Abstract
AIM
To review the literature on adverse drug reactions (ADRs) in children with respect to occurrence, seriousness, type, therapeutic group, age and gender of the child and category of reporter.
METHODS
Medline and Embase databases were searched from origin and updated until February 2010. We included empirically based articles on ADRs in populations aged 0 to 17 years. Studies monitoring ADRs in patients with particular conditions or drug exposure were excluded. We extracted information about types and seriousness of ADRs, therapeutic groups, age and gender of the child and category of reporter. ADR occurrence was calculated as incidence rate and prevalence.
RESULTS
We included 33 studies monitoring ADRs in general paediatric populations. The highest numbers of ADRs were reported in national ADR databases where data were collected over a longer period than in studies monitoring inpatients and outpatients. However, prevalence and incidence were much lower in the national databases. Types of reported ADRs, seriousness of ADRs and types of medicines differed substantially between studies due to differences in time periods and patient populations. Information about ADRs was mainly provided by health care professionals, although parents also contributed reports.
CONCLUSIONS
We found a higher incidence rate of ADRs in hospitalized children and outpatients than in national databases. There seems to be considerable potential for increasing the knowledge of ADRs by advocating the submission of reports to the spontaneous reporting systems. Our study underscores that ADRs in children constitute a significant public health problem.
Keywords: adverse drug reactions, children, incidence, prevalence, spontaneous reporting systems
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
Adverse drug reactions (ADRs) in children are common, and although some are serious, studies on this topic are scarce.
A review of studies published before 2000 showed that the overall incidence of ADRs in hospitalized children was 9.53% (95% CI 6.81, 12.26) and in outpatients 1.46% (95% CI 0.7, 3.03).
THIS STUDY ADDS
Information about the occurrence and seriousness of reported ADRs, suspected medications, age and gender of children and type of reporter is only sparsely available in the literature.
Substantial amounts of information about ADRs occurring in children have been reported to national ADR databases and during chart review of hospitalized children in recent years.
The ADRs most commonly reported in children were of the types: (i) skin and subcutaneous disorders (range 15–65%); (ii) general disorders and administration site conditions (range 5–70%); (iii) gastrointestinal disorders (range 5–60%); and (iv) nervous system and psychiatric disorders (range 5–45%), mainly reported for the therapeutic groups: vaccines, antibiotics and psychotropic medicines.
The majority of reported ADRs concerned paediatric populations from North America and Europe.
Introduction
The safety of prescribed medicines is an important public health issue because serious adverse drug reactions (ADRs) may occur [1]. Medicines are prescribed widely to children, although many drugs have been marketed with no or limited experience regarding the efficacy and safety in this population, and little attention has been paid to the safety of medicines in children [2, 3]. Very few clinical trials involving children have focused on the efficacy of medicines and rarely have they covered safety [4]. The European Medicines Agency (EMEA) and the US Food and Drug Administration (FDA) as well as the World Health Organization (WHO) have acknowledged that information about medicines and their safety in children must be increased [5, 6]. The EMEA and the FDA have launched various initiatives to stimulate licensing of medicines in children, such as establishing national paediatric committees, making several legislative changes which require appropriate studies to be done in children in return for extension of the patent period for new medicines [5, 6]. Besides this, paediatric studies of already-marketed medicines have been requested [5, 6]. A meta-analysis of the incidences of ADRs in hospitalized patients carried out in the 1990s in the USA found that ADRs were between the fourth and sixth leading cause of death [7, 8]. A review published in 2001 analysing 17 prospective articles published in English before the year 2000 estimated the incidence of ADRs in hospitalized children (inpatients) at 9.53% (95% CI 6.81, 12.26) and 1.46% in outpatients (95% CI 0.7, 3.03) [9]. The review estimated the incidence rate of ADRs in children but did not assess the type of reporter, the distribution of ADRs by age and gender of the children, type of reported ADRs or therapeutic groups associated with ADRs. Many new ADR studies have been conducted since the late 1990s and new drugs have entered the market.
The aim of this study was to review systematically published articles on ADRs in children with respect to occurrence, seriousness, type of ADRs, therapeutic group, age and gender of the child and category of reporter.
Methods
Literature search
We systematically searched the references in Medline and Embase (whole databases without language restriction). The literature searches were updated until February 2010. The search strategy used the keywords and/or mesh-terms ‘child’ or ‘paediatric’ combined with any combination of two of the following: ‘adverse drug reaction’, ‘side effect’, ‘adverse effect’, ‘adverse drug reaction reporting system’ (MeSH), ‘drug monitoring’ (MeSH), ‘pharmacovigilance’ and ‘drug surveillance program’. The reference lists of relevant articles were hand-searched for additional potentially relevant articles. Non peer-reviewed articles were not considered. The search strategy is displayed in Table 1.
Table 1.
Search strategies for studies on adverse drug reactions in paediatric populations
| Database | Search terms |
|---|---|
| Medline | (1) Child |
| (2) Paediatric | |
| (3) Adverse drug reaction | |
| (4) Adverse effects | |
| (5) 3 OR 4 | |
| (6) Adverse drug reaction reporting system | |
| (7) Drug monitoring | |
| (8) Pharmacovigilance | |
| (9) 6 OR 7 OR 8 | |
| (10) 2 AND 5 AND 9 | |
| Embase | (1) Child |
| (2) Paediatric or Pediatrics | |
| (3) Paediatric or child | |
| (4) Adverse drug reaction | |
| (5) Side effect | |
| (6) Adverse effect | |
| (7) 4 OR 5 OR 6 | |
| (8) Adverse drug reaction reporting system or drug surveillance program | |
| (9) Drug monitoring | |
| (10) Pharmacovigilance | |
| (11) 8 OR 9 OR 10 | |
| (12) 3 AND 7 AND 11 |
Inclusion and exclusion criteria
To be considered relevant for this review, articles had to report ADRs in children from 0 to 17 years of age prospectively or retrospectively monitored in hospital settings, by general practitioners or as ADR reports to national and international ADR databases. Articles reporting ADRs in whole populations without the possibility to assess results for children and adults separately or reporting clinical events not reported as ADRs were excluded. We excluded articles analysing specific types of ADRs reported for selected therapeutic groups and articles studying ADRs in patients with a particular disease. Case reports, letters, commentaries, interim analyses and review articles were also excluded, as well as articles dealing with information about unintended events not classified as ADRs. Whether causality assessments of ADRs were conducted in the located articles did not influence inclusion. The included articles were not assessed in terms of quality. No articles were excluded due to language.
Extraction of data
We developed a taxonomy inspired by general guidelines for pharmacological research to analyse the articles systematically [10]. The taxonomy covers the following characteristics: publication year, geographic setting and location, sampling period, age of population, number of reported ADRs distributed by age and gender of the children, types of ADRs, reported medications, category of reporter and degree of seriousness of reported ADRs. Detailed information about design including data collection approaches and size of the study population was also extracted. Information about ADR incidence rates and prevalence rates was extracted if reported. Extracted information was entered into data sheets, one for each article. Data were extracted and handled by the first and second author and checked by the third author. Consensus on the interpretation of extracted data was achieved in all cases.
Analysis
For all included articles, we analysed time of publication, characteristics of explored patient populations, occurrence of ADRs and severity and types of reported ADRs in children. We analysed whether there was a relation between the data collection period and types of reported ADRs.
Occurrence of ADRs
The occurrence of ADRs was calculated as new cases (incidence rates), or the total number of cases in the population (prevalence) [10]. Incidence rates (IR) were calculated per year as: IR = number of ADRs in the population divided by person-time [10]. ADR prevalence was calculated as the number of total ADRs reported, divided by the total number of persons in the study population [10]. Information about the study population was extracted from the included articles if available.
Classification of reported ADRs
For each included article, any ADRs reported were classified according to System Organ Class (SOC) in keeping with MedDRA (Medicinal Dictionary for Regulatory Activities) terminology [11], which is an international standard terminology for classifying medicinal information, which makes it possible to analyse and clinically evaluate safety data internationally. ADRs that could be related to more than one SOC were classified according to their primary SOC.
Classification of therapeutic groups
Medicines were categorized according to the Anatomical Therapeutic Chemical (ATC) classification system. For each included article, we categorized the reported medications on ATC level 1 (anatomical main group) [12].
Seriousness of reported ADR
It was not feasible to apply a common definition of ADRs across studies, as the included papers used a range of definitions. 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 [13]. Here serious ADRs are divided into: resulting in death, life-threatening, requiring hospitalization or prolongation of existing hospitalization, resulting in persistent or significant disability/incapacity in the reporter's opinion, a congenital anomaly/birth defect and other medically important conditions. Other reactions were classified as non-serious [13].
Patient age
Patient age was extracted from the articles if available. In many articles, however, age was not specified, the only information being ‘paediatric patients’ or ‘children’ and the maximum age in particular was not specified. In these cases we assumed that only patients under 18 years of age were included following the WHO criteria for children. This is noted in Table 2 as ‘age not specified’.
Table 2.
Design of included articles by setting, publication year, type of reporter and approach
| Studies by publication year | Setting | Country | Data collection | Study period (years) | Approach | Reporter |
|---|---|---|---|---|---|---|
| McKenzie et al. (1973) [14] | In | US | 1971 | 0.5 | Chart rev, Phys int | Pharm |
| Whyte & Greenan (1977) [15] | In | UK | 1977 | 1.0 | Chart rev, Parent int | Nrs, Prnt |
| Mitchell et al. (1979) [16] | In | US | 1974–1977 | 4.0 | Chart rev, Phys/ ptnt int | Nrs |
| Choonara & Harris (1984) [17] | In | UK | NR | 0.5 | Chart rev, Phys/nurse int | Phys |
| Gill et al. (1995) [18] | In | UK | NR | 2.3 | Chart rev, Phys int | Various |
| Gonzalez-Martin et al. (1998) [19] | In | CL | 1997 | 1.0 | Chart rev, Parent int | Phys |
| Martinez-Mir et al. (1999) [20] | In | ES | 1992–1993 | 0.6 | Chart rev, Parent int | Phys |
| Turner et al. (1999) [21] | In | UK | 1995–1996 | 0.25 | Chart rev | Phys |
| Buajordet et al. (2002) [22] | In | NO | 1996 | 0.4 | Chart rev, Parent int | Phys, Prnt |
| Temple et al. (2004) [23] | In | US | 1994–1999 | 6.0 | Chart rev | Various |
| Haffner et al. (2005) [24] | In | DE | 2001 | 0.25 | Chart rev | Various |
| Le et al. (2006) [25] | In | US | 1995–2004 | 10.0 | Retrosp, obs cohort | Various |
| Planchamp et al. (2009) [26] | In | FR | 2005 | 0.5 | Prosp obs | Phys |
| McKenzie et al. (1976) [27] | Hosp | US | NR | 3.0 | Chart rev, Phys int | Phys |
| Yosselson-Superstine et al. (1982) [28] | Hosp | IL | NR | 0.6 | Chart rev, Phys int | Pharm |
| Mitchell et al. (1988) [29] | Hosp | US | 1974–1985 | 11.0 | Chart rev | Nurse |
| Martinez-Mir et al. (1996) [30] | Hosp | ES | 1992–1993 | 0.6 | Chart rev, Parent int | Phys |
| Easton et al. (1998) [31] | Hosp | AU | 1996 | 0.15 | Chart rev, Parent int | Phys |
| Haffner et al. (2005)*[24] | Hosp | DE | 2001 | 0.25 | Computerized alert system | Various |
| Kramer et al. (1985) [32] | Out | CA | 1981–1982 | 1.0 | Chart rev, Ptnt int | Phys |
| Sanz & Boada (1987) [33] | Out | ES | NR | 0.5 | Chart rev | Phys |
| Woods et al. (1987) [34] | Out | UK | 1984–1985 | 0.25 | Survey (parents) | Patients |
| Cirko-Begovic et al. (1989) [35] | Out | YUG | 1986 | 0.25 | Chart rev, Parent int | Phys |
| Menniti-Ippolito et al. (2000) [36] | Out | IT | 1996–1997 | 1.0 | Prosp, obs | Phys |
| Lewis et al. (2001) [37] | Out | DE | 1996 | 0.25 | Chart rev, Parent int | Phys |
| Horen et al. (2002) [38] | Out | FR | 2000–2001 | 0.25 | Prosp, obs | Phys |
| Meyboom (1991) [39] | DB | NL | 1973–1988 | 16.0 | Reports | Phys |
| Morales-Olivas et al. (2000) [40] | DB | ES | 1982–1991 | 10.0 | Reports | Phys |
| Moore et al. (2002) [41] | DB | US | 1997–2000 | 3.2 | Reports | Various |
| Schirm et al. (2004) [42] | DB | NL | 1995–2001 | 7.0 | Reports | Phys, Pharm |
| Ufer et al. (2004) [43] | DB | SE | 2000 | 1.0 | Reports | Phys |
| Kimland et al. (2005) [44] | DB | SE | 1987–2001 | 15.0 | Reports | Phys |
| Carleton et al. (2007) [45] | DB | CA | 1998–2002 | 4.5 | Reports | Various |
| Aagaard et al. (2010) [46] | DB | DK | 1998–2007 | 10 | Reports | Various |
Study using two different settings. DB, National ADR database; Hosp, ADR leading to hospitalization; In, inpatients; Nrs, nurses; Out, outpatients; Pharm, pharmacists; Phys, physicians; Prnt, parents; Prosp, prospective; Retrosp, retrospective; Obs, observational; Int, interview.
Results
The literature search resulted in 476 potentially relevant references of which 96 were selected from the titles and abstracts and further screened for relevance. Additionally, four references were found by hand searching the reference lists of identified papers. Eventually 33 articles were included in the analysis. We did not assess the scientific quality of the papers. A flow chart of the selection and exclusion process is presented in Figure 1.
Figure 1.
Flow chart of included/excluded studies
The included articles monitored ADRs in different patient populations: 13 articles monitored inpatients in prospective or retrospective designs, five articles monitored patients for whom ADRs were the cause of hospitalization, seven articles monitored ADRs in selected out-patients while eight articles retrospectively analysed data reported to national ADR databases for both inpatients and outpatients. Nine studies were conducted in North America, 22 studies in Europe, one study in Israel, one study in Australia and one study in Chile. We did not identify any studies from Asia.
Study characteristics
Table 2 displays the characteristics of the included articles by date of publication, design, country, setting and type of reporter. Articles were published from 1973 onwards, primarily after 1990; however, data were collected previously. The period under study in articles studying inpatients varied widely from 56 days to 11 years and in outpatients from 0.25 to 2 years. For spontaneously reported ADRs, the data collection period varied from 1 to 16 years. Seventeen of the articles were not included in the review by Impicciatore et al.[9] and 16 of the articles were published after May 2000.
Type of reporter
The ADR data were reported by different types of reporters. ADRs were reported by physicians only in 18 articles, by pharmacists only in two articles, by nurses only in one study and by patients only in one study. Eight articles included a mix of various types of reporters. Only five articles specified the share of ADRs reported by the different sources [18, 22, 23, 25, 46]. In these articles, pharmacists, nurses and physicians contributed the majority of reported ADRs. In one study from Norway, 94% of ADRs were reported by consumers (parents) and only 6% by physicians [22].
Age and gender of children
Table 2 shows that only 50% of the included articles reported the distribution of detected ADRs by gender. For inpatients, equal shares of ADRs were reported in boys as well as girls. In data from national ADR databases, 55% of ADRs were reported in boys and 45% in girls [40–44]. Distribution of ADRs by age group was reported in approximately half of the included articles but with varying age intervals. For inpatients approximately 25% of all ADRs were reported in children less than 1 year of age, 50% in children from ages 1–10 years and 25% in children above 10 years. For outpatients the distribution of ADRs by age was only reported in two articles [37, 38], with wide variations between age groups. The pattern was slightly different in studies analysing data from national ADR databases: approximately 25% of ADRs were reported for children less than 1 year of age, 40% for children from 1 to 10 years of age and 33% for children above 10 years of age [40–46].
Occurrence and seriousness of reported ADRs
Table 3 displays the characteristics of the assessed populations including seriousness of reported ADRs and occurrence of ADRs in the included articles. There were variations between studies. The average incidence rate for inpatients was 42% (range 1–179%), for inpatients hospitalized due to ADRs 9% (range <1–28%), for outpatients 14% (range 2–68%) and below 1% in national ADR databases. The average prevalence rate for inpatients was 24% (range 1–72%), for patients hospitalized due to ADRs 4% (range <1–9%), for outpatients 4% (range 1–17%) and below 1% in national ADR databases. On average, 26% of reported ADRs were serious and 74% non-serious. Serious ADRs ranged from 7% to 43% for inpatients, from 18% to 45% in patients hospitalized due to ADRs, from 0 to 18% in outpatients and from 5% to 63% in national ADR databases [39–46].
Table 3.
Characteristics of the assessed populations including seriousness of reported ADRs and occurrence of ADRs
| Studies by publication year | Study population (n) | Population age (years) | ADRs (n) | Prevalence of ADRs (%) | Incidence of ADRs (%) | ADRs by age groups (years) (%) | ADRs by male (%) | Serious ADRs (%) |
|---|---|---|---|---|---|---|---|---|
| McKenzie et al. (1973) [14] | 658 | ≤18 NS | 184 | 28 | 56 | <1: 22, 1–10: 52, >10: 26 | 58 | 23 |
| Whyte& Greenan (1977) [15] | 844 | ≤18 NS | 119 | 14 | 14 | NR | NR | 22 |
| Mitchell et al. (1979) [16] | 1 669 | ≤18 NS | 284 | 17 | 4 | <1: 23, 1–9: 52, >10: 66 | NR | NR |
| Choonara & Harris (1984) [17] | 268 | ≤12 | 17 | 6 | 13 | <1: 29, 1–10: 41, >10: 30 | NR | NR |
| Gill et al. (1995) [18] | 899 | ≤16 | 76 | 8 | 4 | NR | NR | 11 |
| Gonzalez-Martin et al. (1998) [19] | 219 | ≤16 | 46 | 21 | 21 | <1: 30, 1–9: 56, >10: 14 | NR | 28 |
| Martinez-Mir et al. (1999) [20] | 490 | ≤2 | 282 | 58 | 96 | NR | 37 | 7 |
| Turner et al. (1999) [21] | 936 | ≤18 | 157 | 17 | 67 | NR | NR | 11 |
| Buajordet et al. (2002) [22] | 579 | ≤16 | 414 | 72 | 179 | NR | NR | 19 |
| Temple et al. (2004) [23] | 65 864 | ≤18 NS | 565 | 1 | 1 | <2: 15, 2–9: 54, >10: 32 | NR | 43 |
| Haffner et al. (2005) [24] | 703 | ≤18 | 101 | 14 | 57 | <1: 18, 2–10: NR, >10: 6 | 58 | 31 |
| Le et al. (2006) [25] | NR | ≤18 NS | 1087 | NA | 2 | <1: 26, 1–10: 39, >10: 35 | 50 | 11 |
| Planchamp et al. (2009) [26] | 1 676 | <18 | 43 | 3 | 5 | NR | 56 | 33 |
| McKenzie et al. (1976) [27] | 3 556 | ≤18 NS | 72 | 2 | 1 | NR | NR | 44 |
| Yosselson-Superstine et al. (1982) [28] | 906 | ≤16 | 29 | 3 | 5 | <1: 10, 1–10: 69.5, >10: 6 | 57 | 45 |
| Mitchell et al. (1988) [29] | 10 297 | ≤18 NS | 131 | 1 | <1 | <1: 23, 1–9: 40, >10: 35 | NR | NR |
| Martinez-Mir et al. (1996) [30] | 490 | ≤2 | 42 | 9 | 14 | <1: 67, >1: 33 | 33 | 38 |
| Easton et al. (1998) [31] | 1 682 | ≤18 | 58 | 3 | 23 | NR | NR | 37 |
| Haffner et al. (2005) [24] | 636 | ≤18 | 45 | 7 | 28 | NR | 61 | 18 |
| Kramer et al. (1985) [32] | 3 181 | <19 | 200 | 6 | 6 | NR | NR | NR |
| Sanz & Boada (1987) [33] | 1 327 | ≤7 | 17 | 1 | 3 | <1: 29, >1: 71 | 20 | NR |
| Woods et al. (1987) [34] | 1 590 | 3–11 | 270 | 17 | 68 | NR | NR | 18 |
| Cirko-Begovic et al. (1989) [35] | 2 359 | ≤7 | 63 | 3 | 11 | NR | NR | NR |
| Menniti-Ippolito et al. (2000) [36] | 7 890 | ≤14 | 119 | 2 | 2 | <1: 13, 1–7: 65, 7–14: 22 | NR | 0 |
| Lewis et al. (2001) [37] | 12 628 | ≤16 | 152 | 1 | 5 | NR | NR | 17 |
| Horen et al. (2002) [38] | 1 419 | ≤15 | 20 | 1 | 6 | <1: 50, >1: 50 | 45 | 0 |
| Meyboom (1991) [39] | NR | ≤14 | 695 | NA | NA | NR | NR | NR |
| Morales-Olivas et al. (2000) [40] | NR | ≤14 | 2454 | NA | NA | <1: 13, 1–9: 63, >10: 24 | 55 | 5 |
| Moore et al. (2002) [41] | NR | ≤2 | 5976 | NA | NA | <1: 82, >1: 18 | 57 | 63 |
| Schirm et al. (2004) [42] | 57 034 | ≤16 | 773 | NA | 0.2 | <1: 20, 2–11: 52, >12: 28 | 47 | 7 |
| Ufer et al. (2004) [43] | 1 736 656 | ≤15 | 158 | 0.01 | 0.01 | <2: 14, 2–9: 52, >10: 34 | 56 | 31 |
| Kimland et al. (2005) [44] | 1 700 000 | ≤15 | 7887 | 0.5 | 0.03 | <4: 61, 5–9: 16, >10: 23 | 55 | 13 |
| Carleton et al. (2007) [45] | 7 670 000 | ≤19 | 1193 | 0.02 | <0.01 | <1: 12, 1–13: 28, >13: 59 | NR | 61 |
| Aagaard et al. (2010) [46] | 1 100 000 | ≤17 | 4500 | 0.4 | 0.04 | <2: 52, 2–10: 25, 11–17: 23 | 49 | 42 |
NA, not available; NR, not reported; NS, not specified.
Types of reported ADRs
Table 4 displays the share and range of reported ADRs by type (system organ class). The share of reported ADRs varied across studies, the largest shares were from the SOCs ‘skin and subcutaneous disorders’ (range 14–66%), ‘gastrointestinal disorders’ (range 5–60%), ‘nervous system and psychiatric disorders’ (range 5–46%), ‘cardiac disorders’ (range 2–30%), ‘metabolism and nutrition disorders’ (range 9–25%), ‘blood and lymphatic system disorders’ (range 2–62%) and ‘general disorders and administration site conditions’ (range 4–71%). Lower shares of ‘hepatobiliary disorders’ as well as ‘infections and infestations’ ADRs were reported [18, 27–29].
Table 4.
Share (%) and range of reported ADRs by type (system organ class)
| References | [14] | [15] | [16] | [17] | [18] | [19] | [20] | [21] | [22] | [23] | [24] | [25] | [26] | [27] | [28] | [29] | [30] | [31] | [32] | [33] | [34] | [35] | [36] | [37] | [38] | [39] | [40] | [41] | [42] | [43] | [44] | [45] | [46] | Range |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| System organ class | ||||||||||||||||||||||||||||||||||
| Blood and lymphatic system disorders | – | 27 | 10 | – | – | – | – | – | – | NA | 62 | – | – | NA | 36 | NA | – | – | – | – | – | – | 3 | – | – | – | – | – | – | 9 | – | – | 2 | 2–62 |
| Cardiac disorders | 21 | 4 | – | 12 | 18 | – | – | 10 | – | NA | 4 | 23 | NA | – | NA | – | 30 | – | – | – | – | – | – | – | – | – | – | – | – | – | – | 2 | 2–30 | |
| Congenital, familial and genetic disorders | – | – | – | – | – | – | – | – | – | NA | – | – | – | NA | – | NA | – | – | – | – | – | – | – | – | – | – | – | 41 | – | – | – | – | <1 | <1–41 |
| Ear and labyrinth disorders | – | – | – | – | – | – | – | – | – | NA | – | – | – | NA | – | NA | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | <1 | <1 |
| Endocrine disorders | – | – | – | – | – | – | – | – | – | NA | – | – | – | NA | – | NA | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | <1 | <1 |
| Eye disorders | – | – | – | – | – | – | – | – | – | NA | – | – | – | NA | – | NA | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | 2 | 2 |
| General disorders and administration site conditions | – | – | 22 | 35 | – | – | – | – | 12 | NA | – | – | 19 | NA | – | NA | – | – | 4 | – | 71 | – | – | 10 | 10 | 16 | 8 | – | – | – | 20 | – | 31 | 4–71 |
| Gastrointestinal disorders | 24 | 33 | 44 | 24 | 14 | 33 | 37 | 10 | 27 | NA | 60 | – | 12 | NA | 32 | NA | 17 | 40 | 61 | 30 | 10 | 37 | 39 | 28 | 40 | 13 | 19 | – | 19 | 13 | 5 | – | 6 | 5–60 |
| Hepatobiliary disorders | – | – | – | – | – | – | – | – | – | NA | 27 | – | – | NA | – | NA | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | <1 | <1–27 |
| Infections and infestations | – | – | – | 5 | – | – | – | – | – | NA | – | – | – | NA | – | NA | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | 2 | 2–5 |
| Immune system disorders | – | – | – | – | – | – | – | – | – | NA | – | – | – | NA | – | NA | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | 0 | 0 |
| Injury, poisoning and procedural complications | – | – | – | – | – | – | – | – | – | NA | – | – | – | NA | – | NA | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | <1 | <1 |
| Investigations | – | – | – | – | – | – | – | – | – | NA | – | – | – | NA | – | NA | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | 2 | 2 |
| Metabolism and nutrition disorders | 9 | 12 | – | – | – | 18 | – | 25 | – | NA | – | – | – | NA | – | NA | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | 1 | 9–25 |
| Musculoskeletal and connective tissue disorders | – | – | – | – | – | – | – | – | – | NA | – | – | – | NA | – | NA | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | 2 | 2 |
| Neoplasms benign, malignant and unspecified | – | – | – | – | – | – | – | – | – | NA | – | – | – | NA | – | NA | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | <1 | <1 |
| Nervous system and psychiatric disorders | – | 12 | – | 24 | – | 20 | 22 | – | 28 | NA | 6 | 16 | – | NA | – | NA | 41 | 30 | 14 | – | – | – | 5 | 5 | 15 | 29 | 10 | – | 25 | 26 | 15 | 46 | 15 | 5–46 |
| Respiratory, thoracic and mediastinal disorders | – | 2 | – | – | – | – | – | – | – | NA | – | – | – | NA | – | NA | – | – | – | – | – | – | – | – | 5 | – | – | – | – | – | – | – | 3 | 2–5 |
| Pregnancy, puerperium and perinatal conditions | – | – | – | – | – | – | – | – | – | NA | – | – | – | NA | – | NA | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | <1 | <1 |
| Renal and urinary disorders | – | – | – | – | – | – | – | – | – | NA | – | – | – | NA | – | NA | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | <1 | <1 |
| Reproductive system and breast disorders | – | – | – | – | – | – | – | – | – | NA | – | – | – | NA | – | NA | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | <1 | <1 |
| Skin and subcutaneous tissue disorders | – | 17 | 14 | – | 25 | 18 | 10 | 32 | 11 | NA | 27 | 37 | 63 | NA | 19 | NA | 14 | – | 21 | 66 | – | 53 | 36 | 26 | 30 | 40 | 33 | – | 25 | 18 | 45 | – | 18 | 14–66 |
| Surgical and medical procedures | – | – | – | – | – | – | – | – | – | NA | – | – | – | NA | – | NA | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | <1 | <1 |
| Vascular disorders | – | – | – | – | – | – | – | – | – | NA | – | – | – | NA | – | NA | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | 1 | 1 |
| ADRs not specified | 46 | 1 | 10 | – | 43 | 13 | 31 | 23 | 22 | NA | 14 | 24 | 6 | NA | 13 | NA | 19 | – | – | 4 | 19 | 10 | 17 | 32 | – | – | 30 | 59 | 32 | 35 | 15 | 54 | – | 1–59 |
NA, data not available; –, no ADRs reported.
Therapeutic groups associated with ADRs
Table 5 displays the share and range of reported ADRs by therapeutic groups (ATC level 1). The largest share of ADRs was reported for ATC group J (anti-infectives for systemic use) (range 9–83%), ATC group N (nervous system) (range 5–35%), ATC group R (respiratory system) (range 1–35%), ATC group L (anti-neoplastic and immunomodulating agents) (range 8–67%), ATC group B (blood and blood-forming organs) (range 1–24%) and ATC group C (cardiovascular system) (range 1–29%). Minor shares of ADRs were reported for ATC group A (alimentary tract and metabolism) (range 2–10%), ATC group C (cardiovascular system) (range 2–10%) and dermatological (ATC group D) (range 2–10%).
Table 5.
Share and range of reported ADRs by therapeutic group (ATC level 1)
| References | [14] | [15] | [16] | [17] | [18] | [19] | [20] | [21] | [22] | [23] | [24] | [25] | [26] | [27] | [28] | [29] | [30] | [31] | [32] | [33] | [34] | [35] | [36] | [37] | [38] | [39] | [40] | [41] | [42] | [43] | [44] | [45] | [46] | Range |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ATC groups | ||||||||||||||||||||||||||||||||||
| Alimentary tract and metabolism (A) | – | – | – | – | – | 9 | – | – | – | 2 | – | – | – | – | – | – | – | – | NA | – | – | – | – | 4 | – | – | 10 | – | – | 8 | – | NA | 2 | 2–10 |
| Blood and blood-forming organs (B) | – | – | – | – | – | – | – | – | – | 1 | – | – | – | – | – | – | – | – | NA | 24 | – | – | – | – | – | – | – | – | – | – | – | NA | <1 | 1–24 |
| Cardiovascular systems (C) | – | – | 8 | – | 11 | – | 7 | 29 | – | 5 | – | – | – | – | – | – | – | 20 | NA | – | – | – | – | – | – | – | – | – | – | – | – | NA | <1 | <1–29 |
| Dermatological (D) | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | 10 | – | NA | – | – | – | – | – | – | – | – | – | – | – | – | NA | 2 | 2–10 |
| Genitourinary system and sex hormones (G) | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | NA | – | – | – | – | – | – | – | – | – | – | – | – | NA | 2 | 2 |
| Systemic hormonal preparations (H) | 11 | 8 | – | – | – | – | – | – | – | 5 | – | – | – | 15 | – | – | – | 10 | NA | – | – | – | – | – | – | – | – | – | – | – | – | NA | <1 | <1–11 |
| Anti-infectives for systemic use (J) | 9 | 14 | 41 | 20 | 8 | 45 | 22 | 32 | 29 | 83 | 33 | 76 | 13 | 33 | 27 | 25 | 20 | NA | 24 | 74 | 78 | 67 | 78 | 55 | 16 | 53 | 9 | 25 | 14 | 74 | NA | 65 | 9–83 | |
| Antineoplastic and immunomodulating agents (L) | 8 | 67 | 27 | – | – | – | – | – | 16 | 12 | – | 10 | – | 37 | – | – | – | – | NA | 12 | – | – | – | – | – | – | – | 34 | – | – | – | NA | 2 | 8–67 |
| Musculoskeletal system (M) | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | NA | – | – | – | – | – | – | – | – | 5 | 18 | – | – | NA | 1 | 1–18 |
| Nervous system (N) | – | 3 | 16 | 35 | 9 | 11 | 24 | 26 | 24 | 25 | – | 33 | – | 16 | – | 33 | 15 | 30 | NA | 18 | – | – | – | – | – | 7 | – | 6 | – | 20 | 3 | NA | 17 | 3–35 |
| Antiparasitic products (P) | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | NA | – | – | – | – | – | – | – | – | – | – | – | – | NA | 1 | 1 |
| Respiratory system (R) | – | – | 8 | 18 | 11 | 17 | 15 | – | 25 | 1 | 15 | – | – | – | – | – | 35 | 20 | NA | 18 | – | – | 7 | 11 | – | – | 22 | – | 26 | 31 | – | NA | 2 | 1–35 |
| Sensory organs (S) | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | NA | 4 | – | – | – | – | – | – | – | – | – | – | – | NA | <1 | <1–4 |
| Various (V) | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | NA | – | – | – | – | – | – | – | – | – | – | – | – | NA | 3 | 3 |
| Medicines not specified | 72 | 22 | 27 | 6 | 49 | 54 | 9 | 23 | – | 20 | 2 | 19 | 24 | 19 | 67 | 40 | 15 | – | NA | – | 26 | 22 | 26 | 7 | 45 | 77 | 1 | 46 | 33 | 27 | 23 | NA | – | 1–77 |
NA, data not available, no ADRs reported.
Discussion
We identified 33 studies monitoring ADRs in general paediatric populations between 1973 and 2009, half of them published after the year 2000. Information about ADRs was mainly available from studies conducted in hospitalized inpatients in North America and Europe, but since 2001 more articles analysing data reported to national ADR databases have been published. The highest numbers of ADRs were reported in national ADR databases where data have been collected over a longer period of time than in studies monitoring inpatients and outpatients. However, prevalence and incidence were much lower in the national databases. Types of reported ADRs, seriousness of ADRs and types of medicines differed substantially between studies due to differences in time periods and patient populations. Information about ADRs in children was mainly provided by health care professionals.
Occurrence of ADRs in children
The reported incidence and prevalence rates of ADRs were, in general, higher in hospitalized children than in out-patients and in national databases reflecting the closeness of patient-professional contact. A comparison of the incidence and prevalence rates is difficult due to differences in settings, ADR classification systems, data collection approaches and study length [47]. The amount of ADR data available in national databases is low and characterized by gross under-reporting, despite the longer data collection periods and larger populations covered, but with great potential for detecting information about previously unknown ADRs [48]. Among physicians there are several obstacles to spontaneous reporting such as lack of time and confusion about what to report [49], but when this threshold has been overcome and reporting is actually conducted we expect these ADRs to be significant [49]. Incidence and prevalence were higher than in the previous review [9], which could be due to the inclusion of more studies in this review.
Severity of reported ADRs
In some articles, the share, although not the prevalence, of serious ADRs was higher in national ADR databases than in both inpatients and outpatients. Due to differences in time periods, setting, prescribing practices, classification systems, data collection approaches and lack of information about seriousness in many articles, we cannot conclude whether there is a difference in severity between studies. Further, we do not know whether the reported serious ADRs were related to unlicensed and off-label use of medicines in children, as these data were not available in the articles.
Reported ADRs and therapeutic groups
We did not detect significant differences in categories of reported ADRs between the explored populations, data collection approaches or time periods. The level of ADRs reported for the different therapeutic groups was the same as reported in the review by Impicciatore et al.[9], but the sub-groups were presumably different due to changes in prescribing practices for some therapeutic groups over time, e.g. ADRs from barbiturates in older studies vs. CNS stimulants and antidepressants in more recent studies.
Type of reporter
Health care professionals, especially physicians, reported the majority of the ADRs. Pharmacists, nurses or parents also reported some ADRs in inpatients, but little information was available about reporting patterns. Surprisingly, consumers have reported very few ADRs in children despite their having had the opportunity to report to national ADR databases in Canada, Denmark, the Netherlands, Sweden, USA and UK for several years [50]. Thus pharmacists and consumers have so far played only a minor role in reporting ADRs in children. Due to their direct contact and dialogue with patients at the pharmacy, in hospital or as relatives, pharmacists and parents are in an ideal position to detect ADRs and could in future take a more active role in reporting ADRs to national ADR databases.
Strengths and limitations of the study
The objective of this study was to review studies reporting ADRs occurring in children. The number of included articles doubled compared with the previous review by Impicciatore et al.[9]. Of special interest were six studies published since 2001 analysing ADRs reported to national ADR databases. The included studies were conducted over a period of approximately 30 years in 15 different countries, with a great deal of inconsistency in reporting and classifying ADRs and limited data on the age and gender of the children. The information about the occurrence of ADRs as well as types of reported ADRs and seriousness might not be applicable to all countries, but can serve as a benchmark for paediatric populations in which ADRs are poorly reported or characterized. The findings of this review are limited by the quality and content of the included studies but nevertheless illustrate that information about ADRs in children is limited and more knowledge is needed. Hence, we need to conduct large observational studies to be able to detect ADRs across paediatric populations and differences in prescribing patterns and practices. Systematic analyses of ADRs reported to national databases are also necessary, as these databases constitute an underestimated source of important data. The regulatory agencies should monitor prescribing patterns tightly to identify potential risks in the paediatric population in relation to the evolving pattern of medicine use among children.
In conclusion, we found a higher incidence rate of ADRs in hospitalized children and outpatients and a higher incidence rate of ADRs leading to hospitalizations than in the review by Impicciatore et al.[9]. The largest numbers of ADRs reported in children are present in national databases, but studies monitoring specific populations can provide more accurate data on incidence and prevalence. The type of reporters varied widely, and there would seem to be substantial potential for increasing the knowledge of ADRs by advocating the submission of reports by all relevant groups. It was not possible to explore associations between ADRs and off-label prescribing. Our study underscores that ADRs in children are a significant public health problem.
Competing interests
The authors have identified no financial or other conflicts of interest with respect to the content of this article.
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