systematic review and meta-analysis of the literature

CONFIDENTIAL

Work Package 1: Identification of

models of children’s primary care:

Systematic Review and Meta-analysis

of the Literature

February 2016

Commission Deliverable: Report on

systematic review and meta-analysis for

MOCHA WP1 (edition 1).

2

Systematic Review and Meta-analysis of the

Literature

Dr Nadia Minicuci, Dr Barbara Corso, Dr Ilaria Rocco - The CNR Institute of

Neuroscience (CNR-IN), Padova, Italy.

Status

MOCHA Commission Deliverable 2 (D1.1):

Report on systematic review and meta-analysis of the literature on models

for WP1. (1st Edition)

Origin Work Package 1: Identification of Models of Children’s Primary Care

Distribution

European Commission

Internal distributin to the MOCHA project

The project is funded by the European Commission through the Horizon 2020 Framework under the

grant agreement number: 634201. The sole responsibility for the content of this project lies with the

authors. It does not necessarily reflect the opinion of the European Union. The European Commission is

not responsible for any use that may be made of the information contained therein.

Models of Children’s Primary Care - Systematic review and meta analysis of the literature

CONFIDENTIAL 3

Contents Introduction 5 Background 5 Autistic Spectrum Disorder 5

Autistic Spectrum Disorder diagnosis 6 Epidemiology of Autistic Spectrum Disorders 8

Immunisation 8 Materials and methods 17

Search Strategy 17 Eligibility Criteria 17 Data extraction 18 Summary of the study selection process 18

Meta Analysis 20 Type of care country classification 20

Results 23 Autistic Spectrum Disorder 23 Asperger’s syndrome 27 Autistic disorder 29 Pervasive developmental disorder, not otherwise specified 31 Immunisation 32 Measles, Mumps and Rubella (MMR) 33 Measles 36 Mumps 39 Rubella 40

Conclusions 41 Strengths and limitations 42 Appendix 1 43 Appendix 2 47 References 69

References for systematic review – appendix 1 71 References for systematic review – appendix 2 74

Table of Figures

Figure 1: Flow chart age at ASD diagnosis 18 Figure 2: Flow chart age at MMR coverage 19 Figure 3: Meta analysis for mean age at onset of ASD Paediatrician-led system 24 Figure 4: Meta analysis for mean age at onset of ASD GP-led system 25 Figure 5: Meta analysis for mean age at onset of ASD Mixed system 26 Figure 6: Meta analysis for mean age at onset of Asperger’s syndrome Paediatrician-led system

27

Figure 7: Meta analysis for mean age at onset of Asperger’s syndrome GP-led system 28 Figure 8: Meta analysis for mean age at onset of Autistic disorder Paediatrician-led system

29

Figure 9: Meta analysis for mean age at onset of Autistic disorder GP-led system 30 Figure 10: Meta analysis for mean age at onset of PDD-NOS Paediatrician-led system 31 Figure 11: Meta analysis for immunisation coverage for MMR Paediatrician-led system 33 Figure 12: Meta analysis for immunisation coverage for MMR GP-led system 34 Figure 13: Meta analysis for immunisation coverage for MMR Mixed system 35 Figure 14: Meta analysis for immunisation coverage for Measles Paediatrician-led system 36 Figure 15: Meta analysis for immunisation coverage for Measles GP-led system 37 Figure 16: Meta analysis for immunisation coverage for Measles Mixed system 38


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Figure 17: Meta analysis for immunisation coverage for Mumps Paediatrician-led system 39 Figure 18: Meta analysis for immunisation coverage for Measles GP-led system 40

Tables

Table 1: Recommended immunisations for Measles 11 Table 2: Recommended immunisations for Mumps 13 Table 3: Recommended immunisations for Rubella 15 Table 4: Type of primary care for each EU country 21 Table 5: Summary of the meta analysis findings 41

Note

This edition of the deliverable meets the purpose and objectioves as set out in the Description of

Activity of the MOCHA project. However, given the necessity to limit the number of conditions

studied, and the likelihood of new publications during the lifetime of the project, this deliverable

will be refreshed with later ediitons. Such further work is likely to reinforce and refine the

findings in this edition, rather than to change them fundamentally. Thus this edition forms a

sound building block for other MOCHA activities.


CONFIDENTIAL 5

Introduction

This deliverable addresses one of the aims of the WP1 “Identification of Models of Children’s

Primary Health Care”. In order to describe the different models of care provided in Member

States, Norway and Iceland we have conducted a systematic review of the literature and meta-

analysis of the evidence for different models by selecting two of three different aspects of

children’s primary care, each of which reflects a different perspective of the primary care health

system:

1. making an early diagnosis

2. prevention

3. how to deal with a chronic condition

This deliverable addresses the first two perspectives

The first focuses on the age of first diagnosis of Autistic Spectrum Disorder (ASD) (in

particular: Autism/ autistic disorder; Asperger’s syndrome; Pervasive developmental disorder

not otherwise specified; Childhood disintegrative disorder)

The second perspective concentrates on the coverage of immunisation of children (in

particular: measles, mumps and rubella).

The third perspective assesses the control of asthma in children aged over 5, with a particular

focus on unscheduled emergency care and the availability of spirometry at a primary care level-

a key quality indicator . This topic is of particular importance, and will be covered in a further

edition of this deliverable.

The systematic review of Autism spectrum disorders and immunisation produced an

unexpectedly high number of articles to be screened (more than 3000). The findings based on

ASD and Immunisation thus constitute a solid background for the validation of the subsequent

analyses on ADHD and asthma that will be reported in a future report.

Background

Autistic Spectrum Disorder Autism spectrum disorder (ASD) is a disorder of early brain development which affects social

interaction in terms of both verbal and nonverbal communication. Affected children display

restricted and/or repetitive behaviours and can be of varying intelligence.

The core autism behaviours are typically present in early childhood, but features are not always

apparent until the child or young person’s circumstances change, for example when the child

goes to nursery or primary school or moves to secondary school. Autism is strongly associated

with a number of coexisting conditions. Recent studies have shown that approximately 70% of

people with autism also meet diagnostic criteria for at least one other (often unrecognised)

psychiatric disorder that further impairs their psychosocial functioning. Intellectual disability

(intelligence quotient [IQ] below 70) occurs in approximately 50% of young people with autism

(NICE, 2011).All these factors can often make identification a challenge and lead to a delay in

diagnosis.


CONFIDENTIAL 6

Autism Spectrum Disorders: diagnosis

ASD is diagnosed by means of one of two classification of disease systems: the Diagnostic and

Statistical Manual of Mental Disorders (DSM), which is now in its fifth edition and is the

standard classification of ‘mental disorders’ used by mental health professionals in the United

States of America; and the International Statistical Classification of Diseases and Related Health

Problems (ICD), which is now on its 10th edition, updated in 2015, and is the standard diagnostic

tool for epidemiology, health management and clinical purposes devised by the World Health

Organisation.

Autism Spectrum Disorder was first described in 1943, by psychiatrist Leo Kanner, who

reported on a group of 11 children who had a preference for isolation and obsession for

sameness (Kanner, 1943). Independently of Kanner’s report, Hans Asperger, an Austrian

paediatrician published a paper in 1944 describing a similar group of children, but who had

higher verbal and cognitive skills (Asperger, 1944). By 1960, autism was viewed as a form of

childhood schizophrenia. However, as science gained a deeper understanding of brain process

and development the disorder was recognised as a product of differences in brain maturation

(Baker, 2013). In 1970s the concept that autism had a psychological origin, rather than a

physical one began to be disproved; and autism was understood as biological in origin and no

longer incompatible with impaired cognitive development.

In 1980, the Diagnostic and Statistical Manual of Mental Disorders third edition (DSM-III)

defined infantile autism as a pervasive developmental disorder (distinct from schizophrenia)

involving three domains: “lack of responsiveness to other people (autism), gross impairment in

communicative skills, and bizarre responses to various aspects of the environment, all

developing within the first 30 months of age” (American Psychiatric Association, 1980).

The DSM-III revision (American Psychiatric Association, 1987) provided a more complex

definition of autistic disorder that required a child to meet 8 of 16 criteria within the three

domains of social interaction, communication, and restricted interest or activities; this

definition dropped the requirement for early onset in life and provided a new category of

“Pervasive Developmental Disorder, Not Otherwise Specified” (PDD-NOS). This category was

used for children meeting some but not all diagnostic criteria for autistic disorder.

The later DSM editions, DSM-IV (1994) and DSM-IV-TR (2000) introduced further refinement

and increasingly complex criteria for autistic disorder and expanded the number of pervasive

developmental disorders to five, to include Asperger’s disorder and Rett’s syndrome (American

Psychiatric Association, 1994 and 2000).

Existing criteria were updated in DSM-V (2013) to give more precise descriptions and reflect

the scientific advances and clinical knowledge about Autism Spectrum Disorder gained in the

last two decades (American Psychiatric Association, 2013). An ASD diagnosis was given by

incorporating four disorders from the previous manual: autistic disorder, Asperger’s disorder,

childhood disintegrative disorder, and the catch-all diagnosis of pervasive developmental

disorder not otherwise specified. Concern grew that those four diagnoses were inconsistently

applied across clinics and treatment centres and, rather than distinct disorders, actually

represented symptoms and behaviours along a severity continuum. Describing ASD as a

continuum is a more accurate and medically and scientifically useful approach. People


CONFIDENTIAL 7

diagnosed with one of the separate DSM-IV disorders should still meet the criteria for autism

spectrum disorder or a different DSM-V diagnosis.

The World Health Organization International Statistical Classification of Diseases and Related

Health Problems (ICD)contains codes for diseases, signs and symptoms, abnormal findings,

complaints, social circumstances, and external causes of injury or diseases. The latest revision of

the ICD, ICD-10, was updated in 2015 (ICD-10 Version 2015). The ICD-10 classification of

pervasive developmental disorders, such as Autism Spectrum Disorders is schematically

organised as the following:

F84-Pervasive developmental disorders

A group of disorders characterized by qualitative abnormalities in reciprocal social interactions

and in patterns of communication, and by a restricted, stereotyped, repetitive repertoire of

interests and activities. These qualitative abnormalities are a pervasive feature of the

individual's functioning in all situations.

F84.0-Childhood autism

A type of pervasive developmental disorder that is defined by: (a) the presence of abnormal or

impaired development that is manifest before the age of three years, and (b) the characteristic

type of abnormal functioning in all the three areas of psychopathology: reciprocal social

interaction, communication, and restricted, stereotyped, repetitive behaviour. In addition to

these specific diagnostic features, a range of other nonspecific problems are common, such as

phobias, sleeping and eating disturbances, temper tantrums, and (self-directed) aggression.

F84.1-Atypical autism

A type of pervasive developmental disorder that differs from childhood autism either in age of

onset or in failing to fulfil all three sets of diagnostic criteria. This subcategory should be used

when there is abnormal and impaired development that is present only after age three years,

and a lack of sufficient demonstrable abnormalities in one or two of the three areas of

psychopathology required for the diagnosis of autism (namely, reciprocal social interactions,

communication, and restricted, stereotyped, repetitive behaviour) in spite of characteristic

abnormalities in the other area(s). Atypical autism arises most often in profoundly retarded

individuals and in individuals with a severe specific developmental disorder of receptive

language.

F84.2-Rett's syndrome

A condition, so far found only in girls, in which apparently normal early development is

followed by partial or complete loss of speech and of skills in locomotion and use of hands,

together with deceleration in head growth, usually with an onset between seven and 24 months

of age. Loss of purposive hand movements, hand-wringing stereotypes, and hyperventilation

are characteristic. Social and play development are arrested but social interest tends to be

maintained. Trunk ataxia and apraxia start to develop by age four years and choreoathetoid

movements frequently follow. Severe mental retardation almost invariably results.

F84.3-Other childhood disintegrative disorder

A type of pervasive developmental disorder that is defined by a period of entirely normal

development before the onset of the disorder, followed by a definite loss of previously acquired

skills in several areas of development over the course of a few months. Typically, this is

accompanied by a general loss of interest in the environment, by stereotyped, repetitive motor


CONFIDENTIAL 8

mannerisms, and by autistic-like abnormalities in social interaction and communication. In

some cases the disorder can be shown to be due to some associated encephalopathy but the

diagnosis should be made on the behavioural features.

F84.4-Overactive disorder associated with mental retardation and stereotyped movements

An ill-defined disorder of uncertain nosological validity. The category is designed to include a

group of children with severe mental retardation (IQ below 35) who show major problems in

hyperactivity and in attention, as well as stereotyped behaviours. They tend not to benefit from

stimulant drugs (unlike those with an IQ in the normal range) and may exhibit a severe

dysphoric reaction (sometimes with psychomotor retardation) when given stimulants. In

adolescence, the overactivity tends to be replaced by underactivity (a pattern that is not usual in

hyperkinetic children with normal intelligence). This syndrome is also often associated with a

variety of developmental delays, either specific or global. The extent to which the behavioural

pattern is a function of low IQ or of organic brain damage is not known.

F84.5-Asperger’s syndrome

A disorder of uncertain nosological validity, characterized by the same type of qualitative

abnormalities of reciprocal social interaction that typify autism, together with a restricted,

stereotyped, repetitive repertoire of interests and activities. It differs from autism primarily in

the fact that there is no general delay or retardation in language or in cognitive development.

This disorder is often associated with marked clumsiness. There is a strong tendency for the

abnormalities to persist into adolescence and adult life. Psychotic episodes occasionally occur in

early adult life.

F84.8-Other pervasive developmental disorders

F84.9-Pervasive developmental disorder. Unspecified

Epidemiology of Autistic Spectrum Disorders

Over the past 30 years, the number of reported cases of ASD has increased rapidly. The growth

in numbers of ASD cases has been partly explained by changes in diagnosis and classification

criteria, early diagnosis, better awareness and recognition of the condition, taking into account

the type of areas studied (e.g. rural vs urban areas) and also possible differences across

countries.

The lack of mechanisms to obtain consistent and reliable information about ASD trends at a

European level is an important obstacle for the development of better and more equitable

services. Sixteen studies conducted since the year 2000 in European countries by different

teams converge to estimates to a median of 19/10.000 for Autism Disorder (AD) and 62/10.000

for all Pervasive Developmental Disorders (PDDs) combined (Elsabbagh et al., 2012). The

estimate represents an average figure and there is substantial variability across studies;

however this is currently the best estimate for the prevalence of AD and PDDs available.

Immunisation In 1974, WHO established the Expanded Programme on Immunization to ensure that all

children have access to routinely recommended vaccines (Blend, 1998). Since then, global

coverage with the four core vaccines – Bacille Calmette-Guérin vaccine (BCG) for protection

against tuberculosis, diphtheria-tetanus-pertussis vaccine (DTP), polio vaccine, and measles


CONFIDENTIAL 9

vaccine – has increased from <5% to ≥85%, and additional vaccines have been added to the

recommended schedule.

The enhancement of immunization activities contributed to a considerable reduction in child in

the WHO European Region over the past few decades.

Coverage with the first dose of measles-containing vaccine (MCV1), the third dose of DTP

vaccine (DTP3) by age 12 months, and the third dose of polio vaccine (polio3) are some key

indicators of immunization programme performance because they reflect key steps or

completion of the basic infant immunization schedule.

In 2014 estimated global coverage for MCV1 was 85%; for the second routine dose of measles-

containing vaccine (MCV2) was 38% by the end of the second year of life and 56% when

including older age groups; for DTP3 was 86%; for BCG was 91% and for (polio3) was 86%

(WHO, 2015).

Vaccination coverage is calculated as the percentage of persons in a target age group who

received a vaccine dose. Countries report administrative coverage annually to the World Health

Organisation (WHO) and the United Nations Children’s Fund (UNICEF) (Administrative data

reported to WHO and UNICEF, 2015), so that national coverage estimates can be derived

through an annual country-by-country review of all available data.

Significant advances have been made in developing new vaccines, and by the end of 2014

supplementary vaccines were introduced into national routine immunization programmes in

some countries: MCV2 (154 countries, 79%), rubella (140 countries, 72%), hepatitis B (184

countries, 95%), 3 doses of Haemophilus influenzae type b (Hib) (192 countries, 99%), rotavirus

(74 countries, 38%), pneumococcal conjugate vaccine (PCV) (117 countries, 60%). Moreover,

immunization programmes have reached additional regional area leading to a greater coverage.

The Global Vaccine Action Plan (GVAP) calls on all countries to reach a target of 90% national

immunization coverage of all vaccines, and 80% coverage among all districts by 2015, with a

sustained coverage level for 3 years by 2020 (Global Vaccine Action Plan, 2014).

The GVAP highlights the importance of sustainable access to vaccines as 1 of its 6 strategic

objectives for achieving high coverage. Despite progress, weaknesses in vaccine stock

management at national and district level continue to hinder the achievement of this objective.

On 17 September 2014, the Member States of the WHO European Region unanimously adopted

the European Vaccine Action Plan 2015-2020 (Global Vaccine Action Plan, 2015). The aim of the

European Vaccine Action Plan is to complement, regionally interpret and adapt the Global

Vaccine Action Plan in harmony with Health 2020 and other key European regional health

strategies and polices by defining objectives, priority action areas and indicators and taking into

account specific needs and challenges of Member States in the WHO European Region.

Within the aspirational vision of European Vaccine Action Plan, six regional goals have been set,

aligned with the Decade of Vaccines and the Global Vaccine Action Plan and in the context of the

European Region:


CONFIDENTIAL 10

sustain polio-free status;

eliminate measles and rubella;

control hepatitis B infection;

meet regional vaccination coverage targets at all administrative levels throughout the

Region;

make evidence-based decisions on the introduction of new vaccines;

achieve financial sustainability of national immunization programme.

In general, vaccination coverage and time of administration varies greatly by WHO Region, but

despite the wide diversity of health systems in the European Region, national immunization

programmes are generally strong and routine national vaccination coverage is high.

Tables 1, 2, 3 show the immunization schedules for measles, mumps and rubella (MMR)

vaccines in the European countries (European centre for disease prevention, 2016). These

vaccines (generally given together as the MMR vaccine) were chosen because they are routinely

given to all children in Europe. In addition, the MMR vaccination has been the subject of

controversy in the past 20 years.

The first dose of MMR is given within 12 months of age in 10 countries (Belgium, Croatia,

Estonia, France, Ireland, Liechtenstein, Luxembourg, Portugal, Romania and Spain), within 16

months of age in 15 countries (Bulgaria, Cyprus, Czech Republic, Denmark, Germany, Greece,

Hungary, Italy, Latvia, Lithuania, Malta, Netherlands, Norway, Poland and United Kingdom) and

within the second year of age in the rest of the countries (Austria, Finland, Iceland, Slovakia,

Slovenia and Sweden). Almost all countries in the European Union have introduced the second

dose of MMR immunisation. In Austria, Czech Republic, France, Germany, Liechtenstein and

Luxembourg the second dose of MMR is given within the second year of life, while in Belgium,

Bulgaria, Hungary, Iceland, The Netherlands, Norway, Poland, and Slovakia is given after 9 years

old. In the remaining countries the second dose of MMR is administered between 3 and 8 years

old

11

Table 1. Nationally recommended immunisations for Measles (ME)

Months Years

6 11 12 13 14 15 16 17 18 21 23 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 35 45

Austria

ME1

ME2 Belgium

ME

ME

ME ME

Bulgaria

ME

ME Croatia

ME

ME

Cyprus

ME

ME Czech Republic

ME3

ME4

Denmark

ME5

ME

ME6 Estonia

ME

ME

Finland

ME7

ME France ME8 ME

ME

ME9 ME10

Germany

ME11 ME ME ME12

Greece

ME

ME13 Hungary

ME

ME

Iceland

ME

ME Ireland

ME

ME

Italy

ME

ME

ME14 Latvia

ME

ME

ME15

Liechtenstein

ME

ME Lithuania

ME

ME

Luxembourg

ME

ME Malta

ME

ME

Netherlands

ME

ME Norway

ME

ME

Poland

ME

ME ME16 Portugal

ME

ME

Romania

ME

ME17 Slovakia

ME

ME

Slovenia

ME

ME Spain

ME

ME

Sweden

ME

ME

ME18 United

Kingdom

ME

ME

ME19


12

1: Two doses at least 4 weeks apart 2: catch-up for children with no history of vaccination or disease or who received only one dose. Catch-up until 45 years of age 3: first doses given starting at the age of 15 months. second dose should be given 6-10 months after the first dose 4: Administered between 21st and 25th month of life 5: MMR vaccination possible from 9 months of age prior to visiting measles-endemic countries and areas where measles outbreaks are known to occur. The recommended two-dose vaccination schedule at 15 months and 4 years still need to be completed if first vaccination before 12 months 6: previously recommended age at second MMR that will last until 2016 for children who were older than 4 years by 1 April 2008 7: Vaccination can be given from 6 months of age in case of travel abroad. If vaccination starts before 12 months of age, 2 doses are recommended (14-18 months and 6 years) the temporary recommendation of giving measles at 12 months of age was made a permanent recommendation; i.e., now MMR should be given from 12-18 months except if travelling abroad to measles infected countries when it can be given from 6 months on. In case MMR is given at 6-11 months, the child needs a second and third dose to complete the series 8: Update 28 June 2013. For a full description of recommendations, please refer to: http://www.hcsp.fr/explore.cgi/avisrapportsdomaine?clefr=362. The vaccination from 9 months of age of children entering day care was suspended 9: 3 doses of MMR one month apart if no previous vaccination; 1 dose if only one dose previously 10: Two MMR doses in total among individuals born from 1980 11: Vaccination from 9 months in specific circumstances. In this case, the second dose should be given as early as possible in the second year of life 12: One dose of measles for those aged 18 years and over and born from 1970 with no or uncertain vaccination history, with no vaccination history or with only one dose received during childhood. Only an MMR-vaccine is available in Germany 13: Two doses recommended to people belonging to specific occupational categories, please refer to official recommendations. Women found to be seronegative during pregnancy should be vaccinated with 2 doses in the postpartum period 14: Only for those with no vaccination history 15: Catch-up for females not previously vaccinated, with no history of rubella vaccination or disease, 2-dose schedule recommended 16: Catch-up for children who did not receive MMR at 10 years of age (children born before 31 Dec 1996). An additional dose should be given by 19 years of age 17: school-based programme 18: Applicable to children born up to 2001 19: Catch-up programme children, born between 1997 and 2003, who are unvaccinated or only partially vaccinated against measles. For more information please refer to http://www.nhs.uk/news/2013/04April/Pages/New-MMR-catch-up-campaign-one-million-children-targeted.aspx

General recommendation Recommendation for specific groups only Catch-up (e.g. if previous dosed missed)

http://www.hcsp.fr/explore.cgi/avisrapportsdomaine?clefr=362

http://www.nhs.uk/news/2013/04April/Pages/New-MMR-catch-up-campaign-one-million-children-targeted.aspx


13

Table 2. Nationally recommended immunisations for Mumps (MU)

Months Years

11 12 13 14 15 16 17 18 21 23 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 35

Austria MU1

MU2 Belgium

MU

MU

MU MU

Bulgaria

MU

MU Croatia

MU

MU

Cyprus

MU

MU Czech Republic

MU3

MU4

Denmark

MU5

MU

MU6 Estonia

MU

MU

Finland

MU7

MU France

MU

MU

MU8 MU9

Germany MU10 MU MU Greece

MU

MU11

Hungary

MU

MU Iceland

MU

MU

Ireland

MU

MU Italy

MU

MU

MU12

Latvia

MU

MU

MU13 Liechtenstein

MU

MU

Lithuania

MU

MU Luxembourg

MU

MU

Malta

MU

MU Netherlands

MU

MU

Norway

MU

MU Poland

MU

MU MU14

Portugal

MU

MU Romania

MU

MU15

Slovakia

MU

MU Slovenia

MU

MU

Spain

MU

MU Sweden

MU

MU

MU16

United Kingdom

MU

MU

MU17


14

1: Two doses at least 4 weeks apart 2: catch-up for children with no history of vaccination or disease or who received only one dose. Catch-up until 45 years of age 3: first doses given starting at the age of 15 months, second dose should be given 6-10 months after the first dose 4: Administered between 21st and 25th month of life 5: MMR vaccination possible from 9 months of age prior to visiting measles-endemic countries and areas where measles outbreaks are known to occur. The recommended two-dose vaccination schedule at 15 months and 4 years still need to be completed if first vaccination before 12 months 6: previously recommended age at second MMR that will last until 2016 for children who were older than 4 years by 1 April 2008 7: Vaccination can be given from 6 months of age in case of travel abroad. If vaccination starts before 12 months of age, 2 doses are recommended (14-18 months and 6 years). The temporary recommendation of giving measles at 12 months of age was made a permanent recommendation; i.e., now MMR should be given from 12-18 months except if travelling abroad to measles infected countries when it can be given from 6 months on. In case MMR is given at 6-11 months, the child needs a second and third dose to complete the series 8: 3 doses of MMR one month apart if no previous vaccination; 1 dose if only one dose previously 9: Two MMR doses in total among individuals born from 1980 10: Vaccination from 9 months in specific circumstances. In this case, the second dose should be given as early as possible in the second year of life 11: Two doses recommended to people belonging to specific occupational categories, please refer to official recommendations. Women found to be seronegative during pregnancy should be vaccinated with 2 doses in the postpartum period 12: Only for those with no vaccination history 13: Catch-up for females not previously vaccinated, with no history of rubella vaccination or disease, 2-dose schedule recommended 14: Catch-up for children who did not receive MMR at 10 years of age (children born before 31 Dec 1996). An additional dose should be given by 19 years of age 15: school-based programme 16: Applicable to children born up to 2001 17: Catch-up programme children, born between 1997 and 2003, who are unvaccinated or only partially vaccinated against measles. For more information please refer to http://www.nhs.uk/news/2013/04April/Pages/New-MMR-catch-up-campaign-one-million-children-targeted.aspx

General recommendation

Recommendation for specific groups only

Catch-up (e.g. if previous dosed missed)



15

Table 3. Nationally recommended immunisations for Rubella (RU)

Months Years

11 12 13 14 15 16 17 18 21 23 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 45

Austria RU1

RU2 Belgium

RU

RU

RU RU

Bulgaria

RU

RU Croatia

RU

RU

Cyprus

RU

RU Czech Republic

RU3

RU4

Denmark

RU5

RU

RU6 Estonia

RU

RU

Finland

RU7

RU France

RU

RU

RU8 RU9

Germany RU10 RU RU Greece

RU

RU11

Hungary

RU

RU Iceland

RU

RU

Ireland

RU

RU Italy

RU

RU

RU12

Latvia

RU

RU

RU13 Liechtenstein

RU

RU

Lithuania

RU

RU Luxembourg

RU

RU

Malta

RU

RU Netherlands

RU

RU

Norway

RU

RU Poland

RU

RU RU14

Portugal

RU

RU Romania

RU

RU15

Slovakia

RU

RU Slovenia

RU

RU16

Spain

RU

RU Sweden

RU

RU

RU17

United Kingdom

RU

RU

RU18


16

1: Two doses at least 4 weeks apart 2: catch-up for children with no history of vaccination or disease or who received only one dose. Catch-up until 45 years of age 3: first doses given starting at the age of 15 months, second dose should be given 6-10 months after the first dose 4: Administered between 21st and 25th month of life 5: MMR vaccination possible from 9 months of age prior to visiting measles-endemic countries and areas where measles outbreaks are known to occur. The recommended two-dose vaccination schedule at 15 months and 4 years still need to be completed if first vaccination before 12 months 6: previously recommended age at second MMR that will last until 2016 for children who were older than 4 years by 1 April 2008 7: Vaccination can be given from 6 months of age in case of travel abroad. If vaccination starts before 12 months of age, 2 doses are recommended (14-18 months and 6 years) the temporary recommendation of giving measles at 12 months of age was made a permanent recommendation; i.e., now MMR should be given from 12-18 months except if travelling abroad to measles infected countries when it can be given from 6 months on. In case MMR is given at 6-11 months, the child needs a second and third dose to complete the series 8: 3 doses of MMR one month apart if no previous vaccination; 1 dose if only one dose previously 9: Two MMR doses in total among individuals born from 1980. For rubella, one dose of MMR among unvaccinated woman 10: Vaccination from 9 months in specific circumstances. In this case, the second dose should be given as early as possible in the second year of life 11: Two doses recommended to people belonging to specific occupational categories, please refer to official recommendations. Women found to be seronegative during pregnancy should be vaccinated with 2 doses in the postpartum period 12: Only for those with no vaccination history 13: Catch-up for females not previously vaccinated, with no history of rubella vaccination or disease, 2-dose schedule recommended 14: Catch-up for children who did not receive MMR at 10 years of age (children born before 31 Dec 1996). An additional dose should be given by 19 years of age 15: school-based programme 16: Recommended only. Not included in the national immunization schedule 17: Applicable to children born up to 2001 18: Catch-up programme children, born between 1997 and 2003, who are unvaccinated or only partially vaccinated against measles. For more information please refer to http://www.nhs.uk/news/2013/04April/Pages/New-MMR-catch-up-campaign-one-million-children-targeted.aspx

General recommendation Recommendation for specific groups only Catch-up (e.g. if previous dosed missed)


17

Materials and methods

Search strategy A comprehensive electronic search was performed using PubMed.

For Autism Spectrum Disorder (ASD) the following key words have been set for the search in

the title or in the abstract: (autism spectrum disorder OR autistic disorder OR Asperger OR

Asperger’s syndrome OR Asperger’s disorder OR pdd-nos OR pervasive developmental disorder

OR childhood disintegrative disorder OR cdd); moreover ((age) AND (diagnosis OR onset)) was

set for the search in the full-text. The filter child: birth <18 was set.

For immunisation the following key words have been set for the search in the title or in the

abstract: (vaccine* OR immuniz*) AND (measl* OR mump* OR rubell* OR mmr) AND (coverage),

using the filters child: birth <18 and humans.

All potentially eligible articles were screened at title, abstract, and full-text stages in order to

sequentially identify the study country and the availability of the investigated outcomes.

The PubMed search was supplemented with hand-searching of reference lists of all potentially

eligible full-text articles.

Eligibility criteria Types of study design: Any type of study design has been included in the search; however the

search identified mainly observational studies, either cross-sectional or longitudinal.

Reference year: all papers published in the range of years 2000-2016.

Language restriction: only papers published in English were considered

Outcomes investigated:

a) ASD focused on the age at onset of the following conditions:

a1) Autism/ autistic disorder;

a2) Asperger’s syndrome;

a3) Pervasive developmental disorder not otherwise specified;

a4) Childhood disintegrative disorder;

b) Immunisation investigated the coverage of the following conditions:

b1) Measles;

b2) Mumps;

b3) Rubella.


18

Data extraction The following data were extracted from all included papers: the first author’s last name,

publication year, country where the study was conducted, the study design, the outcome

measures investigated, the sample size, the age of reference, and gender.

Summary of the study selection process The following figures show the different steps of the selection process for ASD and

Immunisation, respectively.

The PubMed search retrieved 2122 articles on ASD from year 2000 to 2016 (Fig. 1). Sixty-nine

percent of these papers (1356/2122) have been excluded since the research was not carried out

in a European Country. Selecting the EU countries articles was particularly time-consuming as it

often required reading the full-text. Twenty-one articles were retrieved manually, leading to

787 articles read as a full text. Out of these, only 37 have been included in our systematic review

(4.7%).

Figure 1. Flow chart age at ASD diagnosis

The PubMed search retrieved 1008 articles on Immunisation from year 2000 to 2016 (Fig. 2).

Sixty-four percent of these papers (648/1008) have been excluded since the research was not

carried out in a European Country. The mere selection of the EU and EEA countries’ articles was

Identification of the studies by electronic search

(n=2122)

EU/EEA articles (n=787)

Finally included articles (n=37)

Articles excluded based on: - no full text or not in English

(n=192) - not pertinent or no information

(n=546) - duplication (n=12)

Articles excluded because not EU/EEA

(n=1356)

Articles identified by manual research (n=21)


19

particularly time-consuming since, often, it had required the reading of the full-text. Sixty-four

percent of these papers (648/1008) have been excluded since the research was not carried out

in a European Country. The full-text reading of the 360 articles lead to 101 articles to be

included in our systematic review.

Figure 2. Flow chart MMR coverage

Identification of the studies by electronic search

(n=1008)

EU/EEA articles (n=360)

Finally included articles (n=101)

Articles excluded based on: - no full text (n=117) - not in English (n=21) - not pertinent or no

information (n=121)

Articles excluded because not EU/EEA (n=648)


20

Meta-analysis In our search the primary interest lies in the descriptive estimates, as opposed to comparative

estimates that arise naturally for Randomized Controlled Trial studies or cohort studies (where

exposed are compared with the unexposed) or case-control studies (where people with the

condition are compared with people without the condition).

Investigated outcomes have been combined in a pooled estimate, using the method of the

inverse of the variance, that is the weighting assigned to the different studies is related with the

inverse of the standard error and therefore indirectly to the sample size. This implies that

studies with smaller standard error and larger sample size are given more weight in the

calculation of the pooled estimates. Fixed effects or random effects model have been used,

according to the presence of heterogeneity which was tested by means of the Cochrane’s Q test

and the Higgins I2 statistic which was interpreted as follows: I2 of 25 % = low heterogeneity. I2 of

50 % = medium heterogeneity. I2 = 75 % = high heterogeneity. The results of the different

studies and the overall estimate with its 95% Confidence Interval (95%CI) are illustrated in a

"forest plot" graph.

Type of care: country classification The EU and EEA countries have been classified according to their primary care system defined

as: Paediatrician mainly oriented (Paed); General Practitioner mainly oriented (GP); Mixed. This

classification is the outcome of the MOCHA classification task group based on the Country Agent

investigations upon a specific request from the WP leaders on a case study.

Table 4 reports the description of the health system given by the Country Agents, the findings

from van Esso et al. (2010) ( who have used the term “combined”when referring to GP and

Paediatrician systems) and the MOCHA classification working group. The term mixed

incorporates other professionals involvement as first line contatcs e.g. nursing staff.


21

Table 4: Type of primary care for each EU country

Country Description of type of

primary care

From van Esso et al.

Arch Dis Child 2010;

95:791-5

MOCHA

Classification

Austria GP and paediatrician Combined Mixed

Belgium Family doctor or 1st line

paediatrician Combined Mixed

Bulgaria

GP for those with health

insurance. Pre 2000 was

mandatory to have a

community paediatrician for

children up to 18; this

generation now retiring and

GPs only have 9 weeks

paediatrics training.

GP GP

Croatia Primary care doctor /

paediatrician - Paed

Cyprus

Private paediatrician or

public funded GP who will

refer to hospital

Paediatrician if necessary

Paed Mixed

Czech Republic “registering paediatrician”

accessed via triage nurse Paed Paed

Denmark - GP GP

Estonia GP GP GP

Finland GP GP GP

France

Family physician or GP who

is either a Paediatrician or a

GP

GP Mixed

Germany Paediatrician GP Paed

Greece

GP or Paediatrician chosen

from insurance co list

Usually paediatrician up to

18 years old.

Paed Paed

Hungary - Combined Mixed

Iceland

One family doctor from a

health care centre or private

paediatrician

Combined Mixed

Ireland GP GP GP

Italy

0-14 have paediatrician or

GP if none locally. Max 800

children per paediatrician

Mixed Paed

Latvia GP / family doctor or a GP Mixed


22

paediatrician

Lithuania Family doctor or

paediatrician Combined Mixed

Luxembourg Family doctor. Paediatrician

up to the age of 2 years. Combined Mixed

Malta

Family doctor (private) or

walk in community health

centre

- GP

Netherlands GP (Triaged by nurse) GP GP

Norway GP GP GP

Poland GP or Paediatrician chosen

from insurance company list GP Mixed

Portugal GP (80%) or private

paediatrician GP GP

Romania Family doctor - GP

Slovakia - Paed Paed

Slovenia - Paed Paed

Spain Family doctor in health care

centre or a paediatrician Paed Mixed

Sweden

Child health care nurse up to

age 6; school health nurse

afterwards.

GP/Paediatricians in

hospital contacted by nurse

GP Mixed

United Kingdom GP as a named accountable

professional GP GP

The Paed/GP/Mixed MOCHA classification was used to perform the meta-analysis for each type

of primary care and allow some speculations on possible difference across types of primary care

systems.

Sweden reported a system based on a child health nurse and for our purposes was classified as

Mixed; Luxembourg reported a Paed if the child was under two years and a GP if was over 2

years and for our purposes was classified as Mixed.


23

Results

Autistic Spectrum Disorder Appendix 1 shows the main characteristics of the identified studies for ASD. A total of 37 studies

have been identified, of which 10 investigated ASD only. The age of reference reported in the

studies ranges from 0 to 65 years and the sample size from 6 to 10297 for ASD, from 11 to 4475

for Autism/ autistic disorder, from 3 to 4192 for Asperger’s syndrome, from 19 to 1796 for

Pervasive developmental disorder not otherwise specified, and 6 for Childhood disintegrative

disorder. The majority of the studies had been carried out in one country, with the exception of

Salomone E. (2015) that considered 18 EU countries and Pry R. (2005) that considered 4 EU

countries. Most of the studies (29.7%) have been carried out in UK, followed by Denmark

(13.5%), The Netherlands and Sweden (10.8%), Italy (8%), France (5.4%) and Finland, Greece,

Germany, Czech Republic and Belgium (3.7%).

For the meta-analysis 14 articles have been excluded because they did not provide the mean of

the age at diagnosis and/or the standard error.

The meta-analysis was performed by the MOCHA classification type of primary care in each

country. Paediatrician included 4 countries (Czech Republic, Germany, Greece and Italy), GP

included 8 countries (Denmark, Finland, Ireland, Netherland, Norway, Portugal, Romania and

UK), and Mixed included 7 countries (Belgium, Hungary, France, Iceland, Poland, Spain and

Sweden).


24

For the calculation of the pooled estimate of the mean age at onset for ASD, a random effect

model was used, due to the presence of heterogeneity in Paediatrician-led systems (Q=535.4; p-

value<0.0001; I2=99.44%), in GP-led systems (Q=9159.43; p-value<0.0001; I2=99.84%) and in

Mixed (Q=257.8; p-value<0.0001; I2=96.90%).

The pooled estimated of age at onset for ASD was 50.6 months with a 95% CI = (34.2-66.9) in a

Paediatrician-led primary care system, as presented in fig.3.

Figure 3. Meta-analysis for mean age at onset of ASD, Paediatrician-led primary care system.

Meta-analysis

30 40 50 60 70 80

Estimate

Salomone E., 2015 [Czech Rep.]

Salomone E., 2015 [Germany]

Salomone E., 2015 [Italy]

Ververi A., 2012 [Greece]

Total (fixed effects)

Total (random effects)


25

The pooled estimated of age at onset for ASD was 57.5 months with a 95% CI= (39.8-75.2) in a

GP-led primary care system, as presented in fig.4.

Figure 4. Meta-analysis for mean age at onset of ASD, GP-led primary care system.

Meta-analysis

0 50 100 150 200 250

Estimate

Chakrabarti S., 2005 [UK(Midlands)]

Hathorn C., 2014 [UK (Scotland)]

Latif A.H.A., 2007 [UK(South Wales)]

Mouridsen S.E., 2014 [Denmark]

Oosterling I.J., 2010 [Netherlands (Gelderland)]

Salomone E., 2015 [Denmark]

Salomone E., 2015 [Finland]

Salomone E., 2015 [Ireland]

Salomone E., 2015 [Netherlands]

Salomone E., 2015 [Norway]

Salomone E., 2015 [Portugal]

Salomone E., 2015 [Romania]

Salomone E., 2015 [UK]

Stagg S.D., 2014 [UK (South London)]

van der Ven E., 2013 [Netherlands]

Visser J.C., 2013 [Netherlands]




26

The pooled estimated of age at onset for ASD was 48.4 months with a 95% CI= (43.2-53.5) in a

Mixed primary care system, as presented in fig. 5.

Figure 5. Meta-analysis for mean age at onset of ASD, Mixed primary care system.

Meta-analysis

30 40 50 60 70 80 90 100

Estimate

Chamak B., 2011 [France]

Rasmussen P., 2001 [Sweden (Göteborg)]

Renty J., 2006 [Belgium(Flanders)]

Salomone E., 2015 [Belgium]

Salomone E., 2015 [France]

Salomone E., 2015 [Hungary]

Salomone E., 2015 [Iceland]

Salomone E., 2015 [Poland]

Salomone E., 2015 [Spain]




27

Asperger’s syndrome

For the calculation of the pooled estimate of the mean age at onset for Asperger’s syndrome, a

random effect model was used in Paediatrician-led systems (Q=39.2; p-value<0.0001;

I2=97.45%) and in GP-led systems (Q=1055.5; p-value<0.0001; I2=99.62%), due to the presence

of heterogeneity. Only one (Cederlund M., 2004) of the included articles belonged to a Mixed

primary care model, so for this classification no meta-analysis was performed. This study

reported a mean age at diagnosis of 136.0 (SD=4.6) months.

The pooled estimated of age at onset for Asperger’s syndrome was 85.8 months with a 95% CI =

(3.7-167.6) in a Paediatrician-led primary care system, as presented in fig. 6.

Figure 6. Meta-analysis for mean age at onset of Asperger’s syndrome, Paediatrician-led primary

care system.

Meta-analysis

0 50 100 150 200

Estimate

Noterdaeme M., 2010 [Germany]

Oslejskova H., 2007 [Czech Republic]




28

The pooled estimated of age at onset for Asperger’s syndrome was 111.2 months with a 95% CI

= (93.6-128.9) in a GP-led primary care system, as presented in fig. 7.

Figure 7. Meta-analysis for mean age at onset of Asperger’s syndrome, GP-led primary care

system.

Meta-analysis

70 80 90 100 110 120 130 140 150

Estimate

Begeer S., 2013 [Netherlands]

Begeer S., 2013 [Finland]







29

Autistic disorder

For the calculation of the pooled estimate of the mean age at onset for Autistic disorders, a fixed

effect model was used in Paediatrician-led systems (Q=0.3; p-value=0.619; I2=0.00%) and a

random effect model in GP-led systems (Q=1065.6; p-value<0.0001; I2=99.34%), due to the

presence of heterogeneity. Only one (Boddaert N. et al., 2004) of the included articles belonged

to a Mixed primary care model, so for this classification no meta-analysis was performed. This

study reported a mean age at diagnosis of 51.6 (SD=2.9) months.

The pooled estimated of age at onset for Autistic disorder was 75.5 months with a 95% CI =

(72.1-79.0) in a Paediatrician-led primary care system, as presented in fig. 8.

Figure 8. Meta-analysis for mean age at onset of Autistic disorder, Paediatrician-led primary

care system.

Meta-analysis

65 70 75 80 85

Estimate

Noterdaeme M., 2010 [Germany]

Oslejskova H., 2007 [Czech Republic]




30

The pooled estimated of age at onset for Autistic disorder was 57.5 months with a 95% CI =

(45.1-69.9) in a GP-led primary care system, as presented in fig. 9.

Figure 9. Meta-analysis for mean age at onset of Autistic disorder, GP-led primary care system.

Meta-analysis

10 20 30 40 50 60 70 80 90

Estimate


Campbell M., 2013 [UK (Glasgow)]


Jokiranta E., 2013 [Finland]



Powell J.E., 2000 [UK (West Midlands)]





31

Pervasive Developmental Disorder, Not Otherwise Specified (PDD-NOS)

For the calculation of the pooled estimate of the mean age at onset for PDD-NOS, a random

effect model in GP-led systems (Q=583.2; p-value<0.0001; I2=99.49%) was used, due to the

presence of heterogeneity. None of the articles belonged to either Paediatrician-led or Mixed

primary care model classification.

The pooled estimated of age at onset for PDD-NOS was 72.9 months with a 95% CI = (54.9-90.8)

in a GP-led primary care system, as presented in fig. 10.

Figure 10. Meta-analysis for mean age at onset of PDD_NOS, GP-led primary care system.

Meta-analysis

30 40 50 60 70 80 90 100

Estimate

Begeer S., 2013 [Finland]







32

Immunisation Appendix 2 shows the main characteristics of the identified studies for Measles, Mumps and

Rubella vaccination. A total of 101 studies have been identified, of which the majority

investigated the MMR vaccination alone and Measles alone (56 papers and 23 papers,

respectively), 8 looked at all the three Measles, Mumps and Rubella conditions. Rubella alone

was studied in 6 studies, Mumps alone in 4 studies, and the combination Measles-Rubella,

Measles-MMR, Rubella-MMR and MMRV (MMR+Varicella) were analysed in one study each. In

four studies, immunisation coverage is presented as a comparison of more countries (one on

Measles alone, one on Rubella alone and two in MMR) whereas all the remaining regard only

one country. Germany, Italy, United Kingdom, Poland, Belgium and France are the most

investigated countries with at least 10 papers each (17, 15, 14, 11, 10 and 10, respectively),

whereas no papers were found from Estonia, Finland, Portugal and Iceland.

For the meta-analysis 53 studies have been excluded because neither the sample size nor the

95% CI for the stated percentage of coverage was reported in the paper. The meta-analysis was

performed by the MOCHA classification type of primary care in each country for the remaining

papers. Based on the information retrieved, for each type of primary care the following

countries were included for meta-analyses:

Paediatrician-led: 7 countries (Croatia, Czech Republic, Germany, Greece, Italy, Slovenia,

Slovakia);

GP-led: 6 countries (Bulgaria, Ireland, Malta, Netherlands, Romania, United Kingdom);

Mixed: 9 countries (Austria, Belgium, Cyprus, France, Latvia, Lithuania, Luxembourg,

Spain, Sweden).

There was no information received from 4 countries: Denmark, Hungary, Norway and

Poland.


33

Measles, Mumps and Rubella (MMR)

The pooled estimate of immunisation coverage for MMR was calculated by a random effect

model, due to the presence of heterogeneity in Paediatrician-led models (Q=73994.0; p-

value<0.0001; I2=99.99%), in GP-led models (Q=23375.9; p-value<0.0001; I2=99.96%) and in

Mixed models (Q=789.2; p-value<0.0001; I2=98.48%).

The pooled estimated of immunisation coverage for MMR was 73.1% with a 95% CI = (30.1-

99.0) in a Paediatrician-led primary care system, as presented in fig.11.

Figure 11. Meta-analysis for immunisation coverage for MMR, Paediatrician-led primary care

system.

Meta-analysis

0,0 0,2 0,4 0,6 0,8 1,0

Proportion

Kalies H, 2006 [Germany]

Khetsuriani N, 2011 [Croatia]

Mikolajczyk RT, 2008 [Germany (Bavaria)]

Pavlopoulou ID, 2013 [Greece (Athens)]

Restivo V, 2015 [Italy (Palermo)]

Reuss AM, 2010 [Germany]

Sakou II, 2011 [Greece (Athens)]

Takla A, 2014 [Italy (Friuli-Venezia-Giulia, Tuscany, Marche, Lazio, Calabria)]




34

The pooled estimated of immunisation coverage for MMR was 73.7% with a 95% CI= (66.6-

80.2) in a GP-led primary care system, as presented in fig.12.

Figure 12. Meta-analysis for immunisation coverage for MMR, GP-led primary care system.

Meta-analysis

0,3 0,4 0,5 0,6 0,7 0,8 0,9 1,0

Proportion

Choi YH, 2008 [United Kingdom (England)]

Henderson R, 2004 [United Kingdom (Highland, Scotland)]

Khetsuriani N, 2011 [Ireland]

Lashkari HP, 2010 [United Kingdom (Haringey, London)]

Mixer RE, 2007 [United Kingdom (Brent, London)]

Sandford H, 2015 [United Kingdom (England)]

Simone B, 2014 [United Kingdom (England-LA)]

Simone B, 2014 [United Kingdom (England-LB)]

Stanescu A, 2011 [Romania]

van der Wal MF, 2005 [Netherlands (Amsterdam)]




35

The pooled estimated of immunisation coverage for MMR was 93.9% with a 95% CI= (90.5-

96.6) in a Mixed primary care system, as presented in fig.13.

Figure 13. Meta-analysis for immunisation coverage for MMR, Mixed primary care system.

Meta-analysis

0,8 0,9 1,0

Proportion

Bystrom E, 2014 [Sweden (community near Stockholm)]

Lernout T, 2014 [Belgium (Flanders)]

Robert E, 2014 [Belgium (Wallonia)]

Robert E, 2014 [Belgium (Brussels)]

Barrabeig I, 2011 [Spain (Barcelona-South Health Region)]

Borràs E, 2009 [Spain (Catalonia, public health care)]

Borràs E, 2009 [Spain (Catalonia, private health care)]

Vandermeulen C, 2008 [Belgium (Flanders)]

Guagliardo V, 2007 [France (South-Eastern)]

Alfredsson R, 2004 [Sweden (Göteborg)]

Dannetun E, 2004 [Sweden (Ostergotland)]

Vandermeulen C, 2004 [Belgium (Bruges)]

Vellinga A, 2002 [Belgium (Flanders)]




36

Measles

For the calculation of the pooled estimate of immunisation coverage for Measles, a random

effect model, due to the presence of heterogeneity, was used in Paediatrician-led systems

(Q=36738.2; p-value<0.0001; I2=99.90%), in GP-led systems (Q=870.3; p-value<0.0001;

I2=99.31%) and in Mixed model systems (Q=1066.4; p-value<0.0001; I2=99.06%).

The pooled estimated of immunisation coverage for Measles was 70.9% with a 95% CI = (64.2-


Figure 14. Meta-analysis for immunisation coverage for Measles, Paediatrician-led primary care

system.

Meta-analysis

0,0 0,2 0,4 0,6 0,8 1,0

Proportion

Andrews N, 2008 [Czech Republic]Andrews N, 2008 [Slovakia]Andrews N, 2008 [Slovenia]Bonanni P, 2002 [Italy (Abruzzi)]Bonanni P, 2002 [Italy (Basilicata)]Bonanni P, 2002 [Italy (Boizano)]Bonanni P, 2002 [Italy (Calabria)]Bonanni P, 2002 [Italy (Campania)]Bonanni P, 2002 [Italy (Emilia)]Bonanni P, 2002 [Italy (Friuli–Venezia)]Bonanni P, 2002 [Italy (Liguria)]Bonanni P, 2002 [Italy (Lombardy)]Bonanni P, 2002 [Italy (Marches)]Bonanni P, 2002 [Italy (Milan)]Bonanni P, 2002 [Italy (Molise)]Bonanni P, 2002 [Italy (Naples)]Bonanni P, 2002 [Italy (Piedmont)]Bonanni P, 2002 [Italy (Puglia)]Bonanni P, 2002 [Italy (Sardinia)]Bonanni P, 2002 [Italy (Sicily)]Bonanni P, 2002 [Italy (Trento)]Bonanni P, 2002 [Italy (Tuscany)]Bonanni P, 2002 [Italy (Umbria)]Bonanni P, 2002 [Italy (Val D'Aosta)]Bonanni P, 2002 [Italy (Veneto)]Centers Disease Control Prevention, 2003 [Italy (Campania)]Ciofi degli Atti ML, 2004 [Italy]Heininger U, 2006 [Germany (Erlangen)]Kalies H, 2006 [Germany]Poethko-Müller C, 2009 [Germany]Rieck T, 2014 [Germany]Schönberger K, 2009 [Germany]Siedler A, 2002 [Germany]Stampi S, 2005 [Italy (Bologna)]Stampi S, 2005 [Italy (Emilia Romagna)]Streng A, 2013 [Germany]Wichmann O, 2006 [Germany (Duisburg)]

Total (fixed effects)Total (random effects)


37

The pooled estimated of immunisation coverage for Measles was 91.0% with a 95% CI= (86.9-

94.4) in a GP-led primary care system, as presented in fig.15.

Figure 15. Meta-analysis for immunisation coverage for Measles, GP-led primary care system.

Meta-analysis

0,7 0,8 0,9 1,0

Proportion

Andrews N, 2008 [Bulgaria]

Andrews N, 2008 [England and Wales]

Andrews N, 2008 [Ireland]

Andrews N, 2008 [Malta]

Andrews N, 2008 [Romania]

Hanratty B, 2000 [United Kingdom]

Stanescu A, 2011 [Romania]




38

The pooled estimated of immunisation coverage for Measles was 89.5% with a 95% CI= (85.9-

92.7) in a Mixed primary care system, as presented in fig.16.

Figure 16. Meta-analysis for immunisation coverage for Measles, Mixed primary care system.

Meta-analysis

0,6 0,7 0,8 0,9 1,0

Proportion

Andrews N, 2008 [Belgium]

Andrews N, 2008 [Cyprus]

Andrews N, 2008 [Latvia]

Andrews N, 2008 [Lithuania]

Andrews N, 2008 [Luxembourg]

Andrews N, 2008 [Spain]

Andrews N, 2008 [Sweden]

Fonteneau L, 2013 [France]

Mossong J, 2000 [Luxembourg (Reuler)]

Mossong J, 2000 [Luxembourg (Wincrange)]

Stronegger WJ, 2010 [Austria]




39

Mumps

For the calculation of the pooled estimate of immunisation coverage for Mumps, a random effect

model, due to the presence of heterogeneity, was used in Paediatrician-led systems (Q=2504.7;

p-value<0.0001; I2=99.80%). For the GP-led system no papers addressing Mumps were found,

whereas for Mixed primary care systems only one article was found.

The pooled estimated of immunisation coverage for Mumps was 80.2% with a 95% CI = (73.7-


Figure 17. Meta-analysis for immunisation coverage for Mumps, Paediatrician-led primary care

system.

Only one study (Fonteneau L. et al., 2013) was found for Mumps in the Mixed primary care

system and the reported immunisation coverage was 91.4 (95%CI: 90.8-91.9).

Meta-analysis

0,0 0,2 0,4 0,6 0,8 1,0

Proportion

Heininger U, 2006 [Germany (Erlangen)]


Rieck T, 2014 [Germany]

Stampi S, 2005 [Italy (Bologna)]

Stampi S, 2005 [Italy (Emilia Romagna)]

Takla A, 2014 [Germany (Bavaria)]




40

Rubella

For the calculation of the pooled estimate of immunisation coverage for Rubella, a random effect

model, due to the presence of heterogeneity, was used in the Paediatrician-led model

(Q=2079.0; p-value<0.0001; I2=99.81%). For GP-led models no articles that addressed Rubella

were found, whereas for Mixed primary care system models, only one article was found.

The pooled estimated of immunisation coverage for Rubella was 88.7% with a 95% CI = (83.5-


Figure 18. Meta-analysis for immunisation coverage for Rubella, Paediatrician-led primary care

system.

Only one study (Fonteneau L. et al., 2013) was found for Rubella in the Mixed primary care

system and the reported immunisation coverage was 91.4 (95%CI: 90,8-91,9).

Meta-analysis

0,6 0,7 0,8 0,9 1,0

Proportion

Heininger U, 2006 [Germany (Erlangen)]


Rieck T, 2014 [Germany]

Stampi S, 2005 [Italy (Bologna)]

Stampi S, 2005 [Italy (Emilia Romagna)]




41

Conclusions The meta–analysis performed according to the primary care classification revealed some

similarities and some differences in the investigated outcomes, which are shown in Table 5.

The ASD mean age at onset ranged from 48 to 57 months of age, with no statistical difference

across the three classifications. For Asperger’s syndrome the mean age at onset is higher at 86

months of age for the Paediatrician-led models of primary care and 111 months of age for the

GP-led models of primary care, but again with no statistical difference. As far as Autistic

disorder is concerned, the mean age of diagnosis at onset is statistically lower in the GP system

compared with the Paediatrician-led system (57 months versus 75 months, respectively).

The MMR immunisation coverage is statistically lower for the GP-led versus the Mixed system

(73.7% versus 93.9%), while no differences were found between each of these two

classifications and the Paediatrician system.

For Measles vaccination the findings are always in favour of the GP-led and the Mixed system.

The coverage of Measles vaccinations is lower among Paediatrician-led (70.9%) versus GP-led

(91.0%) and Mixed (89.5%) system.

Table 5. Summary of the meta-analysis findings.

Type of care primary care system Note Paed GP Mixed Mean age (in months) at onset of diagnosis and 95% CI ASD 50.6

(34.2-66.9) 57.5

(39.8-75.2) 48.4

(43.3-55.3) No difference

Asperger’s syndrome

85.8 (3.7-167.9)

111.2 (93.6-128.9)

No article found

No difference

Autistic disorder

75.5 (72.1-79.0)

57.5 (45.1-69.9)

Only one article found

In favour of GP

PDD-NOS No article found

72.9 (54.9-90.8)

No article found

-

Immunisation Coverage (%) and 95% CI MMR 73.1

(30.1-99.0) 73.7

(66.6-80.2) 93.9

(90.5-96.6) Difference between GP and

Mixed (favoured); Measles 70.9

(64.2-77.2) 91.0

(86.9-94.4) 89.5%

(85.9-92.7) Difference between

Paediatrician and GP (favoured);

Difference between Paediatrician and Mixed

(favoured) Mumps 80.2

(73.7-85.9) No article

found Only one

article found -

Rubella 88.7 (83.5-93.0)

No article found

Only one article found

-


42

Strength and limitations A meta-analysis is the statistical part of the systematic review process and has some

advantages. Meta-analysis includes more participants than a single constituent study, which

implies a reduction of random errors and an increase of the power. Moreover, a meta-analysis is

capable of exploring variations between studies. However, there are some limitations of both

the primary studies and the systematic review.

For ASD, depending on the age-range of the analysed sample, the age at diagnosis of ASD could

be subject to bias. For example, some studies considered adolescents as the reference

population while other studies included children under the age of 4 years. It is plausible that the

latter case would underestimate the mean age at diagnosis.

The systematic review for PDD-NOS was unable to retrieve studies for countries using the

Paediatrician-led and Mixed models, which made a true meta-analysis impossible. In terms of

autistic disorder, only one study (conducted in France) was found that referred to the countries

within the Mixed model, while for Asperger’s syndrome, there were no studies carried out in

countries using the Mixed model.

Regarding vaccination, different countries administer the first dose of MMR at different ages:

within 12 months of age in 10 countries, within 16 months of age in 15 countries and within the

second year of age in 6 countries. Almost all countries have introduced the second dose of MMR

vaccination within the second year of life, while in other countries it is administered between 3

and 9 years old.

Usually immunisation coverage is assessed, and reported, at 24, 36 months of age. However,

some of the retrieved studies take into account different age setting and retrospectively assess

the immunisation coverage through child’s personal vaccination card, so the coverage for these

studies could be overestimated if compared to other studies that took into considerations lower

ages.

No comparison was performed for Mumps and Rubella, since no studies were found for the

countries within the GP model and only one study (conducted in France) was found for the

Mixed model.

Finally, the MOCHA country classification of type of primary care is based on the actual health

system running in the country, whereas the retrieved articles for the systematic review refer to

precedent years during which the health system may have had a different legislation and

regulation. As the project progresses and different parameters of models of care are considered,

it is possible to carry out further re- analyses according to typologies of care provision other

than the predominant medical professional type.

43

APPENDIX 1. Main characteristics of the identified studies. ASD; Autism/ autistic disorder; Asperger’s syndrome; Pervasive developmental disorder not otherwise specified; Childhood disintegrative disorder.

Year of publication

1st author Country Age of reference Disease Sample size Age at diagnosis

2015 Ferrante M. Italy (Catania) 0-17 years ASD 1122

Median= 4 years (IQR 3-8) in 2014

Median= 5 years (IQR 3-9) in 2004-2009 Median= 4 years (IQR 3-7) in 2010-2014

2015 Salomone E.

Portugal

>=4 years ASD

113 Mean=33.53 (SD=11.66) months

Italy 88 Mean=35.73 (SD=13.02) months

Spain 186 Mean=36.66 (SD=13.54) months

Romania 44 Mean=37.55 (SD=11.23) months

Poland 60 Mean=37.85 (SD=11.7) months

Macedonia 22 Mean=39.59 (SD=10.53) months

Czech Republic 81 Mean=42.21 (SD=10.26) months

Norway 24 Mean=42.5 (SD=14.37) months

Iceland 46 Mean=42.59 (SD=10.9) months

France 154 Mean=42.76 (SD=12.75) months

UK 92 Mean=43.28 (SD=12.42) months

Finland 41 Mean=44 (SD=11.55) months

Belgium 96 Mean=45.71 (SD=13.33) months

Ireland 22 Mean=46.59 (SD=13.45) months

Hungary 106 Mean=47.88 (SD=12.37) months

Germany 79 Mean=48.44 (SD=10.98) months

Netherlands 90 Mean=50.02 (SD=12.22) months

Denmark 66 Mean=50.17 (SD=14.4) months

Total 1410 Mean=42.16 (SD=13.4) months

2014 Hathorn C. UK (Scotland) Under 15 years (less than 7 years old at diagnosis)

ASD 90 Mean=44.6 (SD=12.9) months


44

2014 Jensen C.M. Denmark 0-65 years

ASD 14997 Median=9 (IQR 6-14) years

Childhood autism 4099 Median=6 (IQR 6-11) years

Atypical autism 1806 Median=10 (IQR 6-15) years

Asperger's syndrome 4691 Median=12 (IQR 8-16) years

PDD-NOS 6262 Median=9 (IQR 6-13) years

2014 Mouridsen S.E. Denmark 1.3-35.9 years (less than 18 years old at diagnosis)

ASD 10297 Mean=8.8 (SD=4.3) years

Asperger syndrome 4192 Mean=10.6 (SD=3.7) years

Childhood autism 4475 Mean=6.9 (SD=4.1) years

Atypical autism 1630 Mean=9.4 (SD=4.2) years

2014 Stagg S.D. UK (South London)

Mean=9.8 (SD=1.8) years ASD 23 (HFA-LD=12; HFA-

LN=11)

Mean=6.37 (SD=2.18) years (High-Functioning Autistic/Language Delay: Mean=5.15. (SD=2.41) years; High-Functioning Autistic/Language Normal: Mean=7.71 (SD=1.90) years)

2013 Begeer S. Netherlands 0-18 years

Autistic disorder 416 (Male=361;

Female=55) Mean=5.2 (SD=2.8); (Male: Mean=5.3 (SD=2.8); Female: Mean=4.7 (SD=2.9))

Asperger's syndrome 306 (Male=277;


PDD-NOS 632 (Male=512;


2013 Campbell M. UK (Glasgow) 0-6 years at referral Autism 246 Mean=54 [I.C.95%:52.38-56.35] months; Range [29-98]

2013 Jokiranta E. Finland 2-20 years

Autism 1132 Mean=5.5 (SD=3.6) years

Asperger's syndrome 1785 Mean=9.6 (SD=3.3) years

PDD-NOS 1796 Mean=7.3 (SD=3.4) years

2013 van der Ven E. Netherlands 2-11 years

ASD 518 Mean=6.2 (SD=2.3) years

Asperger syndrome and PDD-NOS

368 Mean=6.8 (SD=2.1) years

Autistic disorder 150 Mean=4.7 (SD=2.1) years

2013 Visser J.C. Netherlands AD and PDD-NOS 196 Mean=56.47 (SD=19.0) months; Range [15-98]

2012 Ververi A. Greece 1.5-9 years ASD

222 (206 Autism; 11 Rett disorder; 5

Asperger's syndrome)

Mean=43.7 (SD=17.6) months; Range [18-108]


45

2011 Chamak B. France

4-5 years

ASD

19 Mean=2.8 (SD=0.75) years

6-12 years 78 Mean=4.5 (SD=2) years

13-17 years 37 Mean=6.5 (SD=4) years

18-45 years 66 Mean=10 (SD=8) years

4-45 years 200 Mean=5 (SD=3) years

2010 Oosterling I.J. Netherlands (Gelderland)

0-11 years ASD 80 Mean=63.5 (SD=36.9) months

2010 Noterdaeme M. Germany 2-25.3 years at diagnosis

ASD (autism, atypical autism, Asperger’s syndrome) or other PDD

601 (579 ASD, 22 Other PDD)

Mean=6.3 years; Range [2-25.3]

Autism 464 Mean=76 (SD=43) months

Atypical autism 35 Mean=111 (SD=63) months

Asperger's syndrome 80 Mean=110 (SD=43) months

Rett's syndrome 6 Mean=49 (SD=12) months

Disintegrative disorder 6 Mean=60 (SD=25) months

Overactive disorder and stereotyped movements

10 Mean=86 (SD=23) months

2008 Williams E. UK (England) >=11 years

ASD 71 median=81.9 months (IQR 42.7-116.6)

Autism median=44.9 months (IQR 36.5-85.6)

Atypical autism median=75.5 months (IQR 42.7-117.9)

Asperger syndrome median=115.9 months (IQR 93.4-130.6)

2007 Latif A.H.A. UK(South Wales) 0-17 years

ASD

336

Mean=5.5 (SD=2.9) years

Asperger's syndrome Mean=6.6 (SD=2.8) years

Other forms Mean=4.3 (SD=2.3) years

2007 Mouridsen S.E. Denmark Mean=5.4 (SD=2.5) years Infantile autism 111 Mean=5 years 5 months (SD=2 years 6 months )

2007 Oslejskova H. Czech Republic 0-23 years

Childhood Autism 126 Mean=73.9 (SD=41.8) months

Atypical autism 57 Mean=81.1 (SD=37.0) months

Asperger's syndrome 21 Mean=128.5 (SD=57.6) months

2006 Renty J. Belgium(Flanders) 2.69-17.81 years ASD 139 Mean=7.15 (SD=3.55) years

2005 Chakrabarti S. UK(Midlands) 4-6 years olds in a 1996-1998 birth cohort

All PDDs 64 Mean=37.8 (SD=11.4) months

Autistic disorder 25 Mean=32.9 (SD=8.7) months

PDD-NOS 27 Mean=39.3 (SD=9.3) months

Asperger's disorder 12 Mean=44.7 (SD=16.0) months

2005 Larsson H.J. Denmark Infantile or atypical autism

698 ALL: Mean=7.7; Median=6.0; Range[1-24] years

154 DIAGNOSIS BEFORE 1994: Mean=6.2; Median=5.0; Range[1-20] years

554 DIAGNOSIS IN 1994-1999: Mean=8.1; Median=6.0; Range[1-24] years


46

2005 Maestro S. Italy (Pisa) AD 21 Mean=39.0 [36-58] months

PDD-NOS 19 Mean=38.4 [36-58] months

2005 Pry R.

France, Switzerland, Belgium and Luxembourg

Median=60 (IQR 48-72) months Infantile autism (F84.0) 222 Median=17 (IQR 8.4-24) months

2004 Boddaert N. France Mean=6.6 (SD=1.6) years [4-10] Autism 11 Mean=4.3 years (SD=0.8)

2004 Cederlund M. Sweden (Göteborg)

5 years 6 months to 24 years 6 months Asperger's syndrome 100 Mean=11 years 4 months (SD=3 years 10 months)

2004 Keen D. UK(Doncaster) 0–17 years ASD 261 Mean=6.3 years (Range: [3.8-15.8])

2004 Smeeth L. UK Birth year [1973-99] median age 5-9 years

Autism and other PDD 1294 Median=5.4 (IQR 3.6-9.7) years

2004 Sturm H. Sweden (Stockholm)

0-15 years Asperger syndrome. PDDNOS and high-functioning autism

101 Mean=9 years 8 months; [5-12]years

2004 Tebruegge M. UK (Maidstone district, Kent)

4 years in October 2000

Childhood autism

6

Mean=3.13 [2.75-3.50] years

Asperger's syndrome Mean=7.22 [5.75-9.25] years

Autistic spectrum disorder Mean=5.37 [3.33-9.42] years

2003 Lingam R. UK(five districts in north east London)

5-14 years

Childhood autism 266 Median=51 (IQR 40-78) months

Atypical autism 171 Median=40 (IQR 34-48) months

Asperger's syndrome 89 Median=97 (IQR 70-125) months

2002 Hultman C.M. Sweden Diagnosis of infantile autism before 10 years of age in the period 1987-1994

Infantile autism (excluding PDD-NOS)

408 Mean=4.4 years

2002 Madsen K.M. Denmark AD 316 Mean= 4 years 3 months

Other ASDs 422 Mean= 5 years 3 months

2001 Maestro S. Italy AD (excluding PDD-NOS) 15 Mean=4.5 years (4-5.2)

2001 Magnùsson P. Iceland Childhood Autism 37 Median=49 months (Range: [26-165])

Atypical autism 20 Median=52 months (Range: [33-170])

2001 Rasmussen P. Sweden (Göteborg)

4-33 years with Down syndrome ASD 25 Mean=14.4 (SD=7.4) years

2000 Powell J.E. UK (West Midlands)

1 years-4 years 11 months Childhood autism 42 Mean=36.2 (SD=59.1) months

Other ASDs 63 Mean=37.8 (SD=90.2) months

47

APPENDIX 2. Main characteristics of the identified studies. Immunisation. Measles, Mumps, Rubella.

Year of publication

1st author Country Years of study

Disease Sample size % Coverage 1st dose

% Coverage 2nd dose

% Coverage 1st+2nd doses

Age reference (years if not spec)

2015 Amendola A Italy (Lombardy) 2007 Measles 96.7 2

Rubella 96.6 2

2011 Measles 93.7 2

Rubella 93.5 2

Measles 90.1 (range: 72.4; 95.8)

2

2015 Cozza V Italy (Puglia) 2010 MMR 93.0 1 (cohort 2010)

2010 MMR 85.0 5-6 (cohort 2005)

2010 MMR 77.0 adolescents (cohort 1997)

2004-2006 MMR 70.9 49.8 7-15 (cohort 1991-1997)

2015 Giambi C Italy 2013 Rubella 88.0 1

Italy (18/21 Regions) 2008 Rubella 75.0 16

2015 Gross K Switzerland 2005 MMR 86.0 2

2015 Hens N Belgium (Brussels) 1995 MMR 68.1 adolescents

Belgium (Wallonia) 1999 MMR 82.4 adolescents

Belgium (Brussels) 2000 MMR 74.5 (95%CI: 70.1-78.9)

adolescents

Belgium (Wallonia) 2003 MMR 82.5 adolescents

Belgium (Flanders) 2005 MMR 94.0 (95%CI: 92.6-95.3)

83.6 (95%CI: 81.4-85.8)

adolescents


70.5 adolescents

Belgium (Wallonia) 2006 MMR 89.0 (95%CI: 86.3-91.8)

70.5 adolescents


48


90.6 (95%CI: 89.0-92.2)

adolescents


75.5 adolescents


adolescents


92.5 (95%CI: 90.9-94.1)

adolescents


adolescents

2015 Korczyńska MR

Poland 2013 Rubella 97.5 (range: 96.4-99.7)

3

Rubella* 99.3 13

Rubella* 99.5 14

2015 Korczyńska MR

Poland 2013 Mumps 97.5 (range: 96.4-99.7)

3

Poland (małopolskie voivodeship) Mumps 97.3 3

2015 Restivo V Italy (Palermo) nov 2012-may2013

MMR 377/443 85.1 13-15 months

Italy (Sicily) 2010 MMR 85.3 2

2011 MMR 86.8 2

2015 Rogalska J Poland 2013 Measles 82.8 1

Measles 97.5 2

Measles 98.7 3

Measles 99.1 4

Measles 99.4 5

Measles 99.5 6

Measles 79.0 9

Measles 93.2 10

Measles 77.3 11


49

Measles 73.6 12

2015 Sandford H United Kingdom (England) 2007/08 MMR 2365400 mean: 75.1 (sd: 10.4; range: 39.0-89.0)

5

2008/09 MMR 2364700 mean: 78.0 (sd: 10.8; range: 32.0-91.5)

5

2009/10 MMR 2363700 mean: 82.7 (sd: 7.9; range: 49.3-93.8)

5

2010/11 MMR 2363800 mean: 84.2 (sd: 6.3; range: 61.0-95.1)

5

2014 Aasheim ET United Kingdom (England) 2012-2013 MMR 87.7 5

2014 Bystrom E Sweden (community near Stockholm) 2011 MMR 145 89.0 Not reported

2014 Lernout T Belgium 2012 MMR >=95.0 infants

Belgium (Flanders) 2005 MMR 62.0 13 months


18-24 months



18-24 months



18-24 months

2014 Rieck T Germany 2011 Measles 94.27 (95%CI: 94.19-94.35)

68.94 (95%CI: 68.78-69.09)

2

Germany 2011 Measles 96.65 (95%CI: 96.59-96.71)

82.34 (95%CI: 82.21-82.47)

3

Mumps 94.23 (95%CI: 94.15-94.31)

68.92 (95%CI: 68.76-69.07)

2


50

Mumps 96.61 (95%CI: 96.55-96.68)

82.32 (95%CI: 82.19-82.45)

3

Rubella 94.23 (95%CI: 94.15-94.31)

68.92 (95%CI: 68.77-69.07)

2

Rubella 96.61 (95%CI: 96.55-96.68)

82.32 (95%CI: 82.19-82.46)

3

2014 Robert E Belgium (Wallonia) May-July 2012

MMR 519 94.4 (95%CI: 92.4-96.4)

18-24 months

Belgium (Brussels) MMR 538 94.1 (95%CI: 92.1-96.1)

18-24 months

2014 Rogalska J Poland 2012 Rubella 97.9 (range: 96.4-99.7)

3

Rubella* 99.4 (range: 98.7-99.9)

13

Rubella* 99.4 (range: 98.6-100)

14

2014 Rogalska J Poland 2012 Mumps 97.9 (range: 96.4-99.7)

3

Poland (malopolskie voivodeship) Mumps 97.3 3

2014 Rogalska J Poland 2012 Measles 83.6 (range: 77.6-97.3)

1

Measles 97.9 2

Measles 98.9 3

Measles 99.3 4

Measles 99.5 5

Measles 99.6 6

Measles 76.6 9

Measles 94.7 10

Measles 96.7 11

2014 Simone B United Kingdom (England-London Borough (LB) and Local Authority outside London (LA))

01/04/2013 MMR 2407/6644 36.2 10-16


51

United Kingdom (England-LB and LA) 20/08/2013 MMR 2661/6644 40.1 10-16

United Kingdom (England-LB and LA) MMR 2407/5179 46.5 10-16

United Kingdom (England-LB) MMR 1079/1808 60.0 10-16

United Kingdom (England-LA) MMR 1328/3371 39.4 10-16

2014 Smits G Netherlands 2012 MMR 96.0 14 months

MMR 93.0 9

2014 St-Martin G Denmark 1987 MMR range: 85.0-90.0

range: 80.0-85.0

2008 MMR range: 85.0-88.0

9-15

2008 MMR range: 79.0-81.0

1-3

2014 Takla A Germany (Bavaria) 2011 Mumps 100 4.0 89.0 8-12

2014 Tozzi AE Italy 2008 MMR 55.1 2

Italy (Friuli-Venezia-Giulia. Tuscany. Marche. Lazio. Calabria)

2005-2007 MMR 911/1091 84.0 (95%CI: 81.8-86.2)

2

2014 Vareil MO France 2010 Mumps 95.7 88.6 <6

France 2011 Mumps 89.4 67.3 <6

France 2013 Mumps 88.6 >6

2014 Weigel M Germany (Baden-Wrttemberg) 2004-05-06-07

Measles 77.2 school entrance

Germany (Free State of Bavaria) Measles 74.6 school entrance

Germany (Free Hanseatic City of Bremen)


Germany (Hamburg) Measles 82.3 school entrance

Germany (Hesse) Measles 79.9 school entrance

Germany (Lower Saxony) Measles 79.4 school entrance

Germany (North Rhine-Westphalia) Measles 78.5 school entrance

Germany (Rhineland-Palatinate) Measles 85.2 school entrance

Germany (Saarland) Measles 84.7 school entrance

Germany (Schleswig-Holstein) Measles 83.1 school entrance

Germany (Berlin) Measles 71.8 school entrance

Germany (Brandenburg) Measles 94.3 school entrance


52

Germany (Mecklenburg-Western Pomerania)


Germany (Free State of Saxony) Measles not comparable (SIKO)

school entrance

Germany (Saxony-Anhalt) Measles 89.5 school entrance

Germany (Free State of Thuringia) Measles 93.3 school entrance

2013 Antona D France 1990s MMR range: 80.0-85.0

2

2002 MMR range: 93.0-96.0

school children

2008 MMR 96.6 11

2006 MMR 29.3 2

2010 MMR 60.9 2

2003 MMR 28.1 6

2006 MMR 45.1 6

2002 MMR 56.8 11

2005 MMR 74.2 11

2008 MMR 85.0 11

2004 MMR 65.7 15

2009 MMR 84.0 15

2010 MMR 89.1 60.9 2

2010 MMR 95.0 84.0 adolescents

2013 Fonteneau L France 2002-2003 Measles 4362 93.3 28.1 6

2002-2003 Mumps 4362 92.6 24.4 6

2002-2003 Rubella 4362 93.1 28.0 6

2005-2006 Measles 21346 93.7 (95%CI: 93.3-94.2)

45.1 (95%CI: 44.3-46.0)

6

2005-2006 Mumps 21346 91.4 (95%CI: 90.8-91.9)

43.2 (95%CI: 42.3-44.1)

6

2005-2006 Rubella 21346 91.4 (95%CI: 90.8-91.9)

43.3 (95%CI: 42.4-44.1)

6

2013 Karasek E Poland 2011 Rubella 98.1 (range:

3


53

96.7-99.8)

Rubella* 99.1 (range: 98.4-100)

12

2013 Knol M Netherlands 2012 MMR 96.0 2

2012 MMR 93.0 10

2013 Martinot A France 2008 MMR 60.3 24-35 month

2011 MMR 81.0 24-35 months

2013 Mayet A France 2008 MMR 89.1 40.6 2

2013 Pavlopoulou ID

Greece (Athens) Oct 2010-Nov 2011

MMR 660/704 (weighted)

90.5 2


35.9 60 months


63.7 5

2013 Poethko-Müller C

Germany 2010 Measles 91.5 (range: 87.6-95.3)

school entrance

2013 Smits G Netherlands 2011 MMR 96.0 93.0 Not reported

2013 Streng A Germany 2006 Measles 372 86.9 18-36 months

2011 Measles 302 91.1 18-36 months

2012 Bechini A Italy (Tuscany) 2003 MMR 87.0 2

2004 MMR 87.6 2

2006 MMR 91.2 2

2012 Bielicki JA Switzerland 2005-2007 Measles 62.6 (95%CI: 62.3-62.8)

13 months

2005-2007 Measles 84.5 (95%CI: 84.3-84.7)

59.4 (95%CI: 59.1-59.6)

25 months

2005-2007 Measles 85.7 (95%CI: 85.3-86.2)

66.7 (95%CI: 66.1-67.2)

24-35 months

2012 Bouhamam N France 2009-2010 MMR 375 77.0 9 months - 7years


54

2012 Delgado de Los Reyes J

Spain (Elche) 2011 MMR 96.4 1-2

MMR 90.4 3-7

2012 Fitzpatrick G Ireland 1999 MMR 77.0 2

2011 MMR 93.0 2

2012 Hug S Switzerland May 2009-Feb 2010

MMR 592 92.0 (95%CI: 90.0-94.0)

72.0 (95%CI: 69.0-76.0)

2

2012 Karasek E Poland 2010 Rubella* 99.2 13

2012 Karasek E Poland 2010 Measles 84.9 1

Measles 98.2 2

Measles 99.0 3

Measles 99.4 4

Measles 99.5 5

Measles 99.7 6

Measles 0.6 7

Measles 1.8 8

Measles 79.2 9

Measles 93.8 10

Measles 96.6 11

2012 Roggendorf H Germany 2007 Measles 95.0 88.0 5-6

Germany 2008 Measles 89.0 6

Germany (Essen) 2001 Measles 43.0 12

Germany (Essen) 2008 Measles 92.0 6

Germany (Essen) 2008 Measles 97.0 87.0 12

2012 Vainio K Norway 2011 MMR 93.0 2

2011 MMR 94.0 16

2011 Barrabeig I Spain (Barcelona-South Health Region)

01 Oct 2006-15 Jan 2007

MMR 1334 73.8 (range: 45.7-100)

27.3 months (median)

MMR 774/862 89.8 15 months - 4years

MMR 253/259 97.7 >=4


55

2011 Bassetti M Italy 2006 MMR 88.0 child

2011 Cockman P England 1992 MMR 92.0 2

2003 MMR 79.0 2

England (Tower Hamlets) 2011 MMR 94.0 2

2011 Khetsuriani N Croatia 2004 MMR 15042/18959 79.3 6

Ireland 2009 MMR 89034/125754 70.8 15-18

2011 Lang P Switzerland 2005-2007 Measles 8286 86.9 (95%CI: 85.9-87.9)

70.8 (95%CI: 69.3-72.2)

24-35 months

Mumps 8286 86.0 (95%CI: 85.0-87.0)

70.1 (95%CI: 68.6-71.5)

24-35 months

Rubella 8286 86.0 (95%CI: 85.0-87.0)

70.1 (95%CI: 68.7-71.6)

24-35 months

Measles 10314 89.9 (95%CI: 88.8-91.0)

75.2 (95%CI: 73.6-76.8)

8

Mumps 10314 88.8 (95%CI: 87.6-89.9)

74.2 (95%CI: 72.7-75.7)

8

Rubella 10314 88.7 (95%CI: 87.5-89.9)

73.8 (95%CI: 72.3-75.3)

8

Measles 9301 94.3 (95%CI: 93.6-95.0)

76.2 (95%CI: 74.9-77.6)

16

Mumps 9301 93.5 (95%CI: 92.7-94.2)

74.8 (95%CI: 73.5-76.2)

16

Rubella 9301 93.5 (95%CI: 92.7-94.2)

74.5 (95%CI: 73.1-75.8)

16

2011 Sabbe M Belgium (Brussels) 2000 MMR 74.5 18-24 months

Belgium (Wallonia) 2003 MMR 82.5 18-24 months

Belgium (Flanders) 2005 MMR 94.0 18-24 months

2005 MMR 83.6 14-16

Belgium (Brussels) 2006 MMR 91.1 18-24 months

2006 MMR 70.5 14-16


56


2006 MMR 70.5 14-16

Belgium (Flanders) 2008 MMR 96.6 18-24 months

2008 MMR 90.6 14-16


2009 MMR 75.5 18-24 months

2011 Sakou II Greece (Athens) 2009 MMR 911 93.1 (95%CI: 92.0-95.3)

11-19

MMR 381 95.7 11-14

MMR 529 91.5 14-19

2011 Siedler A Germany 2008 Measles 96.0 89.0 6

Germany (North Rhine–Westphalia) 2007-2008 Measles 88.4 10

Measles 87.2 11

Measles 85.2 12

Measles 83.2 13

Measles 82.0 14

Measles 82.1 15

Measles 79.7 16

Measles 77.1 17

Measles 73.3 18

2011 Stanescu A Romania 2000-2008 Measles range: 97.0-98.0

18-24 months

Measles range: 96.0-98.0

7

2009 MMR 85.1 (95%CI: 82.4-87.8)

1

MMR 95.0 (95%CI: 93.4-95.8)

18 months

2010 Measles 93.4 (95%CI: 90.7-95.0)

7


57

2011 Wadl M Germany 2008 Measles 89.0 (range: 85-94)

first graders

Germany (four Bavarian counties) 2006-2007 Measles 69.0 (range: 64-72)

first graders

2011 Zimmerman L Poland 2006 Rubella* 99.2 15

2005 MMR 91.0 3

2008 MMR 98.0 3

2010 Bätzing-Feigenbaum J

Germany 2001 MMR 91.4 25.9 school entrance

2002 MMR 91.3 33.1 school entrance



2005 MMR 94 76.6 school entrance




Germany (Berlin) 2001 MMR 91.2 24 school entrance






2010 Cova M Italy 2003 MMR 84.0 2

2006 MMR 90.0 2

Italy (Ferrara) 2008 MMR 96.7 2

2008 MMR 91.1 6

2010 Curtale F Italy 2003 MMR 82.0 2

2007 MMR 89.6 2

Italy (Lazio) 2003 MMR 83.9 2

2003 MMR 53.0 6-13


58

2003 MMR 14.0 15

2007 MMR 90.7 2

2007 MMR 67.0 6-13

2007 MMR 42.0 15

2010 Jeannot E Switzerland (Geneva) 2003 Measles 3542 65.4 5-6

Mumps 3542 63.2 5-6

Rubella 3542 63.9 5-6

2004 Measles 3679 75.4 5-6

Mumps 3679 73.4 5-6

Rubella 3679 73.6 5-6

2005 Measles 3425 85.2 5-6

Mumps 3425 82.7 5-6

Rubella 3425 83.6 5-6

2006 Measles 3374 87.3 5-6

Mumps 3374 84.9 5-6

Rubella 3374 86.2 5-6

2007 Measles 3164 89.4 5-6

Mumps 3164 87.9 5-6

Rubella 3164 88.5 5-6

2010 Lashkari HP United Kingdom (Haringey. London) 2006 MMR 373 36.0 (95%CI: 31.0-41.0)

55.0 (95%CI: 50.0-60.0)

14.7

2010 Parent du Châtelet I

France 2007 MMR 90.0 2

2004-2005 MMR 96.0 74.0 11

2005-2006 MMR 93.0 44.0 6

2010 Reuss AM Germany 2006 MMRV 281/415078 <1 2

2006 MMRV 95/415078 <1 2

2007 MMRV 16642/404988 4.0 2

2007 MMRV 21718/404988 5.0 2


59

2010 Stronegger WJ Austria Not reported

Measles 658 88.4 6.5

Measles 688 84.9 9.6

Measles 1040 76.8 13.1

Measles 2386 82.4 6-13

2009 Borràs E Spain (Catalonia. public health care) Oct 2003-Sept2004

MMR 428/431 99.3 (95%CI: 97.8-99.8)

15 month

Spain (Catalonia. private health care) MMR 192/196 98.0 (95%CI: 94.8-99.4)

15 month

2009 Poethko-Müller C

Germany May 2003-May2006

Measles 14826 93.6 (95%CI: 93.0-94.2)

2-17

2009 Richard JL Switzerland 2000 MMR 82.0 2

2005-2007 MMR 87.0 (range: 73.0-94.0)

2

2005-2007 MMR 90.0 71.0 8

2005-2007 MMR 94.0 76.0 16

2009 Schönberger K Germany 2116 46.8 (95%CI: 44.5-49.1)

15 month

2009 Theeten H Belgium (Flanders) 2005 MMR 792 88.0 (95%CI: 85.6-90.4)

7-8

2008 Andrews N Belgium 2001-2001 Measles 3374 80.0 2

Bulgaria 2001-2001 Measles 1666 93.0 2

Cyprus 2001-2001 Measles 2901 88.0 2

Czech Republic 2001-2001 Measles 3013 96.0 2

England and Wales 2001-2001 Measles 3570 88.0 2

Hungary 2001-2001 Measles 3490 100 2

Ireland 2001-2001 Measles 2590 77.0 2

Latvia 2001-2001 Measles 3026 97.0 2

Lithuania 2001-2001 Measles 3352 97.0 2

Luxembourg 2001-2001 Measles 2679 91.0 2


60

Malta 2001-2001 Measles 1867 90.0 2

Romania 2001-2001 Measles 3839 98.0 2

Slovakia 2001-2001 Measles 3640 99.0 2

Slovenia 2001-2001 Measles 3399 92.0 2

Spain 2001-2001 Measles 3605 94.0 2

Sweden 2001-2001 Measles 1392 94.0 2

2008 Choi YH England 2004 MMR 1663 n=1343 (80.8)

n=0 (0.0) 2-4

MMR 3582 n=627 (17.5)

n=2684 (74.9)

5-10

MMR 3656 n=826 (22.6)

n=2619 (71.6)

11-17

2008 Gagneur A France 2004 MMR 87.0 2

2008 Mikolajczyk RT

Germany (Bavaria) 2004-2005 MMR 1481 93.0 5-6

2008 Nardone A Belgium 1999 Rubella 82.0 infants

Bulgaria 1999-2003 Rubella 93.0 infants

Cyprus 1999-2003 Rubella 86.0 infants

Czech Republic 1999. 2001. 2003

Rubella 97.0 infants

England and Wales 1999-2003 Rubella 85.0 infants

Hungary 1999. 2001. 2003

Rubella 100 infants

Ireland 1999-2003 Rubella 76.0 infants

Latvia 1999-2003 Rubella 97.0 infants

Lithuania 1999-2003 Rubella 97.0 infants

Malta 1999-2003 Rubella 74.0 infants

Slovakia 1999-2003 Rubella 99.0 infants

Slovenia 1999-2003 Rubella 93.0 infants

Sweden 1999-2002 Rubella 92.0 infants

2008 Paulo AC Spain (La Rioja) 2005-2006 Measles 96.3 15 months


61

2008 Rota MC Italy 2004 MMR 85.1 2-4

MMR 78.3 5-9

MMR 59.2 10-14

2008 Vandermeulen C

Belgium (Flanders) 2005 MMR 1349 94.0 (95%CI: 92.6-95.3)

toddlers (mean age 1.67)

MMR 792 88.0 (95%CI: 85.6-90.4)

primary school children (mean age 7.8)

MMR 1344 80.6 (95%CI: 78.2-83.0)

83.6 (95%CI: 81.4-85.8)

adolescents (mean age 13.9)

2007 Guagliardo V France (South-Eastern) 2002-2003 MMR 2460 86.4 4

2007 Mixer RE United Kingdom (Brent. London) dic-03 MMR 6444 75.0 (95%CI: 74.0-75.1)

13 months - 3 years

2007 Sonnenberg P England 2004 MMR 81.0 2

2007 Tischer A Switzerland (Grabs) 2003 MMR 91 35.2 64.8 14.5

2004 MMR 75 21.3 78.7 14.5

2006 Heininger U Germany (Erlangen) 2002 Measles 1672 96.1 76.3 10-18

Mumps 1672 95.6 74.2 10-18

Rubella 1672 89.4 60.2 10-18

2006 Heininger U Switzerland 2001 Measles 449/505 88.9 7

Mumps 443/505 87.7 7

Rubella 440/505 87.1 7

Measles 135/269 50.2 7

Mumps 135/269 50.2 7

Rubella 135/269 50.2 7

Measles 75.0 2

Measles 82.0 3

Measles 86.0 4

Measles 88.0 19.0 7

Measles 505 33.0 10


62

2006 Kalies H Germany 1999-2004 Measles 394 74.5 (95%CI: 70.0–78.9)

2 (cohort 1996-1997)

Mumps 394 74.5 (95%CI: 70.0–78.9)

2 (cohort 1996-1997)

Rubella 394 72.0 (95%CI: 67.4–76.6)

2 (cohort 1996-1997)

MMR 394 72.0 (95%CI: 67.4–76.5)

0.9 (95%CI: 0.3–2.7)

2 (cohort 1996-1997)

Measles 700 66.7 (95%CI: 62.8–70.6)

2 (cohort 1998-1999)

Mumps 700 66.9 (95%CI: 63.0–70.8)

2 (cohort 1998-1999)

Rubella 700 66.7 (95%CI: 62.8–70.6)

2 (cohort 1998-1999)

MMR 700 66.7 (95%CI: 62.8–70.6)

6.9 (95%CI: 5.1–9.4)

2 (cohort 1998-1999)

Measles 1093 69.5 (95%CI: 66.7–72.2)

2 (cohort 2000-2001)

Mumps 1093 69.4 (95%CI: 66.6–72.2)

2 (cohort 2000-2001)

Rubella 1093 68.6 (95%CI: 65.8–71.4)

2 (cohort 2000-2001)

MMR 1093 68.6 (95%CI: 65.8–71.4)

23.0 (95%CI: 20.6–25.7)

2 (cohort 2000-2001)

Measles 514 71.1 (95%CI: 61.1–81.1)

2 (cohort 2002-2003)

Mumps 514 70.1 (95%CI: 60.3–79.8)

2 (cohort 2002-2003)

Rubella 514 70.1 (95%CI: 60.3–79.8)

2 (cohort 2002-2003)


63

MMR 514 70.1 (95%CI: 60.2–79.4)

20.2 (95%CI: 13.7–29.1)

2 (cohort 2002-2003)

2006 Rota MC Italy 2004 MMR 85.5 2

2005 MMR 88.3 2

2005 MMR 83.0 6-10

2006 Wichmann O Germany (Duisburg) 2002 Measles 90.0 29.0 school entrance

2004 Measles 92.0 70.0 school entrance

2006 Measles 431 95.0 74.0 10-12

2006 Measles 361 95.0 65.0 13-15

2006 Measles 67 94.0 58.0 16-18

2006 Measles 859 95.4 70.4 10-18

2005 Stampi S Italy (Emilia Romagna) 1998 Measles 29662 88.2 2

Rubella* 29662 85.2 2

Measles 83.8 13

Rubella* 85.2 13

1999 Measles 30916 89.1 2

Mumps 30916 84.2 2

Rubella 30916 88.0 2

Measles 89.1 13

Rubella 60.8 13

2000 Measles 31727 90.4 2

Mumps 31727 89.4 2

Rubella 31727 89.4 2

Measles 84.9 13

Rubella 66.3 13

2001 Measles 32866 90.7 2

Mumps 32866 90.1 2

Rubella 32866 90.1 2

Measles 87.4 13


64

Rubella 73.4 13

2002 Measles 34950 92.3 2

Mumps 34950 91.7 2

Rubella 34950 91.7 2

Measles 91.3 13

Rubella 80.6 13

Italy (Bologna) 1998 Measles 2398 79.3 2

Rubella* 2398 77.2 2

Measles 75.1 13

Rubella* 84.7 13

1999 Measles 2560 82.4 2

Mumps 2560 78.8 2

Rubella 2560 78.6 2

Measles 72.5 13

Rubella 49.9 13

2000 Measles 2429 83.5 2

Mumps 2429 83.3 2

Rubella 2429 83.4 2

Measles 85.8 13

Rubella 72.6 13

2001 Measles 2619 86.4 2

Mumps 2619 85.1 2

Rubella 2619 85.6 2

Measles 90.1 13

Rubella 76.1 13

2002 Measles 2706 90.2 2

Mumps 2706 88.8 2

Rubella 2706 88.8 2


65

Measles 92.6 13

Rubella 84.2 13

2005 van der Wal MF

Netherlands (Amsterdam) 2003 MMR 57374 93.9 5-12

2004 Alfredsson R Sweden (Göteborg) 1999 MMR 9726 98.0 18 months

2004 Ciofi degli Atti ML

Italy 2003 Measles 76.9 (95%CI: 74.9–79.0)

2-3

2004 Dannetun E Sweden (Ostergotland) 2000 MMR 1171/1316 88.9 2

Sweden (Ostergotland) 2001 MMR 1012/1262 80.2 2





2004 Henderson R United Kingdom (Highland. Scotland) Oct 2001-Sept 2002

MMR 1700/2108 80.6 2

2004 Vandermeulen C

Belgium (Bruges) giu-96 MMR 1675/1825 91.8 3-12

2003 Centers Disease Control Prevention

Italy (Campania) 2001 Measles 41888 65.0 <=3

2003 Nardone A Denmark 1990 MMR 84.0 2

1991 MMR 86.0 2

1992 MMR 85.0 2

1993 MMR 81.0 2

1994 MMR 88.0 2

1995 MMR 88.0 2

1996 MMR 85.0 2

1997 MMR 84.0 2

1998 MMR 88.0 2

England and Wales 1990 MMR 86.0 2

1991 MMR 90.0 2

1992 MMR 92.0 2


66

1993 MMR 91.0 2

1994 MMR 91.0 2

1995 MMR 92.0 2

1996 MMR 92.0 2

1997 MMR 91.0 2

1998 MMR 88.0 2

France 1990 MMR 54.0 2

1991 MMR 52.0 2

1992 MMR 62.0 2

1993 MMR 80.0 3-4

1994 MMR 84.0 3-4

1995 MMR 85.0 3-4

1996 MMR 88.0 3-4

1997 MMR 89.0 3-4

1998 MMR 91.0 3-4

Netherlands 1990 MMR 95.0 2

1991 MMR 94.0 2

1992 MMR 94.0 2

1993 MMR 95.0 2

1994 MMR 94.0 2

1995 MMR 94.0 2

1996 MMR 94.0 2

1997 MMR 96.0 2

1998 MMR 96.0 2

2002 Bonanni P Italy 1998 Measles 56.0 12-24 months

Italy (Piedmont) 1998 Measles 60.4 (95%CI: 50.4–70.3)

12-24 months

Italy (Val D'Aosta) Measles 43.3 (95%CI: 31.2–56.0)

12-24 months

Italy (Lombardy) Measles 75.9 (95%CI: 68.1–83.7)

12-24 months


67

Italy (Milan) Measles 74.6 (95%CI: 62.5–84.1)

12-24 months

Italy (Boizano) Measles 28.1 (95%CI: 18.7–37.4)

12-24 months

Italy (Trento) Measles 58.0 (95%CI: 48.2–67.7)

12-24 months

Italy (Veneto) Measles 81.2 (95%CI: 75.4–87.0)

12-24 months

Italy (Friuli–Venezia) Measles 77.3 (95%CI: 68.9–85.7)

12-24 months

Italy (Liguria) Measles 62.1 (95%CI: 52.9–71.4)

12-24 months

Italy (Emilia) Measles 87.7 (95%CI: 81.1–94.3)

12-24 months

Italy (Tuscany) Measles 64.8 (95%CI: 55.5–74.2)

12-24 months

Italy (Umbria) Measles 72.3 (95%CI: 64.6–81.0)

12-24 months

Italy (Marches) Measles 58.7 (95%CI: 48.7–68.7)

12-24 months

Italy (Abruzzi) Measles 45.5 (95%CI: 38.5–51.9)

12-24 months

Italy (Molise) Measles 40.5 (95%CI: 29.6–51.4)

12-24 months

Italy (Campania) Measles 26.5 (95%CI: 17.3–35.7)

12-24 months

Italy (Naples) Measles 39.8 (95%CI: 29.2–51.1)

12-24 months

Italy (Puglia) Measles 50.6 (95%CI: 41.0–60.2)

12-24 months

Italy (Basilicata) Measles 44.7 (95%CI: 33.2–56.1)

12-24 months

Italy (Calabria) Measles 25.5 (95%CI: 17.0–33.9)

12-24 months

Italy (Sicily) Measles 44.6 (95%CI: 34.3–54.8)

12-24 months

Italy (Sardinia) Measles 56.3 (95%CI: 46.8–65.7)

12-24 months

2002 Siedler A Germany 1999 Measles 782 21.7 (95%CI: 18.0-25.3)

15 months

Measles 782 77.0 (95%CI: 72.7-81.4)

2

Measles 782 87.6 3


68

2002 Vellinga A Belgium (Flanders) 1999 MMR 1005 83.4 (95%CI: 80.3-86.5)

18-24 months

2000 Hanratty B United Kingdom 1994 Measles & Rubella (MR)

8 million 92 5-16

2000 Janaszek W Poland 1997 Measles 96.9 24-35 months

2000 Mossong J Luxembourg (Reuler) 1996 Measles 227/297 76.4 primary school (4-12)

Luxembourg (Wincrange) Measles 211/302 69.9 primary school (4-12)

* Girls only

69

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