Science against microbial pathogens: communicating current research and technological advances _______________________________________________________________________________ A. Méndez-Vilas (Ed.)

Adverse drug reactions following immunization in Danish children: retrospective analysis of spontaneous reports submitted to the Danish Medicines Agency Lise Aagaard1,2,3, Erik Wind Hansen1 and Ebba Holme Hansen1,2,3 1) Department of Pharmacology and Pharmacotherapy, Faculty of Pharmaceutical Sciences, University of Copenhagen 2) FKL-Research Centre for Quality in Medicine Use, University of Copenhagen, Denmark 3) Danish Pharmacovigilance Research Project (DANPREP), Copenhagen, Denmark We analysed 2,643 suspected adverse drug reactions (ADRs) in children from birth to 17 years reported for immunization in Denmark over a decade with respect to age and gender, type of vaccines, type and seriousness of ADRs. Eighty percent of ADRs were reported in children below 2 years of age. One half of all reported ADRs were of the type “general disorders and administration site conditions”. The largest share of serious ADRs was from the category “nervous system disorders” (33% of serious ADRs). The reported rate of ADRs for children’s immunization programmes (MMR® and Ditekipol/Act-Hib®) was 70 per 100,000 vaccine doses and for the serious ADRs, 10 to 25 per 100,000 vaccine doses. More than one half of all suspected ADRs reported for Danish children were related to national immunization programmes and almost one third of these were serious. However, viewed in relation to the large exposure rates and the benefits of avoiding risky child diseases, the numbers are small. Health authorities should put more efforts into enlightening parents about this issue. Keywords children; vaccines; pharmacoepidemiology; spontaneous reporting systems; immunization; Denmark

1. Introduction Vaccines are usually administered to large populations of healthy individuals, often entire birth cohorts, through national immunization programmes. Evidence is present; that immunization of the paediatric population prevents and protects the population from serious diseases, however administration of vaccines to healthy children also involves risks of adverse drug reactions (ADRs) [1-2]. A particularly safety issue in relation to immunization is that healthy individuals are vaccinated to secure a high level of public health, in contrast to the prescribing of medicines to patients that builds on a benefit-risk assessment in relation to the individual patient’s health state [3]. The risk of ADRs from immunization therapies is poorly documented with regard to occurrence and seriousness and this has caused mistrust in the benefits of national immunization programmes [2]. More than three million children in developing countries die each year from vaccine-preventable diseases such as measles, diphtheria and polio [4]. In richer countries the picture is different: polio was declared eradicated in Europe in 2002. Measles were to follow in 2010, but in 2011 the WHO announced that more than 6,500 cases of measles were reported in Europe [4-5]. If large shares of the paediatric population are not immunized, it has serious consequences for the efficacy of the programmes and the health of the general public [3]. Problems in achieving high immunization rates in children in Western countries are emerging and doubts have been raised about the benefits of immunization because of reports of serious ADRs such as autism, diabetes and asthma possibly being related to immunization against measles, mumps and rubella (MMR®) [6-9]. The study published by Wakefield et al. in the Lancet (1998) suggested a link between MMR® vaccine and autism, but in February 2010 the Lancet retracted the paper, as elements from this study had been found to be incorrect [10]. In spite of previous rejection of suspicion of a link between MMR® vaccination and autism in epidemiological studies [6-7], this issue has implications for past and future causality assessments of ADR reports from MMR® [10]. In the literature we identified nine studies from Western countries Australia, Finland, New Zealand and the USA reporting ADRs from immunization programmes to national ADR databases [11-19]. In the USA a total of 11.4 ADRs per 100,000 vaccine doses was reported between 1991 and 2001, and in Australia annual reporting rates varied from 5.2 to 19.8 ADRs per 100,000 vaccine doses from 2002 to 2007 [11;15-19]. Overall the majority of ADRs reported were neurological and allergenic in character as well as injection-site reactions [11-19] and between 10% to 15% of reported ADRs were serious [11;15-19]. The mentioned studies reveal that evidence about ADRs at the population level with respect to amount of spontaneous reports collected varies in quantity and nature and results are partly contradictory across countries, time periods and childhood immunization programmes [2]. Hence, there is a need for more analysis of ADRs in children, especially studies from other countries with different childhood immunization programmes, and studies analysing the seriousness of the ADRs. The objective of this study was to analyze all suspected ADRs in children reported for vaccines to the Danish Medicines Agency (DKMA) from 1998 to 2007. We analyzed data with respect to time, age of children, type (system organ class [SOC]) and seriousness.

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Science against microbial pathogens: communicating current research and technological advances ______________________________________________________________________________ A. Méndez-Vilas (Ed.)

2. Methods Table 1 provides an overview of the Danish child immunization programme [20]. Participation in the programme is free and voluntary. Immunization against human papilloma virus has been included in the national immunization programme from January 2009 and, hence not included in the present study [20]. The administered MMR® vaccine is a trivalent vaccine comprising three live, attenuated viruses, including a further attenuated preparation of the measles virus Enders-Edmonston strain, the parotitis virus Jeryl-Lynn mumps strain and the rubella Wistar 27/3 virus strain [21]. The Ditekipol/Act-Hib vaccine is a combination vaccine that contains toxoids from Corynebacterium diphtheria, Clostridium tetani and Bordetella pertussis, inactivated polio virus (three serotypes) and a conjugated polysaccharide isolated from Haemophilus influenza type b [22]. Table 1: The Danish Ministry of Health’s immunization schedule for children by January 2011

Age of child

Target disease

Vaccines administered

3 months

Diphtheria, tetanus, pertussis, polio, haemophilus influenza type b

DiTeKiPol/Act-Hib®

5 months

Diphtheria, tetanus, pertussis, polio, haemophilus influenza type b

DiTeKiPol/Act-Hib®

12 months

Diphtheria, tetanus, pertussis, polio, haemophilus influenza type b

DiTeKiPol/Act-Hib ®

15 months

Measles, mumps, rubella

MMR ®

4 years

Measles, mumps, rubella (from April 2008)

MMR ®

5 years

Diphtheria, tetanus, pertussis, polio re-immunization

DiTeKiPolBooster®

12 years

Measles, mumps, rubella (phased out after April 2008)

MMR ®

12-year-old girls

Human papilloma virus (from January 2009)

Gardasil®

Danish ADR reporting system ADR reporting has been obligatory in Denmark since 1 May 1968 [23]. The ADR reporting system receives approximately 2,000 ADR reports annually and on average, each report contains 2 ADRs. Initially only physicians were covered by the reporting obligation, but from 1972 dentists are also required to report ADRs to the authorities [23]. Since 1995 pharmaceutical companies have been under obligation to keep registers of suspected and demonstrated ADRs and to make these available to the authorities. With a revision of the Medicines Act in 2003, consumers were also allowed to report ADRs directly to the authorities [23]. Violations of the reporting requirement are theoretically punishable by a fine, but in practice the DKMA has never taken this step. ADRs are coded by professional staff in the DKMA and categorized in the ADR database by degree of seriousness and type using the criteria of the Council for International Organizations of Medical Sciences (CIOMS) [24] and the Medical Dictionary for Regulatory Activities (MedDRA) terminology [25]. ADR reports are later forwarded to the international WHO database and to the EudraVigilance system [23] as well as to the respective pharmaceutical companies. These companies are obliged to carry out periodic assessments of the ADR reports received, including causality, and to report the results of their assessments to the DKMA via periodic safety update reports (PSURs) [23]. The severity of reported ADRs was classified according to the criteria defined in Volume 9 of the rules governing medicinal products in the European Union guideline [26]. Material The material comprised all suspected ADRs following vaccinations for children from birth to 17 years (below 18) reported to the DKMA from 1998 to 2007. The unit of analysis was one ADR. Reported ADRs were placed at the disposal of this study with encrypted person identification, and information about vaccines, seriousness, age and sex of children were extracted from the ADR database as Microsoft Excel files. ADRs for medications belonging to the Anatomical Therapeutic Chemical (ATC) groups J06 (immune sera and immunoglobulins) and ATC group J07 (vaccines) were included in this study.

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Science against microbial pathogens: communicating current research and technological advances _______________________________________________________________________________ A. Méndez-Vilas (Ed.)

Dose-based reporting rate of suspected ADRs per 100,000 vaccine doses was calculated as the number of reported ADRs divided by the total number of administered vaccine doses. The actual number of vaccine doses administered for MMR® and Ditekipol/Act-Hib® between 1 January 1998 and 31 December 2007 was provided by the National Board of Health as Microsoft Excel files. The number of administered vaccine doses for other types of vaccines and immunoglobulins were not accessible, and therefore dose-based reporting rates could not be calculated.

3. Results A total of 2,643 suspected ADRs following paediatric immunization were reported corresponding to 60 % of all ADRs reported for children from 0 to 17 years of age from 1998 to 2007. Approximately one half of ADRs were reported for each gender. Approximately one-third of all ADRs were classified as “serious” and two deaths were reported. One death in an infant boy was classified as sudden infant death syndrome and was reported for the Ditekipol/Act-Hib® vaccine. The other death, from hydrocephalus, was reported for a 12-year-old girl after vaccination with the MMR® vaccine. Table 2 displays the distribution of ADRs by age group, medications and seriousness. Approximately 98% of ADRs were reported for vaccines, and of these, 95% were reported for vaccines from the childhood immunization programme: the MMR® and the Ditekipol/Act-Hib® vaccines. Almost 80% of ADRs were reported for children below two years of age, followed by 11% of total ADRs for children from four to six years of age. For the MMR® and the Ditekipol/ActHib® vaccines, almost all ADRs were reported for children up to six years of age. One-third of all ADRs for the MMR® and the Ditekipol/Act-Hib® vaccines were serious. For the other vaccines, the share of serious ADRs was approximately 55%, but for immunoglobulins almost 100%.

Table 2: Total number of adverse drug reactions (ADRs) and serious ADRs (italic) reported for vaccines and immunoglobulins by age groups (1998 to 2007)

Age groups (years)

0.25 reports per 100,000 administered doses

ADRs (preferred term)

ADRs (N) ADRs per 100,000 doses

Pyrexia

61

1.79

Injection site reaction

42

0.97

Febrile convulsion

41

0.95

Convulsion

18

0.53

Rash

14

0.41

Crying

13

0.38

Total

189

-

Table 4: Reporting rate for suspected serious adverse drug reactions (ADRs) reported for the MMR® vaccine (1998 to 2007) > 0.25 reports per 100,000 administered doses

ADRs (SOC and preferred term)

ADRs (N) ADRs per 100,000 doses

Febrile convulsion

100

8.31

Pyrexia

48

3.99

Rash

40

3.32

Arthritis

9

0.75

Gait disturbance

7

0.58

Autism

5

0.42

Total

209

-

Table 5 displays the distribution of ADRs by SOC and seriousness reported from 1998 to 2007. ADRs were most commonly reported in the SOCs “general disorders and administration site conditions” (44 % of total ADRs), “skin and subcutaneous tissue disorders” (20 % of total ADRs) and “nervous system disorders” (16 % of total ADRs). Thirtythree percent of all ADRs were classified as serious. The largest numbers of serious ADRs were reported for the SOC “nervous system disorders” (35 % of total serious ADRs) followed by the SOCs “general disorders and administration site conditions” (27 % of total serious ADRs) and “skin and subcutaneous tissue disorders” (14 % of total serious ADRs).

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Science against microbial pathogens: communicating current research and technological advances _______________________________________________________________________________ A. Méndez-Vilas (Ed.)

Table 5: Reported ADRs for vaccines and immunoglobulins by System Organ Class and seriousness from 1998 to 2007 (descending order)

ADRs (% of total) Serious (% of ADRs)* System Organ Class:

N =2643

N = 779

General disorders and administration site conditions

44.1

26.9

Skin and subcutaneous tissue disorders

19.6

13.7

Nervous system disorders

15.6

34.7

Psychiatric disorders

5.3

2.3

Gastrointestinal disorders

3.8

2.4

Infections and infestations

2.6

2.5

Blood and lymphatic system disorders

1.7

3.7

Respiratory, thoracic and mediastinal disorders

1.7

2.7

Musculoskeletal and connective tissue disorders

1.6

3.7

Cardiac disorders