right)

Jeryl Lynn mumps strain

Vaccination status of both cases and controls was derived from medical record review

0 to 14, 0 to 30, 8 to 14 days after immunisation

No statistically relevant difference in exposure to MMR for any of the considered at risk time intervals

- OR (0 to 14 days) 0.50 (95% CI from 0.1 to 4.5)

- OR (0 to 30 days) 0.84 (95% CI from 0.2 to 3.5)

- OR (8 to 14 days) 1.00 (95% CI from 0.1 to 9.2)

LowHigh

Case cross-over

Aseptic meningitis39 subjects with AS aged 13 to 29 months of both sexes identified from insurance claims and hospitalisation data during 1998 in Korea who had received MMR vaccine within 1 year before disease onset and for whom vaccination record were availableGenerically defined as syndrome characterised by acute onset of meningeal symptoms, fever and cerebrospinal fluid pleocytosis, with bacteriologically sterile culturesCases of aseptic meningitis were identified from insurance claims and hospitalisation data during 1998 in Korea. Authors considered cases corresponding to diagnosis criteria occurred in children aged 8 to 36 months who had received MMR vaccine within 1 year before disease onset and for whom vaccination record were availableNot reported42 daysStrong association with exposure to MMR within 42 days. OR 3.0; 95% CI from 1.5 to 6.1ModerateMedium

Self controlled case series

Aseptic meningitisChildren immunised between 1 and 7 years of age between November 82 and June 86 (535,544) with outcome of interest (n = 161)Inflammation of the meninges. Usually a self limiting disease of known or suspected viral cause consisting of fever, headache, signs of meningeal irritation, without evidence of brain parenchymal involvement and a lymphocytic and mononuclear pleocytosis of CSF. The term meningoencephalitis does not differentiate cases with prominent involvement of the brain parenchyma from those with meningeal involvement onlyHospitalisation records (ICD-8 codes: 045.99, 320.88, 320.99) and review of patients' medical record for assess correspondence to case definition

MMR II

Enders-Edmonston (measles)

Jeryl Lynn (mumps)

Wistar RA 27/3 (rubella)

3 months after immunisationNot significant excess of hospitalisation within 3 months of vaccination (P = 0.57)ModerateMedium

Time-series

Aseptic meningitisAbout 452,334 children aged 1 to 11 years in Salvador city (Bahia, NE Brazil). 29 hospitalisations for AM has been recorded during the reference period before the campaign began (surveillance weeks 10 to 33), 58 thereafter weeks (surveillance weeks 34 to 43)

1) Residence in the city of Salvador

2) Age 1 to 11 years

3) Cerebrospinal fluid with a cell count of > 10 and < 1200 cells per ml (higher counts could be attributed to unconfirmed bacterial meningitis)

4) Predominance of lymphocytes in the cerebrospinal fluid of > 50 percent of the total number of cells

5) Exclusion of any bacteriologic or fungal confirmation through the use of Gram stain, latex, immunoelectrophoresis, stain for Cryptococcus neoformans, Ziehl-Neelsen stain, or culture for bacteria and Mycobacterium tuberculosis; and

6) Exclusion of all cases with a history of prior meningitis or any neurologic disorder and any cases with sepsis, pneumonia, otitis, or any other disease that might be associated with an increased cell count in the cerebrospinal fluid

Data about meningitis were obtained from the state Epidemiology Surveillance System and from the neurologic service of the state referral hospital for infectious disease (Hospital Couto Maia), by reviewing hospital records of children admitted between the 10th and the 43rd epidemiological surveillance weeks. Demographic, clinical, and laboratory data were collected on a standardised form.

Pluserix vaccine (Smith-Kline Beecham, UK) containing mumps Urabe Strain.

Vaccination began on 16 August 1997 (National Immunisation Day, surveillance week 33), 45% coverage of the target population was achieved on that day, high coverage (exact data not reported, but very close to 100%) during the 2 following weeks.

Vaccination history was obtained by vaccination cards or visits/ phone call.

1 to 10 weeks after immunisation (as time-series)

3 to 5 weeks (i.e.15 to 35 days) after immunisation (as case series)

Strong association

The incidence of aseptic meningitis hospitalisation was significantly higher during the third (18 cases risk ratio (RR) 14.28; 95% CI 7.93 to 25.71), fourth (15 cases RR 11.90; 95% CI 6.38 to 22.19), fifth (9 cases, RR 7.14; 95% CI 3.38 to 15.08) and sixth (4 cases, RR 3.17; 95% CI 1.12 to 9.02) weeks following the start of the immunisation campaign when compared with that observed during the reference period

ModerateMedium

Time-series

Aseptic meningitisAbout 580,587 in MS (Mato Grosso do Sul) and 473,718 in MT (Mato Grosso) children aged 1 to 11 years. Accordingly to the first case definition 22 cases of AM (with viral or unknown aetiology) were notified before the start of the immunisation campaign (weeks 1 to 31, 1998) and 48 during weeks 32 to 42 in MS. In MT they were 71 before the campaign started (weeks 1 to 37 of 1998) and 103 thereafter (weeks 38 to 48). Data analysis by using the second case definition reflected an analogous trend.

First definition: If the diagnosis in the form was of viral aetiology or unknown aetiology, cases were classified as AM. They were classified as not having AM if they had a suspected or confirmed diagnosis of meningitis by a known (non-viral) agent through any laboratory or clinical finding.

Second definition: cases were considered AM if they had a CSF with the following findings: cell count greater than 10 and lesser than 1500 and presence of lymphocytes greater that 49%. (Applied for the cases in which laboratory data were present in the notification forms. In their absence, cases were excluded).

Cases of aseptic meningitis notified from routine surveillance system were reviewed considering 2 different definitions, one based on the diagnosis reported in the notification form (first definition) and one based on the laboratory findings of the same form (when these are available on it). These definitions are independent but not exclusive.

Serum Institute of India, Ltd, Pune. containing Leningrad-Zagreb mumps strain. Three different lots were used in each state (MS and MT).

Mass immunisation campaign started in mid August 1998 (32nd epidemiological week) in MS and late September in MS (week 38), and lasted for about 1 month, even if the most part of the doses has been administered during the first 2 campaign weeks. Vaccination was reported for 69.4% and 93.5% of the target population in MT and in MS respectively.

1 to 10 weeks after immunisation

Strong association

AM incidence in MS became significantly higher than in the pre-immunisation time from 2 weeks after the start of the campaign (4 cases, RR 5.6; 95% CI 1.3 to 14.1), peaked at 3 weeks (16 cases, RR 22.5; 95% CI 11.8 to 42.9) and 4 weeks after the start of the campaign (15 cases, RR 21.1; 95% CI 11.0 to 40.7) and returned to the average after week 39

In MT, incidence of AM cases became significantly higher during the third week (40) after the start of the campaign (5 cases, RR 2.6; 95% CI 1.1 to 6.5), peaked in week 42 (30 cases, RR 15.6; 95% CI 10.3 to 24.2) and week 43 (23 cases, RR 12.0; 95% CI 7.6 to 19.4) and returned to the average from week 46 onwards

ModerateHigh
Table 8. MMR and febrile seizure
  1. CI: confidence interval

  2. ICD: international classification of diseases

  3. n: number of participants

  4. RR: risk ratio

Study and designOutcomePopulationDefinitionFindingsMMR typeRisk timeResultsRisk of biasGeneralisability

Person-time cohort

Febrile seizure (first episode)Children born in Denmark between 1 January 1991 and 31 December 1998 aged between 3 months and 5 years (n = 537,171)Discharge diagnoses corresponding to the indicated ICD-8 and ICD-10 codes. Only cases without recorded history of non-febrile seizure, cerebral palsy, severe head traumas, intracranial tumours, meningitis, or encephalitis were includedICD-8 code 780.21 or ICD-10 code R56.0 from National Register of Hospitalisations

Moraten measles, Jeryl Lynn mumps, and Wistar RA 27/3.

Vaccination status of the children was ascertained by using data of the National Board of Health to which vaccination data were transmitted by general practitioners

1 to 260 weeks after immunisation

Association within 2 weeks following vaccination

RR 1.10; 95% CI from 1.05 to 1.15

LowHigh
Recurrent febrile seizureNot specified

Association when MMR was administered within 14 days before first episode

RR 1.19; 95% CI from 1.10 to 1.41

Epilepsy subsequent to a first febrile seizure episodeNot specified

Not significant

RR 0.70; 95% CI from 0.33 to 1.50

Self controlled case series

Severe illness with fever and convulsionsChildren aged 12 to 35 months, (immunised with MMR; NK) with outcome of interest diagnosed between October 98 and September 2001 (n = 107)

Severe illness with fever and convulsions

(i) with a total duration of 30 min; or

(ii) followed by encephalopathy for 2 to 23 hours; or

(iii) followed by paralysis or other neurologic signs not previously present for 24 hours

Exclude :

(i) viral (aseptic) meningitis without encephalopathy

(ii) the following confirmed causes were excluded: hypoxic/ischaemic; vascular; toxic; metabolic, neoplastic, traumatic, and pyogenic infections

(iii) uncomplicated convulsions or a series of convulsions lasting < 30 minutes

(iv) immunocompromised children

Paediatrician survey (questionnaires) and review of the collected dataNot reported6 to 11 days after immunisation

Strong association.

RI 5.68; 95% CI from 2.31 to 13.97

LowHigh

Self controlled case series

Febrile convulsionChildren aged 12 to 23 months with discharge diagnosis corresponding to the outcome of interest and hospitalised between January 1998 and June 2002 who received MMR (n = 894)Hospital discharge diagnoses with ICD-10 codes R560 or R568. Case review not performed.Cases with discharge diagnoses corresponding to the given ICD-10 codes (febrile convulsion or fit, not otherwise specified). Episodes within a same individual were considered as separate when occurred at least 10 days apart.

- MMRII (Sanofi Pasteur Lyon, France) containing Jeryl Lynn mumps

- Priorix, mumps vaccine component RIT 4385

- Unknown vaccine type

- Priorix, MMRII or unknown

6 to 11 days after immunisation

15 to 35 days after immunisation

Strong association within 6 to 11 days for all vaccine types

RI 4.09; 95% CI from 3.1 to 5.33

Not statistically relevant within 15 to 35 days after immunisation

RI 1.13; 95% CI from 0.87 to 1.48

ModerateMedium
Febrile convulsion (includes ICD-10 codes R560 only)See abovePriorix, MMRII or unknown.

6 to 11 days after immunisation

15 to 35 days after immunisation

Strong association within 6 to 11 days

RI 4.27; 95% CI from 3.17 to 5.76

Not statistically relevant within 15 to 35 days after immunisation

RI 1.33; 95% CI from 1.00 to 1.77

Table 9. MMR and autism
  1. ADS: autism spectrum disorders

  2. CI: confidence interval

  3. ICD: international classification of diseases

  4. MMR: measles, mumps, rubella vaccine

  5. n: number of participants

  6. OR: odds ratio

  7. PDD: pervasive developmental disorders

  8. RI: relative incidence

Study and designOutcomePopulationDefinitionFindingsMMR typeRisk timeResultsRisk of biasGeneralisability

Retrospective cohort

Autistic disorders or other autistic spectrum disordersDanish children born between January 1991 and December 1998 (n = 537,303)Diagnosis of autism using ICD-10 codes F84.0 or similar DSM-IV code 299; for autistic spectrum disorders ICD-10 codes F84.1 through F84.9 and DSM-IV codes 299.1- through 299.80. (DSM= Diagnostic and Statistical manual of Mental Disorders)From medical records in Danish Psychiatric Central Register

MMR: Moraten (measles), Jeryl Lynn (mumps), Wistar RA 27/3.

Vaccination data reported in the National Board of Health

Not to assessNot significant association either for autism (RR 0.92; 95% CI from 0.68 to 1.24) or for autistic-spectrum disorders (RR 0.83; 95% CI from 0.65 to 1.07)ModerateHigh

Retrospective cohort

Regressive autismStafford sample (96 with PDD children born between 1992 and 1995) and MFS sample (99 cases of autism born between 1954 and 1979 (mean age 17.8 years)Regression defined with Autism Diagnostic Interview-Revised (ADI-R). E.G (“Regression is assessed for language skills as follows: Were you ever concerned that your child might have lost language skills during the first years of his/her life? Was there never a time when he/she stopped speaking for some months after having learned to talk” in Stafford sample. For MFS sample: "slightly different version of ADI...and regression was defined using three items of the original ADI version that assessed probable and definite level of regression and loss of skills, in the first 5 years of life and in 3 domains: language, social interactions, and play and imagination”Autism Diagnostic Interview (ADI) administered to parents

Stafford sample (no description vaccine, but there were immunization data)

MFS sample (none vaccinated with MMR vaccine)

Not to assessNo statistically relevant differences across the 2 samples for the rate of probable or definite regression, P = 0.70HighLow

Retrospective cohort

Regression in autism spectrum disordersChildren born between 1976 and 1999 with clinical diagnosis of ASD (n = 904)

ASD regression defined as “a documented deterioration in any aspect of development or reported loss of skills, however transient”

Note: in process of time 2 different diagnostic processes has been adopted at YPCD: until February 2000 diagnosis process consisted in the assessment of ASD initially conducted by a child psychiatrist using The Diagnostic and Statistical Manual (DSM-IV, American Psychiatric Association, 1994), afterward a clinical psychologist conducted an intelligence test. After admission a psychiatrist followed the patients once or twice a month. All doctors had received a training using a common concept of diagnosis. From February 2000 onwards a child psychiatrist with clinical psychologist conducted the full assessment in one day. Diagnoses of ASD was made by 3 experienced child psychiatrists basing on clinical observations, intellectual and developmental tests, interviews with parents and patients

Consulting of questionnaires about patient's developmental, behavioural and medical history filled out by parents, and archived in a database

Measles, mumps and rubella (MMR) vaccine containing AIK-C (measles), Urabe AM9 (mumps) and To-336 (rubella) strains.

Participants were classified according to the chance of having received MMR vaccine (MMR was administered in Japan in the time April 1989 to April 1993 to children between 12 and 36 months of age):

1) Pre-MMR generation: born between January 1976 and December 1984, n = 113

2) MMR generation: born between January 1985 and December 1991, n = 292

3) Post–MMR generation with an age of 1 to 3 years old after 1993 when MMR programme was terminated, n = 499

Data concerning MMR vaccination were moreover obtained from records of the Maternal and Child Health (MCH) handbook and were referred to the MMR generation group only

Not to assessWithin MMR generation group, the estimate of association between regression and MMR vaccine exposure was not significant (OR 0.744; 95% CI from 0.349 to 1.517, P = 0.490), so as when both pre- and post-MMR vaccine generation groups were used as control (OR 0.626; 95% CI from 0.323 to 1.200)HighLow

Case-control

Pervasive developmental disorder (PDD)Cases: 1294 children with a first diagnosis of a PDD (either by OXMIS or READ codes) during the study period registered with a GPRD practice. Controls:n = 4469“Those with autistic disorders and similar presentations were classified as having “autism” and those with other description (such as Asperger's syndrome) were classified as having “other PDD”". Patients who had more than one PDD diagnostic code recorded at different times (for example, autism and then Asperger's syndrome) were classified as having the most specific diagnosis (in this example Asperger's syndrome)”.From diagnosis contained in UK General Practice Research Database (GPRD electronic records). Codes were available from request.No single clinical code was immediately implemented for MMR, then MMR was identified by codes of measle, mumps and rubella administered at the same dayData on exposure to MMR for cases: from their date of birth up to the index date for cases. For controls: from their date of birth up to index date to the nearest month of age

No significant for PDD and autism only and other PDD

OR 0.86; 95%CI from 0.68 to 1.09

ModerateMedium

Case-control

Autism

Cases: 624 children with autism aged 3-10 years in 1996.

Controls:1824

Defined as behavioural characteristics consistent with the Diagnostic and Statistical Manual of Mental Disorders, 4 th edition (DSM-IV) criteria for autism spectrum disorders (ASDs)Records about children with autism were abstracted from source files at schools, hospitals, clinics and specialty providers. Furthermore clinical psychologists reviewed records according to DMS-IVMMR vaccination was abstracted from “standardized state immunization forms”Not to assess

No significant difference in the age at first vaccination.

- Up 18 months OR 0.94 ; 95%CI from 0.65 to 1.38

- Up to 24 months OR 1.01 ; 95% CI from 0.61 to 1.67

- Up to 36 months OR 1.23 ; 95% CI from 0.64 to 2.36

ModerateMedium

Case-control

Childhood or atypical autism

Cases: 96 children aged between 2 and 15 years with diagnoses of childhood or atypical autism (ICD-10 codes F84.0 and F84.1) identified from practitioner registers in the Lesser Poland region.

Controls:192 children matched for birth year, gender and practice

Cases with ICD-10 diagnoses codes F84.0 and F84.1 determined by child psychiatristData from general practitioner records from Lesser Poland region

MMR (not described) and/or monovalent measles vaccine

Informations about vaccination history were extracted from physician's records

At any time before autism diagnosis

At any time before symptoms onset

No association. Lower risk of autism in children immunised with MMR before diagnosis (OR 0.17; 95% CI from 0.06 to 0.52)

Estimate not statistically relevant when exposure to MMR was considered before symptom onset (OR 0.42; 95% CI from 0.15 to 1.16)

ModerateMedium

Time-series

Pervasive developmental disorders (PDD)Children aged 5 to 11 years (birth cohorts 1987 to 1998 attending a school board in Montreal (n = 27,749 out of whom 180 with PDD)Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV)Administratively identified by code 51 (autism), code 50 (autism spectrum disorder) of Ministry of Education of Quebec (MEQ). In this study a special list was available filled by a team that monitored children with PDD diagnosis

MMR (no description)

Identified by vaccination records

Not to assessNo association. Significant increase in rates of PDDs from 1987 to 1998 (OR 1.10; 95% CI1.05 to 1.16; P < 0.001) despite decrease in MMR uptake through birth cohorts from 1988 to 1998 (X 2 for trend = 80.7; df = 1; P < 0.001)HighMedium

Time-series

Autism spectrum disorders (ADS)Children born from 1988 to 1996ASD cases defined as all cases of pervasive developmental disorders according to ICD-guidelines, but in Kohoku Ward was active an early detection clinical system called DISCOVERY that included items drawn up by the Public Health Bureau of Yokohama called YACHT (Young autism and other developmental disorders Checkup tool)Community-based early detectionMMR (no description)6 years after MMR

No association

Significant increased incidence for ASD (χ2 = 19.25, df = 8, P = 0.01) was assessed after vaccination programme was stopped

ModerateMedium

Self controlled case series

AutismChildren 1 to 7 years old (535,544)Autistic disorder: "Severe qualitative impairment in reciprocal social interaction, in verbal and non verbal communication and in imaginative activity and markedly restricted repertoire of activities and interests" (Steffenburg 1989)Data about first hospital visits during the study period identified by ICD-8/9 codes respectively effective from 1969 to 1986 and from1987 through 1995 (299- Psychoses ex origine infantia; 2990 - Autismus infantilis; 2998- Developmental disorder; 2999- Developmental disorder)MMRII (Merck & Co, West Point, PA) containing Enders-Edmonston strain, Jeryl Lynn, Wistar RA 27/3 strainFor autism the risk period is open endedUnclear without data reported in articleModerateMedium

Self controlled case series

Autistic disorderChildren born since 1979 from 8 health districts (North Thames, UK)“By use of criteria of the International Classification of Diseases, tenth revision (ICD10), the diagnosis of autism was checked against information in the available records on the child's present condition and his or her condition between the ages of 18 months and 3 years.”ICD10-confirmed and non-confirmed cases from computerised special needs/disability registers at child development centres and from records in special schools. Information on children with such disorders who were younger than 16 years of age was extracted from clinical records by 1 of 3 experienced paediatric registrarsMMR vaccination identified by Regional Interactive Child Health Computing System (RICHS)Periods within 1 or 2 years, so as 2, 4, 6 months after vaccination were consideredNo temporal association between onset of autism within 12 months (RI 0.94; 95% CI from 0.60 to 1.47) or 24 months from MMR vaccination (RI 1.09; 95% CI from 0.79 to 1.52)ModerateMedium
Table 10. MMR and thrombocytopaenic purpura
  1. CI: confidence interval

  2. GPRD: general practice research database

  3. ICD: international classification of diseases

  4. IRR: incident rate ratio

  5. ITP: immune thrombocytopaenic purpura

  6. MMR: measles, mumps, rubella vaccine

  7. TP: thrombocytopaenic purpura

  8. yr: years

Study and designOutcomePopulationDefinitionFindingsMMR typeRisk timeResultsRisk of biasGeneralisability

Case-control study

Idiopathic thrombocytopaenic purpura

Cases: 23 children with outcome of interest at 12 to 23 months, between 1988 and 1999, GPRD members.

Controls: 116 subjects matching for index date (age), sex, practice.

From cases with first time diagnosis of thrombocytopaenia (ICD-9 code 287.1) were excluded those with bone marrow failure, congenital thrombocytopaenia, severe malabsorption, severe sepsis and neonatal thrombocytopaeniaGeneral Practice Research Database (GPRD) electronic records with first time diagnosis of thrombocytopaenia (ICD-9 code 287.1)

Not reported

Data about MMR vaccination were presumably obtained from GPRD records (type and composition not reported)

0 to 6 weeks following MMR immunisation

7 to 26 weeks following MMR immunisation

Association within 6 weeks from immunisation.

RR 6.3; 95% CI from 1.3 to 30.1

No significant association within 7 to 26 weeks following MMR immunisation

RR 1.5 ; 95% CI from 0.4 to 4.8

ModerateMedium

Case-control study

Acute immune thrombocytopaenia

Cases: 387 children aged 1 month to 18 years, hospitalised at emergency department with outcome of interest between November 1999 and September 2007, with outcome of interest.

Controls: 1924 children of same age interval hospitalised at emergency department for acute neurological disorders or endoscopically confirmed gastroduodenal lesions

Platelets count < 100,000/μl at admission. Subjects with following conditions were excluded: cancer, immunodeficiency, chronic renal and hepatic failure, so as acute events related to a reactivation of an underlying chronic disease or a congenital anomalyHospitalisation (emergency department) records review

Not reported.

Exposure to the vaccine (and other drugs) was assessed during hospital admission by means of parents interview

0 to 6 weeks following MMR immunisation

Association within 6 weeks following immunisation

OR 2.4; 95% CI from 1.2 to 4.7

HighLow

Self controlled case series

Immune thrombocytopaenic purpura63 children aged 12 to 23 months with outcome of interestSubjects with 2 platelet counts ≤ 50,000/μL within 6 weeks period or with 1 platelets count ≤ 50,000/μL associated with ICD-9 diagnosis codes 287.0-287.9 within 6 weeks, with exclusion of: cases of thrombocytopaenia from a known condition (neonatal thrombocytopenia, aplastic anaemia, defibrination syndrome, acquired haemolytic anaemia, chronic liver disease, malignant neoplasm), thrombocytopaenia diagnosed within the 30th day of life. By subsequent patient charts reviews subjects who did not have not have ITP, who had drug exposure, with acute illness, or with serendipitous finding during routine care were further excludedVaccine Safety Datalink database (1991 to 2000) and patient charts review

Not reported.

MMR vaccination date assessed by means of separate audit of patient charts

0 to 42 days following MMR immunisation

Strong association

IRR 5.38; 95% CI from 2.72 to 10.62

LowHigh
France 2008 Risk intervalImmune thrombocytopaenic purpuraSee aboveSee aboveSee aboveSee above0 to 42 days following MMR immunisation

Strong association

IRR 3.94; 95% CI from 2.01 to 25.03

LowHigh

Ecological study

Thrombocytopaenic purpura (TP)Case observed after vaccine administration between 1984 and June 30th, 1992 (n = 60). Estimate number of administered vaccine doses was 9,205,483Acute haemorrhagic syndrome associated with platelet count of < 100,000/mm³, all cases within 45 days of vaccination, over 8-year periodPharmacovigilance reportsIntervention: ROR, Trimovax (MMR), comparators: Rouvax (measles), DTbis Rudivax (rubella, diptheria, tetanus) Imovax Oreillons (mumps), Rudi-Rouvax (measles/rubella), Rudivax (rubella)2 to 45 days following immunisation

Strict temporal occurrence of TP after MMR makes association possible, even if not proven.

Incidence of TP was estimated between 0.5 and 3 cases/100,000 MMR doses

ModerateMedium
Table 11. MMR and asthma
  1. CI: confidence interval

  2. HMO: Health Maintenance Organisation

  3. ICD: international classification of diseases

  4. n: number of participants

  5. RR: risk ratio

  6. VSD: Vaccine Safety Datalink

Study and designOutcomePopulationDefinitionFindingsMMR typeRisk timeResultsRisk of biasGeneralisability

Cohort Study

AsthmaChildren (0 to 6 years) enrolled in VSD project (4 HMO) between 1991 and 1997 (n = 167,240)

To be classified as having asthma a child had to meet one of the following criteria:

- At least 1 diagnosis of asthma (ICD9 = 493) and at least 1 prescription for an asthma medication; the first diagnosis and the first prescription had to be within a 2-year period. Asthma medications included oral or inhaled beta-antagonist , theophylline, oral or inhaled corticosteroids, cromolyn sodium, adrenergic drugs not elsewhere specified and unclassified asthma medications;

- At least 1 prescription for an inhaled beta-antagonist and at least 1 prescription for cromolyn within a 2 year period;

- At least 5 prescriptions or asthma medications during a 2-year period. In addition to these criteria it was also required that the child had at least one asthma diagnosis or prescription at 1 year of age or older. Authors defined the asthma incidence date as the earliest of the first asthma diagnosis date or the first date of an asthma medication prescription. A child could have had an asthma onset date when younger than 1 years of age, but to be classified as a case the child had to have an indication that asthma was still present when he or she was older than 1 year of age

Reviewing of computerised data bases maintained at each HMO. In these databases hospital discharge, emergency room visits, and medication prescriptions were registered.Not reportedNot specified. Any time after MMR immunisation

No significant association.

RR 0.97; 95% CI from 0.91 to 1.04

ModerateMedium

Cohort Study

AsthmaChildren (n = 16,470) aged from 20 months to 11 years, accounting for 69,602 person-yearsNot providedWest Midlands General Practice Research DatabaseNot reportedNot specified. Any time after MMR immunisationSignificant association only for the group with lower GP consultation during the first 6 live months (hazard ratio 7.18; 95% CI from 2.95 to 17.49)HighMedium

Cohort Study

EczemaChildren (n = 14,353) aged from 20 months to 11 years, accounting for 59,520 person-yearsNot providedWest Midlands General Practice Research DatabaseNot reportedNot specified. Any time after MMR immunisationSignificant association only for the group with lower GP consultation during the first 6 live months (hazard ratio 10.4; 95% CI from 4.61 to 23.29)HighMedium

Person-time cohort

Asthma hospitalisationDanish birth cohorts 1991 to 2003 followed up between 1 January 1991 and 31 December 2003, or between 1 and 5 years of age (n = 871,234; 2,926,406 person-years)

Inpatient hospitalisation with asthma diagnosis (occurred between 1 January 1992 and 31 December 2004)

- Asthma diagnosis: 493.xx (ICD-8) and J45.x, J46.x (ICD-10)

- Severe asthma (status asthmaticus) 493.01 (ICD-8) and J49.9 for severe asthma

Data from the Danish National Hospital Register

MMR: Moraten (measles), Jeryl Lynn (mumps), Wistar RA 27/3

Dates of MMR vaccination were obtained from the National Board of Health, NBH

Not specified. Any time after MMR immunisationSignificant protective effect of MMR vaccination was observed against Asthma (RR 0.75; 95% CI from 0.73 to 0.78) and severe asthma (RR 0.63 ; 95% CI from 0.49 to 0.82) was globally assessedModerateHigh

Person-time cohort

Anti-asthma medicationDanish birth cohorts 1991 to 2003 followed up between 1 January 1996 and 31 December 2003, or between 1 and 5 years of age (n = 600,938; 1,858,199 person-years)

Prescription of the following cases of anti-asthma medications have been considered:

- glucocorticoid inhalants (ATC code R03BA)

- short-acting b2-agonist inhalants (ATC codes R03AC02, R03AC03, and R03AC04)

- long-acting b2-agonist inhalants (ACT codes R03AC12 and R03AC13)

- systemic b2-agonists (ACT code R03CC)

- other types of anti-asthma medication (all other ATC codes under R03)

Data from the Danish Prescription Drug Database

MMR: Moraten (measles), Jeryl Lynn (mumps), Wistar RA 27/3

Dates of MMR vaccination were obtained from the National Board of Health, NBH

Not specified. Any time after MMR immunisation

Use of anti-asthma medications (all types) was significantly less frequent among subjects immunised with MMR (RR 0.92; 95% CI from 0.91 to 0.92).

Considering single classes of medication, reduction in use of b2-agonists was not observed (RR 1.02; 95% CI from 1.01 to 1.02)

ModerateHigh
Table 12. MMR and leukaemia
  1. CI: confidence interval

  2. DTP: diphtheria, tetanus, pertussis vaccine

  3. DT: diphtheria, tetanus vaccine

  4. Hib: Haemophilus influenzae b vaccine

  5. MMR: measles, mumps, rubella vaccine

  6. n: number of participants

  7. NCCLS: northern California childhood leukaemia study

  8. OR: odds ratio

  9. Td: tetanus, diphtheria vaccine

Study and designOutcomePopulationDefinitionFindingsMMR typeRisk timeResultsRisk of biasGeneralisability

Case-control

Leukaemia

Leukaemia cases (n = 323) aged 0 to 14 years identified within the Northern California Childhood Leukaemia Study (NCCLS) between 1995 and 2002.

Controls (n = 409): matched to cases for date of birth, gender, Hispanic status (either parent Hispanic), maternal race (white, African American, or other) and maternal county of residence, by means of birth certificates.

To be eligible, each case or control had to reside in the study area, be less than 15 years of age at the reference date (time of diagnosis for cases and the corresponding date for matched controls), have at least one parent or guardian who speaks English or Spanish, and have no previous history of any malignancy

Not providedWithin the NCCLS study, incident leukaemia cases were ascertained from major paediatric clinical centres within 72 hours after diagnosis.This study was carried out in order to assess if there is a link between exposure to vaccines and leukaemia in children aged below 14 years. Population coverage includes initially 17 countries in the Greater San Francisco Bay Area and since 1999 was expanded to further 18 countries in Northern and Southern California. The present studies relies on cases of leukaemia ascertained between 1995 and 2002

Not reported

A copy of child's complete vaccination record was requested to primary care takers of case or control subjects (usually the biological mother) were interviewed after informed consent was obtained and asked to provide a copy of child's complete vaccination record or to the primary care physician. Other than MMR, vaccinations against diphtheria, pertussis and tetanus (DPT), DT, Td, poliomyelitis, MMR, hepatitis B or Hib has been considered in the study.

Any time after MMR immunisation

No significant association

OR 1.06; 95% CI from 0.69 to 1.63

MediumMedium

Case-control

Acute Lymphoblastic Leukaemia (ALL)

All cases (n = 282) aged 0 to 14 years identified within the Northern California Childhood Leukaemia Study (NCCLS) between 1995 and 2002.

Controls (n = 360) matched to cases for date of birth, gender, Hispanic status (either parent Hispanic), maternal race (white, African American, or other) and maternal county of residence, by means of birth certificates.

To be eligible, each case or control had to reside in the study area, be less than 15 years of age at the reference date (time of diagnosis for cases and the corresponding date for matched controls), have at least one parent or guardian who speaks English or Spanish, and have no previous history of any malignancy

Not providedWithin the NCCLS study, incident leukaemia cases were ascertained from major paediatric clinical centres within 72 hours after diagnosis.This study was carried out in order to assess if there is a link between exposure to vaccines and leukaemia in children aged below 14 years. Population coverage includes initially 17 countries in the Greater San Francisco Bay Area and since 1999 was expanded to further 18 countries in Northern and Southern California. The present studies relies on cases of leukaemia ascertained between 1995 and 2002.

Not reported

A copy of child's complete vaccination record was requested to primary care takers of case or control subjects (usually the biological mother) were interviewed after informed consent was obtained and asked to provide a copy of child's complete vaccination record or to the primary care physician. Other than MMR, vaccinations against diphtheria, pertussis and tetanus (DPT), DT, Td, poliomyelitis, MMR, hepatitis B or Hib has been considered in the study

Any time after MMR immunisation

No significant association

OR 0.87; 95% CI from 0.55 to 1.37

MediumMedium
Table 13. MMR and hay fever
  1. CI: confidence interval

  2. DIN: doctors' independent network

  3. GPRD: general practice research database

  4. MMR: measles, mumps, rubella vaccine

  5. OR: odds ratio

Study and designOutcomePopulationDefinitionFindingsMMR typeRisk timeResultsRisk of biasGeneralisability

Case-control

Hay fever riskThe cases and controls were children with at least 5 years of follow-up from birth and registered “within the practice within 3 months of birth”“Only codes synonymous with "allergic rhinitis” and with seasonal variation in recording were permittedFrom GPRD and DIN databaseMMR II

MMR (first entries)

The time categories for MMR immunisation were:

1st to 13th month, 14th, 15th, 16th, 17th, 18th-24th, 25th month or later

Not significant (comparing vaccinated at 14th month versus unvaccinated children), but with result significant (OR 0.62; 95% CI from 0.48 to 0.80) of reduced hay risk fever after completion of MMR after 2 yearsModerateMedium

Case-control

Hay fever risk in the first grass pollen season

Case of hay fever were children with diagnostic codes and/or treatment for hay fever, after 2 years of age.

Control was child that matched for general practice, sex, birth month and follow-up of control to at least date of diagnosis case

"Cases of hayfever were those who had diagnostic codes and/or treatment for hayfever, after 2 years of age”From GPRD and DIN databaseMMR IIMMR exposure by 24 months in a grass pollen season (May, June, July) versus outside 1

Not significant

OR 1.05; 95% CI from 0.94 to 1.18

ModerateMedium
Table 14. MMR and type 1 diabetes
  1. CI: confidence interval

  2. ICD: international classification of diseases

  3. MMR: measles, mumps, rubella vaccine

  4. RR: risk ratio

Study and designOutcomePopulationDefinitionFindingsMMR typeRisk timeResultsRisk of biasGeneralisability

Person time

Type 1 diabetes coded as 249 and E10A cohort of children born from 1 January 1990 to 31 December 2000 from the Danish Civil Registration System (739,694)

From 1990 to 1993 the codes used (E10) were obtained from a modified version of the International Classification of Diseases, 8th version (ICD-8).

From 1994 to 2001 the codes used (249 and E10) were obtained by the International Classification of Disease, 10th version

The diagnosis of type 1 diabetes, within 1 January 1990 to 31 December 2001, was obtained from the Danish National Hospital Register that in 1995 began to register outpatients visits and visits to the emergency room.

Type 1 diabetes among siblings of cases (aged 0 to 14 years between 1 January 1997 to 31 December 2001) were obtained from the Danish National Hospital Register. Before 1 January 1987 ICD-8 code 250 was used for type 1 diabetes diagnosis, whereas codes 249 or E10 were used thereafter

Measles, mumps, and rubella (1990 to 2001); schedule (15 months and 12 years of age); composition (Live , attenuated measles (Moraten), mumps (Jeryl Lynn), and rubella (Wistar RA 27/3)) virus.

The authors did not obtain information about the second dose of MMR vaccine because the administration of this dose was recommended at 12 years of years (out of inclusion range)

Not specified. Any time after MMR immunisation

No significant association.

RR 1.14; 95% CI from 0.90 to 1.45

LowHigh
Table 15. MMR and gait disturbances
  1. CI: confidence interval

  2. CSF: cerebro-spinal fluid

  3. GP: general practitioner

  4. RI: relative incidence

Study and designOutcomePopulationDefinitionFindingsMMR typeRisk timeResultsRisk of biasGeneralisability

Self controlled case series

Hospitalisation for gait disturbance127 children aged 12 to 24 months with admission between April 1995 and June 2001

(1) presumptive viral/post-viral ataxia (clinical history of ataxia and evidence of encephalomyelitis or cerebellitis with lymphocytosis in the cerebrospinal fluid (CSF) or encephalographic changes);

(2) probable post-viral ataxia (history consistent with ataxia but CSF/other investigations inconclusive or not done and no other cause identified);

(3) probably not post-viral gait disturbance (vague symptoms not suggestive of cerebellar ataxia, e.g. unsteady gait associated with constipation or gastroenteritis);

(4) non-ataxic, non-viral gait disturbance (including limp after trauma, septic bone or joint disease, unsteadiness following drug ingestion);

(5) transient synovitis/“irritable hip” (a transient condition described following viral illnesses and with no long term sequelae)

Review of hospital computerised records (April 1995 to June 2001, children aged 12 to 24 months) with ICD-10 diagnoses related to acute gait disorder (G111, G112, G25, R26, R27, R29, H55, and F984)Not reported0 to 30 and 0 to 60 days

No significant association.

Relative incidence not statistically relevant neither for the to 30 days risk time (RI 0.83; 95% CI 0.24 to 2.84) nor for the 31 to 60 days risk time (RI 0.20; 95% CI 0.03 to 1.47)

MediumLow

Self controlled case series

GP visits for gait disturbance1398 children aged 12 to 24 months born between 1988 and 1997

(A) ataxia (including cerebellar ataxia and ataxic gait)

(B) unsteady/veering/shuffling gait

(C) gait abnormality - unspecified

(D) limp/limping gait

(E) poor mobility

(F) abnormal /involuntary movements

Analysis of General Practice Research Database (GPRD) records (children aged 12 to 24 months, born between 1988 and 1997)Not reported0 to 5, 6 to 30, 31 to 60, 6 to 60 days

No significant association.

Relative incidence of all cases (A to F):

- within 6 to 30 days: 0.90; 95% CI from 0.70 to 1.17

- within 31 to 60 days: 0.95; 95% CI from 0.77 to 1.19

- within 6 to 60 days: 0.93; 95% CI from 0.78 to 1.12

MediumMedium
Table 16. MMR and inflammatory bowel disease
  1. CD: Crohn's disease

  2. CI: confidence interval

  3. IBD: inflammatory bowel diseases

  4. HMO: Health Maintenance Organisation

  5. OR: odds ratio

  6. RR: risk ratio

Study and designOutcomePopulationDefinitionFindingsMMR typeRisk timeResultsRisk of biasGeneralisability

Case-control

Inflammatory bowel diseases (IBD) hospitalisation

142 IBD cases (75 with Crohn's disease and 67 with ulcerative colitis)

432 controls matched for sex, Health Maintenance Organisation and birth year

After abstraction of medical records, IBD cases were classified as:

Definite IBD: as persons diagnosed with IBD by a gastroenterologist at one of the HMOs who had at least 1 sign or symptom compatible with IBD (such as bloody stool and/or bloody diarrhoea or severe and/or recurrent abdominal pain) recorded and a diagnostic test result (such as biopsy with pathology specimen, colonoscopy, or sigmoidoscopy) consistent with IBD.

Probable IBD: the diagnosis of IBD was made by either an HMO non-gastroenterologist physician or a gastroenterologist outside the HMO, there was at least 1 sign or symptom compatible with IBD, and there was a diagnostic test result consistent with IBD

IBD cases (suspected or questionable), that did not correspond to these criteria were excluded from analysis. IBD (definite and probable) were further classified as Crohn's disease and ulcerative colitis cases

Review of medical records contained in the Vaccine Safety Datalink database of 4 Health Maintenance Organisations (HMOs) and identified by using ICD-9 codes specific for Crohn's disease, ulcerative colitis and idiopathic proctocolitis (555 and 556). Outpatient, emergency department, urgent care clinic visits were available for 3 out of the 4 HMOs and were also taken in accountNot reportedNot specified. MMR administered at any time before index date

No statistically relevant association between MMR vaccine exposure and increased risk of:

- all IBD (OR 0.59; 95% CI 0.21 to 1.69);

- CD (OR 0.4; 95% CI 0.08 to 2.0)

- ulcerative colitis (OR 0.80; 95% CI 0.18 to 3.56)

LowHigh

Ecological

Crohn's disease (CD) emergency admissionsCD emergency admission cases (n = 4463) observed between April 1991 and March 2003 in England population aged below 19 years (about 11.6 million) Emergency admissions for CD between April 1991 and March 2003 among subjects aged 4 to 18 years in EnglandNot reportedNot specified

No significant association

RR 0.95; 95% CI from 0.84 to 1.08

HighMedium
Table 17. MMR and demyelinating diseases
  1. CHSH: child health and school health records

  2. CI: confidence interval

  3. CIS: clinically isolated syndromes

  4. MMR: measles, mumps, rubella vaccine

  5. MS: multiple sclerosis

  6. OR: odds ratio

Study and designOutcomePopulationDefinitionFindingsMMR-typeRisk timeResultsRisk of biasGeneralisability

Cohort study

Multiple sclerosis (MS, probable or definite) and Clinically Isolated Syndromes (CIS)Birth cohorts 1959 to 1990 from residents in the greater Gothenburg area (Sweden), corresponding to 5.9 million person-years. 534 MS and CIS cases with onset between 10 and 39 years before July 2004 has been ascertainedMS defined accordingly to the 4 Poser's criteria with addition of CIS casesAnalysis, review, and reclassification of medical records contained in the Gothenburg MS registerNot specified. Impact of mass vaccination with different vaccine type (monovalent measles, mumps or rubella, so as MMR) in different birth cohorts in different times on MS incidence was assessedNot specifiedNo vaccine related changes in MS incidence changes were detectedHighMedium

Case-control study

Multiple sclerosis (MS, probable or definite) and Clinically Isolated Syndromes (CIS)

Cases (n = 206) : Birth years 1959 to 1986, to be resident in the greater Gothenburg area (Sweden), MS onset from age of 10 years onwards, did attend the 6th school grade within study area, availability of CHSH records

Controls (n = 888): matched to cases for year of birth by random selection from the population register. Controls should have attended the 6th school grade within study area, and have available CHSH record

See aboveSee above

Not specified.

Exposure to MMR vaccine was classified in 4 categories, accordingly to age of subjects at MMR immunisation:

- no MMR vaccination;

- early MMR vaccination only (MMR immunisation within 10 years of age);

- late MMR vaccination only (MMR immunisation after 10 years of age);

- both an early and late MMR vaccination

Not specified

No significant association for vaccinated versus unvaccinated

OR 1.13; 95% CI from 0.62 to 2.05

HighMedium
Table 18. MMR and bacterial or viral infections
  1. CI: confidence interval

  2. ICD: international classification of diseases

  3. n: number of participants

  4. OR: odds ratio

Study and designOutcomePopulationDefinitionFindingsMMR typeRisk timeResultsRisk of biasGeneralisability

Self controlled case series

Lobar pneumoniaInfants aged 12 to 23 months hospitalised for viral or bacterial infection between April 1995 and May 2005 identified from hospital admission records (n = 2025 accounting for 2077 admissions)

ICD-9 codes: 481

ICD-10 codes: J18.1

Review of computerised hospital admission records from North, East, and South London, Essex, East Anglia, Sussex and Kent using ICD-9 or ICD-10 codesNot specified0 to 30; 31 to 60; 61 to 90; 0 to 90 days after immunisationLower risk association within 0 to 30 (OR 0.65; 95% CI from 0.48 to 0.86) or 0 to 90 days after immunisation (OR 0.77; 95% CI from 0.64 to 0.93)HighLow

Self controlled case series

Invasive bacterial infectionsSee above

ICD-9 codes: 036, 038, 320, 711.0, 730.0

ICD-10 codes: A39, A40, A41, G00, M00, M86, J13 X

See aboveNot specified0 to 30; 31 to 60; 61 to 90 ; 0 to 90 days after immunisationNo significant association within any of the considered times intervals after immunisationHighLow

Self controlled case series

Encephalitis/meningitisSee above

ICD-9 codes: not specified

ICD-10 codes: A85, A86, A87, A88, A89

See aboveNot specified0 to 30; 31 to 60; 61 to 90; 0 to 90 days after immunisationNo significant association within any of the considered times intervals after immunisationHighLow

Self controlled case series

HerpesSee above

ICD-9 codes: not specified

ICD-10 codes: B00

See aboveNot specified0 to 30; 31 to 60; 61 to 90; 0 to 90 days after immunisationIncreased risk between 31 and 60 days after immunisation (OR 1.69; 95% CI from 1.06 to 2.70). No significant association for the other time intervalsHighLow

Self controlled case series

PneumoniaSee above

ICD-9 codes: not specified

ICD-10 codes: J12

See aboveNot specified0-30; 31-60; 61-90; 0-90 days after immunisationNo significant association within any of the considered times intervals after immunisationHighLow

Self-controlled case series

Varicella zosterSee above

ICD-9 codes: not specified

ICD-10 codes: B01, B02

See aboveNot specified0 to 30; 31 to 60; 61 to 90; 0 to 90 days after immunisationLower risk within 30 days after immunisation. No significant association for the other time intervalsHighLow

Self controlled case series

Miscellaneous viral infectionsSee above

ICD-9 codes: not specified

ICD-10 codes: B08, B09, B15, B17, B25, B27, B34

See aboveNot specified0 to 30; 31 to 60; 61 to 90; 0 to 90 days after immunisationNo significant association within any of the considered times intervals after immunisationHighLow

Appendices

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Characteristics of studies
  11. Data and analyses
  12. Additional Tables
  13. Appendices
  14. Feedback
  15. What's new
  16. History
  17. Contributions of authors
  18. Declarations of interest
  19. Sources of support
  20. Differences between protocol and review
  21. References

Appendix 1. Definitions

A case-control study is an epidemiological study usually used to investigate the causes of disease. Study participants who have experienced an adverse outcome or disease are compared with participants who have not. Any differences in the presence or absence of hypothesised risk factors are noted.

A cohort study is an epidemiological study where groups of individuals are identified who vary in their exposure to an intervention or hazard and are followed to assess outcomes. Association between exposure and outcome are then estimated. Cohort studies are best performed prospectively but can also be undertaken retrospectively if suitable data records are available.

An historical controlled trial (HCT) is a study with control participants for whom data were collected at a time preceding that at which the data are gathered on the group being studied.

Indirect comparisons are comparisons of the two or more index groups with a control (usually in randomly allocated groups). The comparisons are usually not contemporaneous and inference is made from the comparisons to the general population.

A randomised controlled trial (RCT) is any study on humans in which the individuals (or other experimental units) followed in the study were definitely or possibly assigned prospectively to one of two (or more) alternative forms of health care using random allocation.

A controlled clinical trial (CCT) is any study on humans in which the individuals (or other experimental units) followed in the study were definitely or possibly assigned prospectively to one of two (or more) alternative forms of health care using some quasi-random method of allocation (such as alternation, date of birth or case record number).

A time-series study is a comparative design with controls in which measurements are made at different times to allow trend detection and before-and-after exposure assessment.

An ecological study is a study in which the units of analysis are populations or groups of people rather than individuals. Inference is then made by observing the difference in incidence between populations of the event in question.

A case cross-over study is a design in which exposures of individuals during one period is compared by matched-pair analyses to their own exposure during a preceding period of similar length.

Case-coverage design is a study comparing prevalence of exposure in individuals with exposure in the reference population. No denominator data are required and the population coverage information is derived from summary statistics. When coverage information is derived from a population sample, the design is that of a case-base study.

A self controlled case series study uses individuals as their own controls. The ages at vaccination are regarded as fixed and the age at the time of an adverse event is the random variable of interest within a pre-determined observation period.

A person-time cohort study is a study in which outcome rates in higher and lower risk periods for the same individuals are compared. The time of exposure is regarded as fixed and person-time periods for the risk categories are added and the rates are compared. When the risk periods are not summed but are within each individual, the design is that of a self controlled case series study.

Appendix 2. EMBASE search strategy

Effectiveness

#1 'vaccine'/exp OR

#2 (trivalen* OR combin* OR simultan* OR tripl* OR trebl*) AND (vaccin* OR immuni* OR inoculat*)

#3 ('measles'/exp OR 'mumps'/exp OR 'rubella'/exp) OR (measles:ab,ti AND mumps:ab,ti AND rubella:ab,ti)

#4 1# OR #2

#5 #4 AND #3

#6 'measles vaccine'/exp OR 'mumps vaccine'/exp OR 'rubella vaccine'/exp OR 'measles mumps rubella vaccine'/exp

#7 'measles mumps rubella':ab,ti OR mmr:ab,ti

#8 #5 OR #6 OR #7

#9 #8 AND ([child]/lim OR [adolescent]/lim)

#10 #8 AND (child* OR pediatric OR paediatric OR adolescent* OR infant* OR preschool* OR school* OR toddler*)

#11 #9 OR #10

#12 #11 AND [embase]/lim AND [01-06-2004]/sd

Safety

#1 ('vaccine'/exp) OR ((trivalen* OR combin* OR simultan* OR tripl* OR trebl*) AND (vaccin* OR immuni* OR inoculat*))

#2 measles AND mumps AND rubella

#3 #1 AND #2

#4 'measles vaccine'/exp AND 'mumps vaccine'/exp AND 'rubella vaccine'/exp

#5 mmr:ti,ab

#6 (measles AND mumps AND rubella) AND (vaccin* OR immuni* OR inoculat*)

#7 #3 OR #4 OR #5 OR #6

#8 'adverse drug reaction'/exp OR 'chemically induced disorder'/exp OR 'toxicity'/exp

#9 ((adverse OR side OR serious OR severe OR threatening OR long AND term OR 'long term') AND (event* OR effect* OR disease* OR condition*)) OR hypersensitiv* OR sensitiv* OR safe* OR pharmacovigil*

#10 'postmarketing surveillance'/exp OR 'drug monitoring'/exp OR 'drug screening'/exp OR 'risk'/exp

#11 'relative risk' OR risk OR causation OR causal OR 'odds ratio' OR etiol* OR aetiol*

#12 #8 OR #9 OR #10 OR #11

#13 #7 AND #12

#14 #7 AND #12 AND ([child]/lim OR [adolescent]/lim)

#15 child* OR pediatric OR paediatric OR adolescent* OR infant* OR preschool* OR school* OR toddler*

#16 #13 AND #15

#17 #14 OR #16

#18 #14 OR #16 AND [embase]/lim AND [01-06-2004]/sd

Appendix 3. Previous searches

Effectiveness

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2004, Issue 4) which contains the Cochrane Acute Respiratory Infections (ARI) Group's specialised trials register, and MEDLINE (1966 to December 2004) to identify randomised and quasi-randomised controlled trials identified through electronic databases and handsearches. We used the following search terms.

MEDLINE (Webspirs)

# 1 explode 'Vaccines-Combined' / all subheadings

# 2 explode 'Vaccines-Attenuated' / all subheadings

# 3 #1 or #2

# 4 trivalen* or combin* or simultan* or tripl* or trebl*

# 5 vaccin* or immuni* or inoculat*

# 6 # 4 and # 5

# 7 # 3 or # 6

# 8 explode 'Measles-' / all subheadings

# 9 explode 'Mumps-' / all subheadings

# 10 explode 'Rubella-' / all subheadings

# 11 measles and mumps and rubella

# 12 #8 or #9 or #10 or #11

# 13 #7 and #12

# 14 explode 'Measles-Vaccine'

# 15 explode 'Mumps-Vaccine'

# 16 explode 'Rubella-Vaccine'

# 17 explode 'Measles-Mumps-Rubella-Vaccine' / all subheadings

# 18 measles mumps rubella or MMR

# 19 #14 or #15 or #16 or #17 or #18

# 20 #13 or #19

We adapted these subject terms to search the other databases. We searched EMBASE (1980 to the end of 2004) to identify controlled trials in combination with subject terms adapted for EMBASE; Biological Abstracts (1985 to the end of 2004); and Science Citation Index (1980 to present). We also searched the Cochrane Database of Systematic Reviews (CDSR) and NHS Database of Abstracts of Reviews of Effects (DARE) for published reviews.

We updated the searches during the third July week of 2010, performing searches on the same databases and using the same search strategy terms.

Safety

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2004, Issue 4) which contains the Cochrane Acute Respiratory Infections (ARI) Group's specialised trials register to identify reports of randomised and quasi-randomised controlled trials and published reviews. We searched The Cochrane Library to identify reports from the results of handsearching the journal Vaccine (1983 to 2004).

We also searched MEDLINE (1966 to December 2004) using the following search terms.

MEDLINE (OVID)

1 Vaccines-Combined [mesh word (mh)]

2 Vaccines-Attenuated

3 ((trivalen*[text word (tw)] or combin* (tw) or simultan* (tw) or tripl* (tw) or trebl* (tw) and (vaccin* (tw) or immuni* (tw) or inoculat* (tw)))

4 or/1-3

5 measles (tw) and mumps (tw) and rubella (tw)

6 4 and 5

7 Measles-Vaccine(mh) and Mumps-Vaccine (mh) and Rubella-Vaccine (mh)

8 MMR [title, abstract (ti,ab)]

9 (measles (tw) and mumps (tw) and rubella (tw) and (vaccin* (tw) or immuni* (tw) or inoculat* (tw))

10 or/6-9

11 adverse events [floating sub-heading (fs)] or chemically induced (fs) or complications (fs) or contraindications (fs) or toxicity (fs) or poisoning (fs) or drug effects (fs)

12 ((adverse (tw) near (effect* (tw) or event* (tw)) or side effect* (tw) or hypersensitiv* (tw) or sensitiv* (tw) or safe* (tw) or pharmacovigil* (tw)

13 explode Product-Surveillance-Postmarketing (mh) or Drug-Monitoring (mh) or Drug-Evaluation (mh) or explode Risk (mh) or Odds-Ratio (mh) or explode Causality (mh)

14 relative risk (tw) or risk (tw) or causation (tw) or causal (tw) or odds ratio (tw) or etiol* (tw) or aetiol* (tw) or etiology (fs) or epidemiology (fs)

15 or/11-14

16 10 and 15

This filter was adapted for searching EMBASE (1980 to the end of 2004), Biological Abstracts (1985 to the end of 2004) and Science Citation Index (1980 to the end of 2004).

Appendix 4. Data extraction form

PART 1

Description of study

Methods

Participants

Interventions-Exposure

Outcomes effectiveness

Outcomes safety

Results

Notes

PART 2a

Methodological quality assessment(RCT and CCT only)

Type of randomisation:

A = individual participants allocated to vaccine or control group.

B = groups of participants allocated to vaccine or control group.

Generation of the allocation sequence:

A = Random

B = Quasi-random

C = Not described

Allocation concealment:

A = adequate, e.g. numbered or coded identical containers administered sequentially, on-site computer system that can only be accessed after entering the characteristics of an enrolled participant, or serially numbered, opaque, sealed envelopes.

B = possibly adequate, e.g. sealed envelopes that are not sequentially numbered or opaque.

C = inadequate, e.g. open table of random numbers.

D = not described.

Blinding:

A = double-blinding

B = single-blind

C = no blinding

D = unclear

Baseline data :

1 = reported

2 = not reported

Participant flow:

1 = Reported

2 = Only described

3 = Absent

Exclusion of participants :

1 = mentioned

2 = not mentioned

3 = not applicable

Follow-up:

Average duration of follow-up and number of losses to follow-up.

Note

PART 2b

Description of interventions and outcomes (RCT and CCT only)

Vaccines used

Vaccines and composition | Product and manufacturer | Schedule & dosage and status | Route of administration

Arm 1

Arm 2

Arm 3

Arm 4

Placebo

Rule: index vaccine goes in the Arm 1 line, placebo in the last line

Status: primary, secondary or tertiary immunisation.

Details of participants

Enrolled | Missing | Reasons | Inclusion in analysis | Notes

Active arm 1

Active arm 2

Active arm 3

Active arm 4

Controls

Outcomes list efficacy/effectiveness

Outcome | How defined | Description/Follow-up/Notes

Outcomes list - safety

Outcome | How defined | Description/Follow-up/Notes

Investigators to be contacted for more information? Yes/No

Contact details (principal investigator, fill in only if further contact is necessary)

PART 2c

Data extraction and manipulation (to be used for dichotomous or continuous outcomes; RCT and CCT only)

Comparison

Outcomes | n/N Index Arm | n/N Comparator

Outcomes | n/N Index Arm | n/N Comparator

Outcomes | n/N Index Arm | n/N Comparator

Notes (for statistical use only)

PART 3a

Methodological quality assessment (non-randomised studies only)

NEWCASTLE - OTTAWA QUALITY ASSESSMENT SCALE - CASE-CONTROL STUDIES

Selection

1. Is the case definition adequate?

a. yes, with independent validation

b. yes, e.g. record linkage or based on self reports

c. no description

2. Representation of the cases

a. consecutive or obviously representative series of cases

b. potential for selection biases or not stated

3. Selection of controls

a. community controls

b. hospital controls

c. no description

4. Definition of controls

a. no history of disease (endpoint)

b. no description of source

Comparability

1. Comparability of cases and controls on the basis of the design or analysis

a. study controls for _______________ (select the most important factor)

b. study controls for any additional factor (this criteria could be modified to indicate specific control for a second important factor)

Exposure

1. Ascertainment of exposure

a. secure record (e.g. surgical records)

b. structured interview where blind to case/control status

c. interview not blinded to case/control status

d. written self report or medical record only

e. no description

2. Same method of ascertainment for cases and controls

a. yes

b. no

3. Non-response rate

a. same rate for both groups

b. non-respondents described

c. rate different and no designation

NEWCASTLE - OTTAWA QUALITY ASSESSMENT SCALE - COHORT STUDIES

Note: a study can be awarded a maximum of one star for each numbered item within the Selection and Outcome categories. A maximum of two stars can be given for Comparability

Selection

1. Representation of the exposed cohort

a. truly representative of the average _______________ (describe) in the community

b. somewhat representative of the average ______________ in the community

c. selected group of users e.g. nurses, volunteers

d.no description of the derivation of the cohort

2. Selection of the non-exposed cohort

a. drawn from the same community as the exposed cohort

b. drawn from a different source

c. no description of the derivation of the non-exposed cohort

3. Ascertainment of exposure

a. secure record (e.g. surgical records)

b. structured interview

c. written self report

d. no description

4. Demonstration that outcome of interest was not present at start of study

a. yes

b. no

Comparability

1. Comparability of cohorts on the basis of the design or analysis

a. study controls for _____________ (select the most important factor)

b. study controls for any additional factor * (this criteria could be modified to indicate specific control for a second important factor)

Outcome

1. Assessment of outcome

a. independent blind assessment

b. record linkage

c. self report

d. no description

2. Was follow-up long enough for outcomes to occur

a. yes (select an adequate follow-up period for outcome of interest)

b. no

3. Adequacy of follow-up of cohorts

a. complete follow-up - all subjects accounted for

b. subjects lost to follow-up unlikely to introduce bias - small number lost - > ____ % (select an adequate %) follow-up, or description provided of those lost) *

c. follow-up rate < ____% (select an adequate %) and no description of those lost

d. no statement

CRD QUALITY ASSESSMENT SCALE HISTORICAL CONTROLLED TRIALS

- Was the assignment to the treatment groups really random?

Adequate: random numbers table or computer and central office or coded packages

Possibly adequate: sealed envelopes without further description or serially number opaque, sealed envelopes

Inadequate: alternation, case record number, birth date, or similar procedures.

Unknown: just the term ‘randomised’ or ‘randomly allocated’ used

- Was the treatment allocation concealed?

Adequate: the person who decides on eligibility cannot distinguish or predict cases from controls centralised or pharmacy-controlled randomisation, serially numbered identical vials, unreadable, random sequence, etc.

Inadequate: where foreknowledge of allocation to group is possible: use of alternation, case record numbers, birth dates or week days, open random number list.

Unknown: no details given in text.

- Were the groups similar in baseline regarding the prognostic factors?

Reported: details reported on which patients were recruited.

Unknown: no details given.

- Were the eligibility criteria specified?

Adequate: reported: appropriate criteria listed.

Inadequate: insufficient, inappropriate criteria given.

Unknown: no details given.

- Were the outcome assessors blinded to the treatment allocation?

Adequate: independent person(s) or investigator if secure double-blind conditions met.

Inadequate: clinician is assessor on trial were it is possible (from symptoms, lab results, etc) to distinguish allocation.

Unknown: no mention in text.

- Was the care provider blinded?

Adequate: placebo described as ‘indistinguishable.’

Possibly adequate: just ‘double-blind’ and no further description of procedures or placebo.

Inadequate: placebo distinguishable from vaccine

Unknown: no details in text.

- Was the patient blinded?

Adequate: placebo described as ‘indistinguishable’ and blinding procedures secure.

Possibly adequate: the phrase ‘double-blind’ used in text with no further description.

Inadequate: no placebo or clearly distinguishable from vaccine.

Unknown: no details given.

- Did the analysis include an intention-to-treat analysis?

Adequate: details of analysis presented including a.) percentage of missing, distribution over groups, and procedure for handling; b.) Drop-out rate less than 20% for each group and reasons given.

Possibly adequate: incomplete data.

Inadequate: wrong procedures used.

Unknown: no mention in text or not deducible from tables.

CRD QUALITY ASSESSMENT SCALE - INTERRUPTED TIME SERIES AND CASE CROSS-OVER STUDIES

- Were the eligibility criteria specified?

Adequate: criteria appropriate to outcomes being measured.

Inadequate: exclusion criteria impact on outcomes being measured.

Unknown: no mention in text.

- Were objective measurements taken both before and after the intervention?

Adequate: relevant data recorded before and after a verifiable intervention.

Inadequate: non-verifiable intervention points or incomplete data before/after records.

- Was the time frame appropriate?

Adequate: the outcomes being measured are detectable within the study time frame.

Inadequate: brevity of time frame precludes accurate measure, e.g. of long-term outcomes.

Unknown: no mention in text.

- Was exposure adequate and appropriate?

Adequate: sufficient time to allow plausible association was allowed. Exposure was to the vaccine and no obvious confounding interventions were present.

CRD QUALITY ASSESSMENT SCALE - ECOLOGICAL STUDIES

- Were the population selection criteria appropriate?

Appropriate - anything likely to minimise the play of confounders e.g. same age and ethnic group

- Were the populations comparable for exposure?

Comparable - anything likely to minimise the play of confounders e.g. same type of records.

- Were the outcomes verifiable?

Verifiable anything likely to minimise the play of confounders.

- Were the conclusions of the study justified by the evidence presented?

Justified anything likely to minimise the play of confounders, e.g. stock taken of the limitations of the study and alternative explanation offered.

CRD QUALITY ASSESSMENT SCALE - PERSON TIME COHORT DESIGN

1) Representativeness of the cohort

a) truly representative of the average____________(describe) in the community

b) somewhat representative of the average___________in the community

c) selected group of users, e.g. nurses, volunteers

d) no description of the derivation of the cohort

2) Ascertainment of the exposure

a) secure record (e.g. surgical records)

b) structured interview

c) written self report

d) no description

3) Exposures to multiple vaccines

a) has been documented in the analysis

b) has been accounted for in the analysis

c) unclear

4) Are the risk periods well-defined?

5) Are the risk periods appropriate?

6) Have known confounders been controlled for?

a) Yes (for the example of exposure to live attenuated vaccines: are the risk periods consistent with what is known of the effects of the vaccine)

b) No

C) Unclear

CRD QUALITY ASSESSMENT SCALE - SELF CONTROLLED CASE SERIES

1) Are the risk periods well-defined?

2) Are the risk periods appropriate?

3) Has exposure been verified?

4) Exposure to multiple vaccines

a) has been documented in the analysis

b) has been accounted for in the analysis

c) unclear

PART 3b

Description of interventions and outcomes. Non-randomised longitudinal studies only

Vaccines used

Vaccines and composition | Product and manufacturer | Schedule & dosage and status | Route of administration

Group 1

Group 2

Group 3

Group 4

Comparator

Rule: index vaccine goes in the Group 1 line, placebo in the last line

Vaccine batch numbers

Details of participants

Enrolled | Missing | Reasons | Inclusion in analysis | Notes

Group 1

Group 2

Group 3

Group 4

Comparator

Outcomes list - effectiveness

Outcome | How defined (including length of follow-up) | Description/Follow-up/Notes

Outcomes list - safety

Outcome | How defined (including length of follow-up) | Description/Follow-up/Notes

Investigators to be contacted for more information? Yes/No

Contact details (principal investigator, fill in only if further contact is necessary):

PART 3c

Data extraction and manipulation (to be used for dichotomous outcomes). Non-randomised longitudinal studies only

Comparison

Outcomes | n/N Index Group | n/N Comparator

Notes (for statistical use only)

PART 3d

Description of studies. Case-control studies only

Event 1

How defined | Enrolled | Missing | Reasons | Inclusion in analysis

Cases n =

Controls n =

Exposure

How defined | How ascertained | Notes

Vaccine Exposure 1

Vaccine Exposure 2

Event 2

How defined | Enrolled | Missing | Reasons | Inclusion in analysis

Cases n =

Controls n =

Exposure

How defined | How ascertained | Notes

Vaccine exposure 1

Vaccine exposure 2

Notes (for statistical use only)

Part 3e

Data extraction and manipulation. Case-control studies only

Status | Numerator | Denominator

Cases

Control

Notes (for statistical use only)

Feedback

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Characteristics of studies
  11. Data and analyses
  12. Additional Tables
  13. Appendices
  14. Feedback
  15. What's new
  16. History
  17. Contributions of authors
  18. Declarations of interest
  19. Sources of support
  20. Differences between protocol and review
  21. References

Vaccines for MMR in children

Summary

Based on the title and the introduction, this is a review of the effectiveness and safety of MMR vaccine. However, the authors concluded that they "could find no comparative studies assessing the effectiveness of MMR that fitted [their] inclusion criteria as all had serological outcomes" and then continued to discuss only studies of MMR vaccine safety. The review and discussion of the safety of these vaccines accurately reflects the literature; rather this letter is about the conclusions regarding vaccine effectiveness.

The authors' conclusion that no comparative studies exist about the effectiveness of MMR vaccines do not seem to be borne out by other reviews of the literature. Using the stated inclusion criteria, one can find several studies of the effectiveness of MMR vaccine against individual diseases (measles, mumps or rubella) using cohort and case-control methods. Numerous retrospective studies have also documented the effectiveness of measles-containing vaccines (vs. MMR vaccine) for preventing measles. A partial list of articles found in PubMed using the criteria (measles OR mumps OR rubella) AND "vaccine efficacy", screened for articles including calculation of clinical vaccine efficacy, follows this feedback.

The authors also restricted their search to articles appearing in 1966 and later; given that measles vaccines were developed and used in clinical trials in the late 1950s and 1960s, the authors should strongly consider repeating their search for all years ? or, at a minimum, from 1954 to the present, given that measles virus was first isolated in 1954.

The authors fail to note that the effectiveness of measles, mumps and rubella vaccines were documented individually before their combination into MMR vaccine, and that the serological correlates of protection are well defined for protection against measles and rubella virus infections. These serological correlates of protection are now used to compare various vaccine virus strains and combinations.

I would strongly suggest that this review be revised so that it includes a discussion of articles that assess the efficacy of MMR vaccines or the individual vaccines included in MMR vaccines against their target diseases using any appropriate methodology. The authors could then compare the efficacy of the individual vaccines with that of the combined vaccine. If they choose not to include any of the articles found that demonstrate clinical vaccine efficacy, it would be helpful if the authors could provide a clear justification for doing so. At the very least, the title and introduction should be changed so that it is clear that the review is of studies of the safety of the vaccines, not their efficacy.

Thank you for your consideration of these comments

Reply

Dear Dr. Perry,

Many thanks for the attention paid to our MMR vaccines review. We have read with interest you observation, we must though call your attention to the fact that for Cochrane Reviews inclusion criteria are established rigorously from an experienced team of specialists with the aim to made comparisons so homogeneous as possible and to consider preferably those outcomes that have direct implications for decision making in Public Health. For this reason the evaluation of evidences based only on serological parameters is debatable or at least not overall accepted at the rate of their indirect nature.

It shouldn't be forgotten that our review was also performed in order to provide some responses to an important specific question in Public Health regarding the suspected association of MMR vaccine with serious diseases. As reported in the conclusions, vaccine efficacy is in any case out of the question, since we consider as important point of evidence the fact that in many countries eradication of the targeted diseases could be achieved by means of mass immunisation programs.

We agree that studies in which single MMR antigens are tested could contribute some evidence, but in this review the only MMR in comparison with placebo or not intervention was considered. Effectiveness or efficacy of measles vaccine has been already reviewed by other authors (e.g. 1, 2, 3 ; all present in DARE).

Many studies out of those indicated by you in the list, report results of a single component vaccines and are for this reason not includible. In some of them MMR is tested, but all appear results of surveys and consequently their design is markedly affected from different types of biases which would preclude in any case their inclusion in the analysis. To complete background information about efficacy of MMR vaccines (or of different strain combinations), we may comment briefly on the evidence from these and other similar reports in occasion of the next update of the review.

All Authors

1. Aaby P, Samb B, Simondon F, Seck A M, Knudsen K, Whittle H. Non-specific beneficial effect of measles immunisation: analysis of mortality studies from developing countries. BMJ. 1995; 311:481-485.

2. Anders J F, Jacobson R M, Poland G A, Jacobsen S J, Wollan P C. Secondary failure rates of measles vaccines: a metaanalysis of published studies. Pediatric Infectious Disease Journal. 1996; 15(1):62-66.

3. Cooper W O, Boyce T G, Wright P F, Griffin M R. Do childhood vaccines have non-specific effects on mortality?. Bulletin of the World Health Organization. 2003; 81(11):821-826.

Contributors

Robert Perry, MD, MPH

Feedback added 09/08/06

What's new

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Characteristics of studies
  11. Data and analyses
  12. Additional Tables
  13. Appendices
  14. Feedback
  15. What's new
  16. History
  17. Contributions of authors
  18. Declarations of interest
  19. Sources of support
  20. Differences between protocol and review
  21. References

Last assessed as up-to-date: 12 May 2011.

DateEventDescription
12 May 2011New search has been performedThe searches have been updated and 33 new trials have been included in the review, including one previously excluded trial (Marolla 1998). Fifty new trials were excluded and 13 new trials are awaiting classification. The conclusions remain unchanged.
1 February 2011New citation required but conclusions have not changedA new author joined the team to update this review.

History

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Characteristics of studies
  11. Data and analyses
  12. Additional Tables
  13. Appendices
  14. Feedback
  15. What's new
  16. History
  17. Contributions of authors
  18. Declarations of interest
  19. Sources of support
  20. Differences between protocol and review
  21. References

Protocol first published: Issue 3, 2003

Review first published: Issue 4, 2005

DateEventDescription
6 May 2008AmendedConverted to new review format.
8 August 2006Feedback has been incorporatedFeedback comment and reply added to review.
18 December 2004New search has been performedSearches conducted.

Contributions of authors

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Characteristics of studies
  11. Data and analyses
  12. Additional Tables
  13. Appendices
  14. Feedback
  15. What's new
  16. History
  17. Contributions of authors
  18. Declarations of interest
  19. Sources of support
  20. Differences between protocol and review
  21. References

For this update Alessandro Rivetti (AR) performed the searches, and together with Maria Grazia Debalni (MGD) and Carlo Di Pietrantonj (CDP) applied inclusion criteria and extracted data. Vittorio Demicheli (VD) arbitrated on both study inclusion and extraction. All authors contributed to the final draft.

In the previous version, Vittorio Demicheli (VD), Tom Jefferson (TOJ) and Deirdre Price (DP) designed the protocol and carried out data extraction. VD arbitrated on study inclusion. Alessandro Rivetti (AR) carried out the effectiveness assessment and updated safety searches. All authors contributed to the final draft.

References

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Characteristics of studies
  11. Data and analyses
  12. Additional Tables
  13. Appendices
  14. Feedback
  15. What's new
  16. History
  17. Contributions of authors
  18. Declarations of interest
  19. Sources of support
  20. Differences between protocol and review
  21. References
  • References to studies included in this review
  • Ahlgren 2009a {published data only}
  • Ahlgren C, Oden A, Toren K, Andersen O. Multiple sclerosis incidence in the era of measles-mumps-rubella mass vaccinations. Acta Neurologica Scandinavica 2009;119(5):313-20.
  • Ahlgren 2009b {published data only}
  • Ahlgren C, Toren K, Oden A, Andersen O. A population-based case-control study on viral infections and vaccinations and subsequent multiple sclerosis risk. European Journal of Epidemiology 2009;24(9):541-52.
  • Beck 1989 {published data only}
  • Beck M, Welsz-Malecek R, Mesko-Prejac M, Radman V, Juzbasic M, Rajninger-Miholic M, et al.Mumps vaccine L-Zagreb, prepared in chick fibroblasts. I. Production and field trials. Journal of Biological Standards 1989;17(1):85-90.
  • Benjamin 1992 {published data only}
  • Benjamin CM, Chew GC, Silman AJ. Joint and limb symptoms in children after immunisation with measles, mumps, and rubella vaccine. BMJ 1992;304(6834):1075-8.
  • Bertuola 2010 {published data only}
  • Bertuola F, Morando C, Menniti-Ippolito F, Da Cas R, Capuano A, Perilongo G, et al.Association between drug and vaccine use and acute immune thrombocytopenia in childhood: a case-control study in Italy. Drug Safety 2010;33(1):65-72.
  • Black 1997 {published data only}
  • Black S, Shinefield H, Ray P, Lewis E, Chen R, Glasser J, et al.Risk of hospitalization because of aseptic meningitis after measles-mumps-rubella vaccination in one- to two-year-old children: an analysis of the Vaccine Safety Datalink (VSD) Project. Pediatric Infectious Disease Journal 1997;16(5):500-3.
  • Black 2003 {published data only}
  • Black C, Kaye JA, Jick H. MMR vaccine and idiopathic thrombocytopaenic purpura. British Journal of Clinical Pharmacology 2003;55(1):107-11.
  • Bloom 1975 {published data only}
  • Bloom JL, Schiff GM, Graubarth H, Lipp RW Jr, Jackson JE, Osborn RL, et al.Evaluation of a trivalent measles, mumps, rubella vaccine in children. Journal of Pediatrics 1975;87(1):85-7.
  • Bremner 2005 {published data only}
  • Bremner SA, Carey IM, DeWilde S, Richards N, Maier WC, Hilton SR, et al.Timing of routine immunisations and subsequent hay fever risk. Archives of Disease in Childhood 2005;90(6):567-73.
  • Bremner 2007 {published data only}
  • Bremner SA, Carey IM, DeWilde S, Richards N, Maier WC, Hilton SR, et al.Vaccinations, infections and antibacterials in the first grass pollen season of life and risk of later hayfever. Clinical and Experimental Allergy 2007;37(4):512-7.
  • Castilla 2009a {published data only}
  • Castilla J, Garcia Cenoz M, Arriazu M, Fernandez-Alonso M, Martinez-Artola V, Etxeberria J, et al.Effectiveness of Jeryl Lynn-containing vaccine in Spanish children. Vaccine 2009;27(15):2089-93.
  • Ceyhan 2001 {published data only}
  • Ceyhan M, Kanra G, Erdem G, Kanra B. Immunogenicity and efficacy of one dose measles-mumps-rubella (MMR) vaccine at twelve months of age as compared to monovalent measles vaccination at nine months followed by MMR revaccination at fifteen months of age. Vaccine 2001;19(31):4473-8.
  • Chamot 1998 {published data only}
  • Chamot E, Toscani L, Egger P, Germann D, Bourquin C. Estimation of the efficacy of three strains of mumps vaccines during an epidemic of mumps in the Geneva canton (Switzerland). Revue d'Epidemiologie et de Sante Publique 1998;46(2):100-7.
  • da Cunha 2002 {published data only}
  • da Cunha SS, Rodrigues LC, Barreto ML, Dourado I. Outbreak of aseptic meningitis and mumps after mass vaccination with MMR vaccine using the Leningrad-Zagreb mumps strain. Vaccine 2002;20(7-8):1106-12.
  • Davis 2001 {published data only}
  • Davis RL, Kramarz P, Bohlke K, Benson P, Thompson RS, Mullooly J, et al.Measles-mumps-rubella and other measles-containing vaccines do not increase the risk for inflammatory bowel disease: a case-control study from the Vaccine Safety Datalink project. Archives of Pediatric and Adolescent Medicine 2001;155(3):354-9.
  • DeStefano 2002 {published data only}
  • DeStefano F, Gu D, Kramarz P, Truman BI, Iademarco MF, Mullooly JP, et al.Childhood vaccinations and risk of asthma. Pediatric Infectious Disease Journal 2002;21(6):498-504.
  • DeStefano 2004 {published data only}
  • DeStefano F, Bhasin TK, Thompson WW, Yeargin-Allsopp M, Boyle C. Age at first measles-mumps-rubella vaccination in children with autism and school-matched control subjects: a population-based study in metropolitan Atlanta. Pediatrics 2004;113(2):259-66.
  • Dourado 2000 {published data only}
  • Dourado I, Cunha S, Teixeira MG, Farrington CP, Melo A, Lucena R, et al.Outbreak of aseptic meningitis associated with mass vaccination with a Urabe-containing measles-mumps-rubella vaccine: implications for immunization programs. American Journal of Epidemiology 2000;151(5):524-30.
  • Dunlop 1989 {published data only}
  • Dunlop JM, RaiChoudhury K, Roberts JS, Bryett KA. An evaluation of measles, mumps and rubella vaccine in a population of Yorkshire infants. Public Health 1989;103(5):331-5.
  • Edees 1991 {published data only}
  • Edees S, Pullan CR, Hull D. A randomised single blind trial of a combined mumps measles rubella vaccine to evaluate serological response and reactions in the UK population. Public Health 1991;105(2):91-7.
  • Fombonne 2001 {published data only}
  • Fombonne E, Chakrabarti S. No evidence for a new variant of measles-mumps-rubella-induced autism. Pediatrics 2001;108(4):E58.
  • Fombonne 2006 {published data only}
  • Fombonne E, Zakarian R, Bennett A, Meng L, McLean-Heywood D. Pervasive developmental disorders in Montreal, Quebec, Canada: prevalence and links with immunizations. Pediatrics 2006;118(1):e139-50.
  • France 2008 {published data only}
  • France EK, Glanz J, Xu S, Hambidge S, Yamasaki K, Black SB, et al.Risk of immune thrombocytopenic purpura after measles-mumps-rubella immunization in children. Pediatrics 2008;121(3):e687-92.
  • Freeman 1993 {published data only}
  • Freeman TR, Stewart MA, Turner L. Illness after measles-mumps-rubella vaccination. Canadian Medical Association Journal 1993;149(11):1669-74.
  • Giovanetti 2002 {published data only}
  • Giovanetti F, Laudani E, Marinaro L, Dogliani MG, Giachelli V, Giachino G, et al.Evaluation of the effectiveness of mumps immunization during an outbreak [Valutazione dell'efficacia della vaccinazione contro la parotite durante un'epidemia]. L'igiene Moderna 2002;117(3):201-9.
  • Goncalves 1998 {published data only}
  • Goncalves G, De Araujo A, Monteiro Cardoso ML. Outbreak of mumps associated with poor vaccine efficacy - Oporto Portugal 1996. Euro surveillance: European Communicable Disease Bulletin 1998;3(12):119-21.
  • Harling 2005 {published data only}
  • Harling R, White JM, Ramsay ME, Macsween KF, van den Bosch C. The effectiveness of the mumps component of the MMR vaccine: a case control study. Vaccine 2005;23(31):4070-4.
  • Honda 2005 {published data only}
  • Honda H, Shimizu Y, Rutter M. No effect of MMR withdrawal on the incidence of autism: a total population study. Journal of Child Psychology and Psychiatry, and Allied Disciplines 2005;46(6):572-9.
  • Hviid 2004 {published data only}
  • Hviid A, Stellfeld M, Wohlfahrt J, Melbye M. Childhood vaccination and type 1 diabetes. New England Journal of Medicine 2004;350(14):1398-404.
  • Hviid 2008 {published data only}
  • Hviid A, Melbye M. Measles-mumps-rubella vaccination and asthma-like disease in early childhood. American Journal of Epidemiology 2008;168(11):1277-83.
  • Jonville-Bera 1996 {published data only}
  • Jonville-Bera AP, Autret E, Galy-Eyraud C, Hessel L. Thrombocytopenic purpura after measles, mumps and rubella vaccination: a retrospective survey by the French regional pharmacovigilance centres and Pasteur-Merieux serums et vaccins. Pediatric Infectious Disease Journal 1996;15(1):44-8.
  • Lerman 1981 {published data only}
  • Lerman SJ, Bollinger M, Brunken JM. Clinical and serologic evaluation of measles, mumps, and rubella (HPV-77:DE-5 and RA 27/3) virus vaccines, singly and in combination. Pediatrics 1981;68(1):18-22.
  • Lopez Hernandez 2000 {published data only}
  • Lopez Hernandez B, Martin Velez RM, Roman Garcia C, Penalver Sanchez I, Lopez Rosique JA. An epidemic outbreak of mumps. A study of vaccinal efficacy [Brote epidemico de parotiditis. Estudio de la efectividad vacunal]. Atencion primaria/Sociedad Española de Medicina de Familia y Comunitaria 2000;25(3):148-52.
  • Ma 2005 {published data only}
  • Ma X, Does MB, Metayer C, Russo C, Wong A, Buffler PA. Vaccination history and risk of childhood leukaemia. International Journal of Epidemiology 2005;34(5):1100-9.
  • Mackenzie 2006 {published data only}
  • Mackenzie DG, Craig G, Hallam NF, Moore J, Stevenson J. Mumps in a boarding school: description of an outbreak and control measures. British Journal of General Practice 2006;56(528):526-9.
  • Madsen 2002 {published data only}
  • Madsen KM, Hviid A, Vestergaard M, Schendel D, Wohlfahrt J, Thorsen P, et al.A population-based study of measles, mumps, and rubella vaccination and autism. New England Journal of Medicine 2002;347(19):1477-82.
  • Makela 2002 {published data only}
  • Makela A, Nuorti JP, Peltola H. Neurologic disorders after measles-mumps-rubella vaccination. Pediatrics 2002;110(5):957-63.
  • Makino 1990 {published data only}
  • Makino S, Sasaki K, Nakayama T, Oka S, Urano T, Kimura M, et al.A new combined trivalent live measles (AIK-C strain), mumps (Hoshino strain), and rubella (Takahashi strain) vaccine. Findings in clinical and laboratory studies. American Journal of Diseases in Children 1990;144(8):905-10.
  • Marin 2006 {published data only}
  • Marin M, Nguyen HQ, Langidrik JR, Edwards R, Briand K, Papania MJ, et al.Measles transmission and vaccine effectiveness during a large outbreak on a densely populated island: implications for vaccination policy. Clinical infectious Diseases 2006;42(3):315-9.
  • Marolla 1998 {published data only}
  • Marolla F, Baviera G, Cacciapuoti, Calia V, Cannavavo R, Clemente A, et al.A field study on vaccine efficacy against mumps of three MMR vaccines [Efficacia verso la parotite di tre diversi vaccini a tripla componente : studio sul campo]. Rivista Italiana Di Pediatria 1998;24(3):466-72.
  • McKeever 2004 {published data only}
  • McKeever TM, Lewis SA, Smith C, Hubbard R. Vaccination and allergic disease: a birth cohort study. American Journal of Public Health 2004;94(6):985-9.
  • Miller 1989 {published data only}
  • Miller C, Miller E, Rowe K, Bowie C, Judd M, Walker D. Surveillance of symptoms following MMR vaccine in children. Practitioner 1989;233(1461):69-73.
  • Miller 2005 {published data only}
  • Miller E, Andrews N, Grant A, Stowe J, Taylor B. No evidence of an association between MMR vaccine and gait disturbance. Archives of Disease in Childhood 2005;90(3):292-6.
  • Miller 2007 {published data only}
  • Miller E, Andrews N, Stowe J, Grant A, Waight P, Taylor B. Risks of convulsion and aseptic meningitis following measles-mumps-rubella vaccination in the United Kingdom. American Journal of Epidemiology 2007;165(6):704-9.
  • Mrozek-Budzyn 2010 {published data only}
  • Mrozek-Budzyn D, Kieltyka A, Majewska R. Lack of association between measles-mumps-rubella vaccination and autism in children: a case-control study. Pediatric Infectious Disease Journal 2010;29(5):397-400.
  • Ong 2005 {published data only}
  • Ong G, Goh KT, Ma S, Chew SK. Comparative efficacy of Rubini, Jeryl-Lynn and Urabe mumps vaccine in an Asian population. Journal of Infections 2005;51(4):294-8.
  • Ong 2007 {published data only}
  • Ong G, Rasidah N, Wan S, Cutter J. Outbreak of measles in primary school students with high first dose MMR vaccination coverage. Singapore Medical Journal 2007;48(7):656-61.
  • Park 2004 {published data only}
  • Park T, Ki M, Yi SG. Statistical analysis of MMR vaccine adverse events on aseptic meningitis using the case cross-over design. Statistics in Medicine 2004;23(12):1871-83.
  • Peltola 1986 {published data only}
  • Peltola H, Heinonen OP. Frequency of true adverse reactions to measles-mumps-rubella vaccine. A double-blind placebo-controlled trial in twins. Lancet 1986;1(8487):939-42.
  • Ray 2006 {published data only}
  • Ray P, Hayward J, Michelson D, Lewis E, Schwalbe J, Black S, et al.Encephalopathy after whole-cell pertussis or measles vaccination: lack of evidence for a causal association in a retrospective case-control study. Pediatric Infectious Disease Journal 2006;25(9):768-73.
  • Robertson 1988 {published data only}
  • Robertson CM, Bennett VJ, Jefferson N, Mayon-White RT. Serological evaluation of a measles, mumps, and rubella vaccine. Archives of Diseases of Children 1988;63(6):612-6.
  • Schlegel 1999 {published data only}
  • Schlegel M, Osterwalder JJ, Galeazzi RL, Vernazza PL. Comparative efficacy of three mumps vaccines during disease outbreak in Eastern Switzerland: cohort study. BMJ 1999;319(7206):352.
  • Schwarz 1975 {published data only}
  • Schwarz AJ, Jackson JE, Ehrenkranz NJ, Ventura A, Schiff GM, Walters VW. Clinical evaluation of a new measles-mumps-rubella trivalent vaccine. American Journal of Diseases of Children 1975;129(12):1408-12.
  • Seagroatt 2005 {published data only}
  • Seagroatt V. MMR vaccine and Crohn's disease: ecological study of hospital admissions in England, 1991 to 2002. BMJ 2005;330(7500):1120-1.
  • Sharma 2010 {published data only}
  • Sharma HJ, Oun SA, Bakr SS, Kapre SV, Jadhav SS, Dhere RM, et al.No demonstrable association between the Leningrad-Zagreb mumps vaccine strain and aseptic meningitis in a large clinical trial in Egypt. Clinical Microbiology and Infection 2010;16(4):347-52.
  • Smeeth 2004 {published data only}
  • Smeeth L, Cook C, Fombonne E, Heavey L, Rodrigues LC, Smith PG, et al.MMR vaccination and pervasive developmental disorders: a case-control study. Lancet 2004;364(9438):963-9.
  • Stokes 1971 {published data only}
  • Stokes JJ, Weibel RE, Villarejos VM, Arguedas JA, Buynak EB, Hilleman MR. Trivalent combined measles-mumps-rubella vaccine. Findings in clinical-laboratory studies. JAMA 1971;218(1):57-61.
  • Stowe 2009 {published data only}
  • Stowe J, Andrews N, Taylor B, Miller E. No evidence of an increase of bacterial and viral infections following measles, mumps and rubella vaccine. Vaccine 2009;27(9):1422-5.
  • Swartz 1974 {published data only}
  • Swartz TA, Klingberg W, Klingberg MA. Combined trivalent and bivalent measles, mumps and rubella virus vaccination. A controlled trial. Infection 1974;2(3):115-7.
  • Taylor 1999 {published data only}
  • Taylor B, Miller E, Farrington CP, Petropoulos MC, Favot-Mayaud I, Li J, et al.Autism and measles, mumps, and rubella vaccine: no epidemiological evidence for a causal association. Lancet 1999;353(9169):2026-9.
  • Uchiyama 2007 {published data only}
  • Uchiyama T, Kurosawa M, Inaba Y. MMR-vaccine and regression in autism spectrum disorders: negative results presented from Japan. Journal of Autism and Developmental Disorders 2007;37(2):210-7.
  • Vestergaard 2004 {published data only}
  • Vestergaard M, Hviid A, Madsen KM, Wohlfahrt J, Thorsen P, Schendel D, et al.MMR vaccination and febrile seizures: evaluation of susceptible subgroups and long-term prognosis. JAMA 2004;292(3):351-7.
  • Ward 2007 {published data only}
  • Ward KN, Bryant NJ, Andrews NJ, Bowley JS, Ohrling A, Verity CM, et al.Risk of serious neurologic disease after immunization of young children in Britain and Ireland. Pediatrics 2007;120(2):314-21.
  • Weibel 1980 {published data only}
  • Weibel RE, Carlson AJ Jr, Villarejos VM, Buynak EB, McLean AA, Hilleman MR. Clinical and laboratory studies of combined live measles, mumps, and rubella vaccines using the RA 27/3 rubella virus. Proceedings of the Society for Experimental Biology and Medicine 1980;165(2):323-6.
  • References to studies excluded from this review
  • Akobeng 1999 {published data only}
  • Akobeng AK, Thomas AG. Inflammatory bowel disease, autism, and the measles, mumps, and rubella vaccine. Journal of Pediatric Gastroenterology and Nutrition 1999;28(3):351-2.
  • Andre 1984 {published data only}
  • Andre FE. Summary of clinical studies with the Oka live varicella vaccine produced by Smith Kline-RIT. Biken Journal 1984;27(2-3):89-98.
  • Anonymous 1982 {published data only}
  • Anonymous. Adverse effects of Virivac. Lakartidningen 1982;79(42):3822.
  • Anonymous 1997 {published data only}
  • Anonymous. Vaccination: news on precautions, contraindications, and adverse reactions. Consultant 1997;37(3):756-60.
  • Anonymous 1999 {published data only}
  • Anonymous. Incidence of measles vaccine-associated adverse events is low. Drugs & Therapy Perspectives 1999;14(11):13-6.
  • Anonymous 2004 {published data only}
  • Anonymous. Childhood vaccination does not increase the incidence of type 1 diabetes. Evidence-based Healthcare and Public Health 2004;8(5):286-7.
  • Aozasa 1982 {published data only}
  • Aozasa K, Nara H, Kotoh K, Watanabe Y, Sakai S, Honda M. Malignant histiocytosis with slow clinical course. Pathology, Research and Practice 1982;174(1-2):147-58.
  • Asaria 2008 {published data only}
  • Asaria P, MacMahon E. Measles in the United Kingdom: can we eradicate it by 2010?. BMJ 2006;333(7574):890-5.
  • Autret 1996 {published data only}
  • Autret E, Jonville-Bera AP, Galy-Eyraud C, Hessel L. Thrombocytopenic purpura after isolated or combined vaccination against measles, mumps and rubella [Purpura thrombopenique apres vaccination isolee ou associee contre la rougeole, la rubeole et les oreillons]. Therapie 1996;51(6):677-80.
  • Bakker 2001 {published data only}
  • Bakker W, Mathias R. Mumps caused by an inadequately attenuated measles, mumps and rubella vaccine. Canadian Journal of Infectious Diseases 2001;12(3):144-8.
  • Balraj 1995 {published data only}
  • Balraj V ME. Complications of mumps vaccines. Reviews in Medical Virology 1995;5(4):219-27.
  • Beck 1991 {published data only}
  • Beck SA, Williams LW, Shirrell MA, Burks AW. Egg hypersensitivity and measles-mumps-rubella vaccine administration. Pediatrics 1991;88(5):913-7.
  • Bedford 2010 {published data only}
  • Bedford HE, Elliman DA. MMR vaccine and autism. BMJ 2010;340:c655.
  • Beeler 1996 {published data only}
  • Beeler J, Varricchio F, Wise R. Thrombocytopenia after immunization with measles vaccines: review of the vaccine adverse events reporting system (1990 to 1994). Pediatric Infectious Disease Journal 1996;15(1):88-90.
  • Benjamin 1991 {published data only}
  • Benjamin CM, Silman AJ. Adverse reactions and mumps, measles and rubella vaccine. Journal of Public Health Medicine 1991;13(1):32-4.
  • Berger 1988a {published data only}
  • Berger R, Just M, Gluck R. Interference between strains in live virus vaccines. I: combined vaccination with measles, mumps and rubella vaccine. Journal of Biological Standardization 1988;16(4):269-73.
  • Berger 1988b {published data only}
  • Berger R, Just M. Interference between strains in live virus vaccines. II: Combined vaccination with varicella and measles-mumps-rubella vaccine. Journal of Biological Standardization 1988;16(4):275-9.
  • Berlin 1983 {published data only}
  • Berlin BS. Convulsions after measles immunisation. Lancet 1983;1(8338):1380.
  • Bernsen 2008 {published data only}
  • Bernsen RM, van der Wouden JC. Measles, mumps and rubella infections and atopic disorders in MMR-unvaccinated and MMR-vaccinated children. Pediatric Allergy and Immunology 2008;19(6):544-51.
  • Bhargava 1995 {published data only}
  • Bhargava I, Chhaparwal BC, Phadke MA, Irani SF, Chhaparwal D, Dhorje S, et al.Immunogenicity and reactogenicity of indigenously produced MMR vaccine. Indian PediatrIcs 1995;32(9):983-8.
  • Bonanni 2005 {published data only}
  • Bonanni P, Bechini A, Pesavento G, Boccalini S, Tiscione E, Graziani G, et al.Implementation of the plan for elimination of measles and congenital rubella infection in Tuscany: evidence of progress towards phase II of measles control. Journal of Preventive Medicine and Hygiene 2005;46(3):111-7.
  • Borchardt 2007 {published data only}
  • Borchardt SM, Rao P, Dworkin MS. Is the severity of mumps related to the number of doses of mumps-containing vaccine?. Clinical Infectious Diseases 2007;45(7):939-40.
  • Borgono 1973 {published data only}
  • Borgono JM, Greiber R, Solari G, Concha F, Carrillo B, Hilleman MR. A field trial of combined measles-mumps-rubella vaccine. Satisfactory immunization with 188 children in Chile. Clinical Pediatrics 1973;12(3):170-2.
  • Boxall 2008 {published data only}
  • Boxall N, Kubinyiova M, Prikazsky V, Benes C, Castkova J. An increase in the number of mumps cases in the Czech Republic, 2005-2006. Euro surveillance: European Communicable Disease Bulletin 2008;13(16):18842 [pii].
  • Brockhoff 2010 {published data only}
  • Brockhoff HJ, Mollema L, Sonder GJ, Postema CA, van Binnendijk RS, Kohl RH, et al.Mumps outbreak in a highly vaccinated student population, The Netherlands, 2004. Vaccine 2010;28(17):2932-6.
  • Bruno 1997 {published data only}
  • Bruno G, Grandolfo M, Lucenti P, Novello F, Ridolfi B, Businco L. Measles vaccine in egg allergic children: poor immunogenicity of the Edmoston-Zagreb strain. Pediatric Allergy and Immunology 1997;8(1):17-20.
  • Buntain 1976 {published data only}
  • Buntain WL, Missall SR. Letter: Local subcutaneous atrophy following measles, mumps, and rubella vaccination. American Journal of Diseases of Children 1976;130(3):335.
  • Buynak 1969 {published data only}
  • Buynak EB, Weibel RE, Whitman JE Jr, Stokes J Jr, Hilleman MR. Combined live measles, mumps, and rubella virus vaccines. JAMA 1969;207(12):2259-62.
  • Cardenosa 2006 {published data only}
  • Cardenosa N, Dominguez A, Camps N, Martinez A, Torner N, Navas E, et al.Non-preventable mumps outbreaks in schoolchildren in Catalonia. Scandinavian Journal of Infectious Diseases 2006;38(8):671-4.
  • Castilla 2009b {published data only}
  • Castilla J, Fernandez Alonso M, Garcia Cenoz M, Martinez Artola V, Inigo Pestana M, Rodrigo I, et al.Resurgence of mumps in the vaccine era. Factors involved in an outbreak in Navarre, Spain, 2006-2007 [Rebrote de parotiditis en la era vacunal. Factores implicados en un brote en Navarra, 2006-2007]. Medicina Clínica 2009;133(20):777-82.
  • Chang 1982 {published data only}
  • Chang HH. Immunisation problems in measles, rubella and mumps. Journal of the Korean Medical Association 1982;25(9):801-6.
  • Chen 1991 {published data only}
  • Chen RT, Moses JM, Markowitz LE, Orenstein WA. Adverse events following measles-mumps-rubella and measles vaccinations in college students. Vaccine 1991;9(5):297-9.
  • Chen 2000 {published data only}
  • Chen RT, Mootrey G, DeStefano F. Safety of routine childhood vaccinations. An epidemiological review. Paediatric Drugs 2000;2(4):273-90.
  • Cherian 2010 {published data only}
  • Cherian MP, Al-Kanani KA, Al Qahtani SS, Yesurathinam H, Mathew AA, Thomas VS, et al.The rising incidence of type 1 diabetes mellitus and the role of environmental factors - three decade experience in a primary care health center in Saudi Arabia. Journal of Pediatric Endocrinology and Metabolism 2010;23(7):685-95.
  • Chiodo 1992 {published data only}
  • Chiodo F. Effectiveness and security of the trivalent vaccine against measles, parotitis and rubella (MPR). Igiene Moderna 1992;97(Suppl 1):77-86.
  • Cinquetti 1994 {published data only}
  • Cinquetti S, Tonetto L, Portello A, Chermaz E, Sernagiotto F, De Noni R, et al.Adverse reactions following vaccination with two different types of measles mumps-rubella vaccine [Reazioni indesiderate a due diverse preparazioni di vaccine 'triplo' antimorbillo-parotite-rosolia]. Igiene Moderna 1994;101(6):793-800.
  • Contardi 1989 {published data only}
  • Contardi I. Clinical and immunologic valuation of a new triple measles, mumps and rubella vaccine. Giornale di Malattie Infettive e Parassitarie 1989;41(11):1106-7.
  • Contardi 1992 {published data only}
  • Contardi I, Lusardi C, Cattaneo GG. A comparative study of 3 different types of trivalent measles-mumps-rubella vaccine. Pediatria Medica e Chirurgica 1992;14(4):421-4.
  • Coplan 2000 {published data only}
  • Coplan P, Chiacchierini L, Nikas A, Shea J, Baumritter A, Beutner K, et al.Development and evaluation of a standardized questionnaire for identifying adverse events in vaccine clinical trials. Pharmacoepidemiology and Drug Safety 2000;9(6):457-71.
  • Coronado 2006 {published data only}
  • Coronado F, Musa N, El Tayeb el SA, Haithami S, Dabbagh A, Mahoney F, et al.Retrospective measles outbreak investigation: Sudan, 2004. Journal of Tropical Pediatrics 2006;52(5):329-34.
  • Cox 2009 {published data only}
  • Cox AR, McDowell S. A response to the article on the association between paracetamol/acetaminophen: use and autism by Stephen T. Schultz. Autism: The International Journal of Research and Practice 2009;13(1):123-4; author reply 124-5.
  • Curtale 2010 {published data only}
  • Curtale F, Perrelli F, Mantovani J, Atti MC, Filia A, Nicoletti L, et al.Description of two measles outbreaks in the Lazio Region, Italy (2006-2007). Importance of pockets of low vaccine coverage in sustaining the infection. BMC Infectious Diseases 2010;10:62.
  • Czajka 2009 {published data only}
  • Czajka H, Schuster V, Zepp F, Esposito S, Douha M, Willems P. A combined measles, mumps, rubella and varicella vaccine (Priorix-Tetra): immunogenicity and safety profile. Vaccine 2009;27(47):6504-11.
  • D'Argenio 1998 {published data only}
  • D'Argenio P, Citarella A, Manfredi Selvaggi MT, Arigliani R, Casani A, et al.Field evaluation of the clinical effectiveness of vaccines against pertussis, measles, rubella and mumps. The Benevento and Compobasso Pediatrician's Network for the Control of Vaccine-Preventable Diseases. Vaccine 1998;16(8):818-22.
  • D'Souza 2000 {published data only}
  • D'Souza RM, Campbell-Lloyd S, Isaacs D, Gold M, Burgess M, Turnbull F, et al.Adverse events following immunisation associated with the 1998 Australian Measles Control Campaign. Communicable Diseases Intelligence 2000;24(2):27-33.
  • Dales 2001 {published data only}
  • Dales L, Hammer SJ, Smith NJ. Time trends in autism and in MMR immunization coverage in California. JAMA 2001;285(9):1183-5.
  • Dallaire 2009 {published data only}
  • Dallaire F, De Serres G, Tremblay FW, Markowski F, Tipples G. Long-lasting measles outbreak affecting several unrelated networks of unvaccinated persons. Journal of Infectious Diseases 2009;200(10):1602-5.
  • Dankova 1995 {published data only}
  • Dankova E, Domorazkova E, Skovrankova J, Vodickova M, Honzonova S, Stehlikova J, et al.Immune reactivity and risk of an undesirable response after vaccination. Ceskoslovenská Pediatrie 1995;50(9):515-9.
  • Dashefsky 1990 {published data only}
  • Dashefsky B, Wald E, Guerra N, Byers C. Safety, tolerability, and immunogenicity of concurrent administration of Haemophilus influenzae type b conjugate vaccine (meningococcal protein conjugate) with either measles-mumps-rubella vaccine or diphtheria-tetanus-pertussis and oral poliovirus vaccines in 14- to 23-month-old infants. Pediatrics 1990;85(4 Pt 2):682-9.
  • Davis 1997 {published data only}
  • Davis RL, Marcuse E, Black S, Shinefield H, Givens B, Schwalbe J, et al.MMR2 immunization at 4 to 5 years and 10 to 12 years of age: a comparison of adverse clinical events after immunization in the Vaccine Safety Datalink project. The Vaccine Safety Datalink Team. Pediatrics 1997;100(5):767-71.
  • Dayan 2008a {published data only}
  • Dayan GH, Quinlisk MP, Parker AA, Barskey AE, Harris ML, Schwartz JM, et al.Recent resurgence of mumps in the United States. New England Journal of Medicine 2008;358(15):1580-9.
  • Deforest 1986 {published data only}
  • Deforest A, Long SS, Lischner HW. Safety and efficacy of simultaneous administration of measles-mumps-rubella (MMR) with booster doses of diphtheria-tetanus-pertussis (TP) and trivalent oral poliovirus (OPV) vaccines. Developments in Biological Standardization 1986;65:111.
  • Deforest 1988 {published data only}
  • Deforest A, Long SS, Lischner HW, Girone JA, Clark JL, Srinivasan R, et al.Simultaneous administration of measles-mumps-rubella vaccine with booster doses of diphtheria-tetanus-pertussis and poliovirus vaccines. Pediatrics 1988;81(2):237-46.
  • De Laval 2010 {published data only}
  • De Laval F, Haus R, Spiegel A, Simon F. Lower long-term immunogenicity of mumps component after MMR vaccine. Pediatric Infectious Disease Journal 2010;29(11):1062-3.
  • DeStefano 2000 {published data only}
  • DeStefano F, Chen RT. Autism and measles, mumps, and rubella vaccine: no epidemiological evidence for a causal association. Journal of Pediatrics 2000;136(1):125-6.
  • Diaz-Ortega 2010 {published data only}
  • Diaz-Ortega JL, Bennett JV, Castaneda D, Vieyra JR, Valdespino-Gomez JL, de Castro JF. Successful seroresponses to measles and rubella following aerosolized Triviraten vaccine, but poor response to aerosolized mumps (Rubini) component: comparisons with injected MMR. Vaccine 2010;28(3):692-8.
  • Dobrosavljevic 1999 {published data only}
  • Dobrosavljevic D, Milinkovic MV, Nikolic MM. Toxic epidermal necrolysis following morbilli-parotitis-rubella vaccination. Journal of the European Academy of Dermatology and Venereology 1999;13(1):59-61.
  • Dominguez 2008 {published data only}
  • Dominguez A, Torner N, Barrabeig I, Rovira A, Rius C, Cayla J, et al.Large outbreak of measles in a community with high vaccination coverage: implications for the vaccination schedule. Clinical Infectious Diseases 2008;47(9):1143-9.
  • Doshi 2009 {published data only}
  • Doshi S, Khetsuriani N, Zakhashvili K, Baidoshvili L, Imnadze P, Uzicanin A. Ongoing measles and rubella transmission in Georgia, 2004-05: implications for the national and regional elimination efforts. International Journal of Epidemiology 2009;38(1):182-91.
  • Dos Santos 2002 {published data only}
  • Dos Santos BA, Ranieri TS, Bercini M, Schermann MT, Famer S, Mohrdieck R, et al.An evaluation of the adverse reaction potential of three measles-mumps-rubella combination vaccines. Revista Panamericana de Salud Pública 2002;12(4):240-6.
  • Dyer 2010a {published data only}
  • Dyer C. Wakefield was dishonest and irresponsible over MMR research, says GMC. BMJ 2010;340:c593.
  • Dyer 2010b {published data only}
  • Dyer C. Lancet retracts Wakefield's MMR paper. BMJ 2010;340:c696.
  • Ehrenkranz 1975 {published data only}
  • Ehrenkranz NJ, Ventura AK, Medler EM, Jackson JE, Kenny MT. Clinical evaluation of a new measles-mumps-rubella combined live virus vaccine in the Dominican Republic. Bulletin of the World Health Organization 1975;52(1):81-5.
  • Elphinstone 2000 {published data only}
  • Elphinstone P. The MMR question. Lancet 2000;356(9224):161.
  • Englund 1989 {published data only}
  • Englund JA, Suarez CS, Kelly J, Tate DY, Balfour HH Jr. Placebo-controlled trial of varicella vaccine given with or after measles-mumps-rubella vaccine. Journal of Pediatrics 1989;114(1):37-44.
  • Farrington 1996 {published data only}
  • Farrington CP, Nash J, Miller E. Case series analysis of adverse reactions to vaccines: a comparative evaluation. American Journal of Epidemiology 1996;143(11):1165-73.
  • Farrington 2001 {published data only}
  • Farrington CP, Miller E, Taylor B. MMR and autism: further evidence against a causal association. Vaccine 2001;19(27):3632-5.
  • Fitzpatrick 2007 {published data only}
  • Fitzpatrick M. The end of the road for the campaign against MMR. British Journal of General Practice 2007;57(541):679.
  • Fletcher 2001 {published data only}
  • Fletcher AP. MMR safety studies. Adverse Drug Reactions and Toxicological Reviews 2001;20(1):57-60.
  • Garrido L 1992 {published data only}
  • Garrido Lestache A, Martin Hernandez D. Triple virus vaccination: study of its efficacy and safety. Pediatrika 1992;12:42-7.
  • Geier 2004 {published data only}
  • Geier DA, Geier MR. A comparative evaluation of the effects of MMR immunization and mercury doses from thimerosal-containing childhood vaccines on the population prevalence of autism. Medical Science Monitor 2004;10(3):PI33-9.
  • Gerber 2009 {published data only}
  • Gerber JS, Offit PA. Vaccines and autism: a tale of shifting hypotheses. Clinical Infectious Diseases 2009;48(4):456-61.
  • Goodson 2010 {published data only}
  • Goodson JL, Perry RT, Mach O, Manyanga D, Luman ET, Kitambi M, et al.Measles outbreak in Tanzania, 2006-2007. Vaccine 2010;28(37):5979-85.
  • Griffin 1991 {published data only}
  • Griffin MR, Ray WA, Mortimer EA, Fenichel GM, Schaffner W. Risk of seizures after measles-mumps-rubella immunization. Pediatrics 1991;88(5):881-5.
  • Grilli 1992 {published data only}
  • Grilli G, Cimini D, Vacca F. Vaccination against measles, mumps and rubella: incidence of side effects using different vaccine strains. Giornale di Malattie Infettive e Parassitarie 1992;44(1):38-42.
  • Hilton 2009 {published data only}
  • Hilton S, Hunt K, Langan M, Hamilton V, Petticrew M. Reporting of MMR evidence in professional publications: 1988-2007. Archives of Disease in Childhood 2009;94(11):831-3.
  • Hindiyeh 2009 {published data only}
  • Hindiyeh MY, Aboudy Y, Wohoush M, Shulman LM, Ram D, Levin T, et al.Characterization of large mumps outbreak among vaccinated Palestinian refugees. Journal of Clinical Microbiology 2009;47(3):560-5.
  • Hornig 2008 {published data only}
  • Hornig M, Briese T, Buie T, Bauman ML, Lauwers G, Siemetzki U, et al.Lack of association between measles virus vaccine and autism with enteropathy: a case-control study. PLoS ONE 2008;3(9):e3140.
  • Hu 2007 {published data only}
  • Hu JY, Tao LN, Shen J, Wang YC. Study on the epidemiological characteristics of rubella from 1990-2006 in Shanghai. Zhonghua Liu Xing Bing Xue Za Zhi 2007;28(7):645-8.
  • Hua 2009 {published data only}
  • Hua W, Izurieta HS, Slade B, Belay ED, Haber P, Tiernan R, et al.Kawasaki disease after vaccination: reports to the vaccine adverse event reporting system 1990-2007. Pediatric Infectious Disease Journal 2009;28(11):943-7.
  • Huang 1990 {published data only}
  • Huang LM, Lee CY, Hsu CY, Huang SS, Kao CL, Wu FF. Effect of monovalent measles and trivalent measles-mumps-rubella vaccines at various ages and concurrent administration with hepatitis B vaccine. Pediatric Infectious Disease Journal 1990;9(7):461-5.
  • Ipp 2003 {published data only}
  • Ipp M, Cohen E, Goldbach M, McArthur C. Pain response to measles-mumps-rubella (MMR) vaccination at 12 months of age: a randomised clinical trial. Journal of Paediatrics and Child Health 2003;39(6):A3.
  • Jiang 2009 {published data only}
  • Jiang Y, Pang H. Surveillance of adverse events following immunization of MMR in Changning District of Shanghai. Zhongguo Ji Hua Mian Yi 2009;15(6):496-7, 526.
  • Jones 1991 {published data only}
  • Jones AG, White JM, Begg NT. The impact of MMR vaccine on mumps infection in England and Wales. CDR (London, England: review) 1991;1(9):R93-6.
  • Just 1985 {published data only}
  • Just M, Berger R, Gluck R, Wegmann A. Field trial with a new human diploid cell vaccine (HDCV) against measles, mumps and rubella [Feldversuch mit einer neuartigen Humandiploidzellvakzine (HDCV) gegen Masern, Mumps und Roteln]. Schweizerische Medizinische Wochenschrift 1985;115(48):1727-30.
  • Just 1986 {published data only}
  • Just M, Berger R, Just V. Evaluation of a combined measles-mumps-rubella-chickenpox vaccine. Developments in Biological Standardization 1986;65:85-8.
  • Just 1987a {published data only}
  • Just M, Berger R. Immunogenicity of vaccines. A comparative study of a mumps-measles-rubella vaccine given with or without oral polio vaccine [Immunantwort auf Impstoffe. Vergleichende Studie mit Mumps- , Masern- , und Roeteln-Impfstoff allein oder zusammen mit Polio-Impfstoff appliziert]. Muenchner Medizinische Wochenschrift 1987;129(11):188-90.
  • Just 1987b {published data only}
  • Just M BR. Trivalent vaccines. A comparative study of the immunogenicity of two trivalent mumps-measles-rubella vaccines given with or without diphtheria-tetanus vaccine [Trivalente Impfstoffe. Vergleichende Studie zweier Mumps-Masern-Roeteln-Vakzinen in Kombination mit Diphtherie-Tetanus-Impfstoff]. Münchener Medizinische Wochenschrift 1987;129(23):446-7.
  • Kaaber 1990 {published data only}
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  • Patja A, Davidkin I, Kurki T, Kallio MJ, Valle M, Peltola H. Serious adverse events after measles-mumps-rubella vaccination during a fourteen-year prospective follow-up. Pediatic Infectious Disease Journal 2000;19(12):1127-34.
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  • Peltola H, Kulkarni PS, Kapre SV, Paunio M, Jadhav SS, Dhere RM. Mumps outbreaks in Canada and the United States: time for new thinking on mumps vaccines. Clinical Infectious Diseases 2007;45(4):459-66.
  • Puvvada 1993 {published data only}
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  • Ramos-Alvarez M, Bessudo L, Kenny MT, Jackson JE, Schwarz AJ. Simultaneous administration at different dosages of attenuated live virus vaccines against measles, mumps and rubella [Administracion simultanea en diferentes dosificaciones de las vacunas de virus vivos atenuados contra el sarampion, parotiditis y rubeola]. Boletín Médico del Hospital Infantil de México 1976;33(4):875-86.
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  • Roost HP, Gassner M, Grize L, Wuthrich B, Sennhauser FH, Varonier HS, et al.Influence of MMR-vaccinations and diseases on atopic sensitization and allergic symptoms in Swiss schoolchildren. Pediatric Allergy and Immunology 2004;15(5):401-7.
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  • Saraswathy TS, Zahrin HN, Norhashmimi H, Az-Ulhusna A, Zainah S, Rohani J. Impact of a measles elimination strategy on measles incidence in Malaysia. Southeast Asian Journal of Tropical Medicine and Public Health 2009;40(4):742-7.
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  • Scarpa B, Masia G, Contu P, Origa P, Sanna CM, Pintor C, et al.Trivalent vaccine against measles, rubella and parotitis: clinic and serological evaluation [Vaccino trivalente contro morbillo, rosolia e parotite : valutazione clinica e sierologica]. Giornale di Malattie Infettive e Parassitarie 1990;42(6):344-7.
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  • Schettini 1989 {published data only}
  • Schettini F, Manzionna MM, De Mattia D, Amendola F, Di Bitonto G. Clinico-immunologic evaluation of a trivalent vaccine against measles, rubella and mumps [Valutazione clinico-immunologica di un vaccino trivalente contro morbillo, rosolia e parotite]. Minerva Pediatrica 1989;41(3):117-22.
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  • Schettini F, Manzionna MM, De Mattia D, Amendola F, Di Bitonto G. The clinico-immunological evaluation of a bivalent vaccine against measles and rubella [Valutazione clinico-immunologica di un vaccino bivalente contro morbillo e rosolia]. Minerva Pediatrica 1990;42(12):531-6.
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  • Schmid D, Holzmann H, Alfery C, Wallenko H, Popow-Kraupp TH, Allerberger F. Mumps outbreak in young adults following a festival in Austria, 2006. Euro Surveillance: European Communicable Disease Bulletin 2008;13(7):8042 [pii].
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  • Shinefield HR, Black SB, Staehle BO, Matthews H, Adelman T, Ensor K, et al.Vaccination with measles, mumps and rubella vaccine and varicella vaccine: safety, tolerability, immunogenicity, persistence of antibody and duration of protection against varicella in healthy children. Pediatric Infectious Disease Journal 2002;21(6):555-61.
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  • Vesikari T, Elo O. Vaccination against measles, mumps and rubella--together or separately? [Tuhkarokon, sikotaudin ja vihurirokon torjunta--yhdessa vai erikseen?]. Duodecim 1979;95(9):527-9.
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  • References to studies awaiting assessment
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  • Additional references
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