Perceived adverse drug reactions among non-institutionalized children and adolescents in Germany

Authors


Dr Hildtraud Knopf MD, RKI 22, Robert Koch Institute, General-Pape-Strasse 64-66, D-12101 Berlin, Germany.
Tel.: + 49 30 4547 3213
Fax: + 49 30 4547 3211
E-mail: KnopfH@rki.de

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

Drug safety in paediatric medication is a public health concern. According to previous studies, the incidence of adverse drug reactions (ADRs) varies greatly from 0.7% to 2.7% among paediatric outpatients and from 2.6% to 18.1% among paediatric inpatients. Little has been reported on the risks of drug use in the general child population.

WHAT THIS STUDY ADDS

Our study showed that the prevalence of perceived ADRs in Germany was 0.9% among non-institutionalized children in general and 1.7% among children who had used at least one medicine within the 7 days before the medical interview. Perceived ADRs in the general child population were clustered with gastrointestinal disorders and subcutaneous tissue disorders. They appeared to be mild and at the lower limits of the range reported in other studies. Health surveys covering the use of a diverse range of drugs might be suitable for computing ADR prevalence and for identifying risk factors among non-institutionalized children. They should be taken into account together with other pharmacovigilance systems.

AIMS

Little has been reported on the risks of drug use in the general child population. This study investigated perceived adverse drug reactions (ADRs) among non-institutionalized children in Germany.

METHODS

All medicines used in the last 7 days before the medical interview were recorded among the 17 450 children aged 0–17 years who participated in the 2003–06 German Health Interview and Examination Survey for Children and Adolescents (KiGGS). Perceived ADRs were reported by the children's parents and confirmed by trained medical professionals during the medical interview.

RESULTS

One hundred and fifty-seven medicines were involved in the occurrence of 198 perceived ADRs in 153 patients. This corresponded to 1.1% of total used drugs, 0.9% (95% confidence intervals 0.7, 1.1%) of all children, and 1.7% (1.4, 2.1%) of children treated with medications. About 40% of all perceived ADRs involved gastrointestinal disorders and 16% involved skin tissue disorders. Perceived ADRs were most frequently reported in relation to drugs acting on the nervous system (25.8%), followed by systemic anti-infectives (18.7%) and drugs acting on the respiratory system (16.2%). Risk factors for perceived ADRs included older age groups, polypharmacy (≥2) and a poor health status.

CONCLUSION

Perceived ADRs in the general child population were clustered with gastrointestinal disorders and subcutaneous tissue disorders. They appeared to be mild and at the lower limits of the range reported in other studies. Health surveys covering the use of a diverse range of drugs might be suitable for computing ADR prevalence and identifying risk factors among non-institutionalized children. They should be taken into account together with other pharmacovigilance systems.

Introduction

For a long time now, adverse drug reactions (ADRs) have been recognized as one of the main causes of paediatric morbidity in the USA and some European countries [1–3]. Many studies on paediatric ADR occurrence have been published since then. Most of them are based on an analysis of data on hospitalized children [4–9], outpatient paediatric clinics or drug consumption [10–14]. Results on ADR incidence vary greatly in these studies, between 0.7% [10] and 2.7% [11] for paediatric outpatients and between 2.6% [10] and 18.1% [9] for paediatric inpatients. An earlier meta-analysis of 17 prospective studies published between 1973 and 2000 estimated that the overall incidence of ADRs was 1.46% for paediatric outpatients and 9.53% for paediatric inpatients [15] and a recent meta-analysis of eight prospective studies published between 2001 and 2007 reported weighted average ADR incidence rates of 1.0% for paediatric outpatients and 10.9% for paediatric inpatients [16].

In Germany, ADR incidence has been investigated by means of intensive monitoring in hospital. In a 10-bed paediatric isolation ward of a German university hospital in Erlangen, the ADR incidence was estimated at 17.4–21.5% [17–19] using this method. Another study conducted in the HELIOS Klinikum Wuppertal teaching hospital reported that 14.1% of inpatient children experienced an ADR over a period of 3 months [20]. These studies were conducted in paediatric wards. Few results have been reported in Germany from non-clinical settings on epidemiological aspects of the risks of paediatric drug use. An early regional ADR monitoring programme in the federal state of Brandenburg estimated that ADR incidence was approximately 1% among children given medications [21]. This study was conducted 10 years ago. More up-to-date population-representative national data on non-institutionalized children not necessarily using medical services have so far been very rare both in Germany and worldwide. Against this background, we investigated the perceived ADRs reported by children's parents among non-institutionalized children and adolescents in Germany using the drug-use data from the latest German Health Interview and Examination Survey for Children and Adolescents (KiGGS).

Methods

Data source and study population

The German KiGGS survey was conducted by the Robert Koch Institute from 2003 to 2006. KiGGS investigated 0- to 17-year-old children and adolescents usually resident in Germany with the aim of providing comprehensive and representative data on their health status [14].

The design, sampling strategy and study protocol of KiGGS have been described in detail elsewhere [14]. Briefly, two-stage sampling procedures were applied. In the first stage, a sample of 167 German municipalities (112 in the former West Germany, 55 in the former East Germany) was drawn which was representative of municipality sizes and structures in Germany. In the second stage, the addresses of all 28 299 children and adolescents were chosen randomly from the local population registers. Children and adolescents with a foreign nationality were also included. Excluded were children who were currently in institutions such as hospitals, medical and nursing stations [22]. The overall percentage of non-deliverable survey contacts was 5.3%. The final survey sample included 17 641 children and adolescents with a response rate 66.6% [22]. One hundred and ninety-one children did not provide drug-use data and were therefore excluded from the present study, resulting in a study population of 17 450 children (8880 boys, 8570 girls; see Table 1). All survey participants were informed of the purpose of the study and other relevant concerns. Informed consent was obtained prior to the medical examination either from the children's parents or from the children themselves if they were over the age of 14 years [14].

Table 1. 
Socio-demographic and health-related characteristics of survey participants by gender. German Health Interview and Examination Survey for Children and Adolescents (KiGGS), 2003–06
 BoysGirls
n%95% CIn%95% CI
  • *

    The amounts in each category may not add up to the total because of missing data. ADRs, adverse drug reactions.

Total8880100 8570100 
Age groups (years)      
 0–2139713.613.2, 13.9137313.613.2, 14.0
 3–6192521.020.7, 21.3190721.120.8, 21.4
 7–10210321.721.4, 22.1200421.821.4, 22.1
 11–13157217.317.0, 17.6146817.317.0, 17.7
 14–17188326.425.8, 27.0181826.325.7, 26.9
Region      
 East288916.512.3, 21.9284716.512.3, 21.9
 West599183.578.1, 87.7572383.578.1, 87.7
Urbanicity      
 Rural town195817.912.6, 24.8193917.912.6, 24.7
 Small town233727.620.9, 35.6222927.220.5, 35.1
 Medium-sized town249829.022.2, 37.0247529.322.4, 37.2
 Large city208725.519.0, 33.3192725.619.1, 33.5
Immigrant background*      
 Yes135017.415.4, 19.6123016.914.9, 19.1
 No749882.680.4, 84.6729283.180.9, 85.1
Social class*      
 Low245427.726.1, 29.4230627.325.9, 28.8
 Intermediate401145.243.7, 46.8389045.744.1, 47.2
 High218527.025.2, 29.0218127.125.2, 29.0
Parent-rated health status*      
 Very good340738.236.8, 39.6346640.138.7, 41.6
 Good475954.753.2, 56.1449153.652.2, 55.0
 Moderate5676.96.2, 7.64865.95.3, 6.6
 Bad190.20.1, 0.4180.30.2, 0.5
 Very bad70.10, 0.250.10, 0.1
Children who used medications436248.747.2, 50.3453753.151.5, 54.7
Children with perceived ADRs770.80.6, 1.1760.90.7, 1.3

Data collection and assessment

All the children's parents/guardians and all children aged 11 years or older were asked to fill in a standard parents' or children's questionnaire. These questionnaires were used to collect information on socio-demographic data, family backgrounds, parents-rated children's health status, and health-related living conditions and behaviour patterns. In addition, trained physicians conducted a standardized, computer-assisted personal interview with the children's parents and the children themselves on medical history, health problems and all medicines used within the 7 days prior to the interview [23]. Parental social status was defined as lower, intermediate or upper according to the total scores of a composite social-status index integrating the parents' levels of education, household incomes and professions [24]. Children who themselves (or whose mother/father) did not have German nationality or were not born in Germany were defined as having an immigration background [25].

Medicine use was investigated by asking the following question:

‘Has your child taken any medicines in the last 7 days? Please also mention the use of any ointments, linaments, contraceptive pills, vitamin and mineral supplements, medicinal teas, herbal medicines or homoeopathic medicines’.

Children aged 14 years and older were encouraged to add data on the use of medicines themselves. All prescription or over-the-counter (OTC) medicines used in the 7 days before the interview were recorded in the answers to this question. The definition of ‘medicines’ here was broader than that used by the German Medicines Act [26].

We collected the following information on every medicine mentioned by parents or the children themselves:

  • brand name: as free text;

  • indications: as free text;

  • form of administration: i.e. tablets, dragees, drops, ointments, injections, liniments, etc.;

  • frequency of intake: ‘several times a day’, ‘every day’, ‘regularly but not daily’ or ‘every week’;

  • origin of the medicine: ‘prescribed by a doctor’, ‘prescribed by a non-medical practitioner’, ‘bought over the counter’, or ‘obtained from other sources’;

  • duration of use: ‘<1 week’, ‘1–4 weeks’, ‘1–12 months’ or ‘1 year or longer’;

  • improvement in the condition(s) treated: ‘great’, ‘partial’, ‘not much’, ‘not at all’ or ‘does not apply’;

We also asked the children's parents or the children themselves whether or not the medicine used was well tolerated and to describe the degree of tolerability (‘very good/good’, ‘partial’, ‘not good’ or ‘poor’). Another question was whether any ADRs/side effects were noticed following the use of the medicine (‘yes’ or ‘no’). If the answer was ‘yes’, the ADRs/side effects reported were documented and confirmed informally by interviews conducted by physicians with medical knowledge. No standardized causality/severity assessment was made on the reported ADRs, however.

The free texts on medicine brand names were coded according to WHO ATC (Anatomical-Therapeutic-Chemical) codes [27] as follows: A00 (alimentary system and metabolism), B00 (blood and blood-forming organs), C00 (cardiovascular system), D00 (dermatologicals), G00 (genito-urinary system and sex hormones), H00 (systemic hormonal preparations excluding sex hormones and insulin), J00 (anti-infectives for systemic use), L00 (antineoplastic and immunmodulating agents), M00 (musculoskeletal system), N00 (nervous system), P00 (antiparasitic products, insecticides and repellents), R00 (respiratory system), S00 (sensory organs) and V00 (various). Homoeopathic preparations, which were commonly used among children and adolescents in Germany [28], were given an additional new code ‘Z00’ as they were not covered by the ATC classification system. Indications of medicines were coded according to WHO ICD-10 [29] and ADRs according to MedDRA (Medical Dictionary for Regulatory Activities, version 10.1); the so-called ‘preferred terms’[PT System Organ Class (SOC)] were assigned [30, 31].

Statistical analysis

All statistical analyses were performed using SPSS statistical software (release 17.0). Descriptive statistics were used to analyze characteristics of the study population including the prevalence of perceived ADRs. Associations of the perceived ADRs with socio-demographic and health-related characteristics were quantified by using odds ratios (OR) and their 95% confidence intervals (95% CIs), which were derived from multiple logistic regression models among children who had taken medications. The complex sample method was used to obtain the 95% CIs by the SPSS procedure [22]. Group differences were considered statistically significant if a P value was less than 0.05 or if the 95% CIs for two rates did not overlap.

Results

Table 1 lists the main characteristics of the study sample by gender. The vast majority of boys and girls had a good/very good health status, came from families with no immigration background and resided in the former West Germany and in cities. Nearly half of boys and girls lived in a family with an intermediate social status, one quarter, respectively, in a family with a low or high social status. No significant difference was found between boys and girls with regard to these characteristics.

Eight thousand eight hundred and ninety-nine children (51%) had used at least one medicine during the last 7 days before the interview (Table 1), with girls showing a higher proportion than boys (P < 0.05). One hundred and fifty-three children reported perceived ADRs, corresponding to a population prevalence rate of 0.9% (95% CIs 0.7, 1.1%) with no difference between boys and girls (P= 0.835). Among children who used at least one medicine, the prevalence of perceived ADRs was 1.7% (1.4, 2.1%) (data not shown in Table 1).

Among children who had used medications, no significant difference in the prevalence of perceived ADRs was found in subgroups stratified by gender, regions of residence, immigration background and parental social status (Table 2). Along with age, the prevalence of perceived ADRs showed a J-shape curve; the highest rate was found in the 14–17 year age group, the lowest in the 3–6 and 7–10 year age groups (P < 0.001). A significant difference was also found in the number of concomitantly used medicines and the children's parents-rated health status. The prevalence of perceived ADRs was seven times higher in children using four or more medicines than in children using only one. This association was found in both sexes and all age groups (data not shown). The difference was significant within users of one to four medicines, but disappeared when stratified by age and sex (data not shown). The prevalence of perceived ADRs was more than nine times higher among children with a bad/very bad health status than among children with a good/very good health status. The risks of perceived ADRs were confirmed in the multivariate regression analysis. The interaction between the number of drugs and children's health status was not statistically significant (data not shown in Table 2).

Table 2. 
Prevalence rates and risk factors of perceived ADRs among children who used medications. German Health Interview and Examination Survey for Children and Adolescents (KiGGS), 2003–06
 Prevalence (%)95% CIOdds ratio*95% CIP value
  • *

    Adjusted for age group, gender, region, immigrant background, social status, number of drugs, parents-rated children's health status.

Gender    0.799
 Boys1.71.3, 2.21.10.7, 1.5 
 Girls1.81.4, 2.41  
Age groups (years)    <0.001
 0–21.61.1, 2.41  
 3–61.00.6, 1.60.50.3, 1.1 
 7–101.10.7, 1.80.70.4, 1.4 
 11–132.01.3, 3.11.50.8, 2.6 
 14–172.72.0, 3.71.81.0, 3.0 
Region    0.716
 East2.01.2, 3.21.10.6, 1.9 
 West1.71.3, 2.11  
Immigrant background    0.924
 Yes1.61.0, 2.61.00.6, 1.9 
 No1.81.4, 2.21  
Social status    0.495
 Low1.51.0, 2.20.90.5, 1.5 
 Intermediate1.91.5, 2.51.20.7, 1.8 
 High1.71.1, 2.41  
Number of drugs used    <0.001
 11.000.8, 1.31  
 21.81.2, 2.71.81.1, 2.8 
 33.42.2, 5.13.52.1, 5.9 
 4+7.24.7, 10.26.74.1, 11.0 
Parent-rated children's health status    <0.001
 Very good/good1.51.2, 1.81  
 Moderate4.43.0, 6.62.21.4, 3.5 
 Bad/very bad13.84.8, 33.98.72.6, 28.7 

A total of 14 588 medicines were recorded in the study sample; 157 medicines (1.1%) were reportedly involved in the occurrence of perceived ADRs (Table 3). A significantly lower proportion was found among the non-prescription medicines, medicines obtained from other sources, and preparations used for a short term (<1 week) or irregularly. By contrast, a significantly higher proportion was found in prescription medicines, medicines used for a medium period (from 1 week to 12 months) and in medicines that were used regularly.

Table 3. 
Perceived ADRs among children in Germany by origin of drugs, duration and frequency of use. German Health Interview and Examination Survey for Children and Adolescents (KiGGS), 2003–06
 Number of drugsSuspected drugsP value
n (%)nProportion % (95% CI)
  • *

    The amounts in each category may not add up to the total because of missing data. P value: chi-square test for the difference within the subgroup.

Origin of the medicine   <0.001
 Prescription8 565 (59.2)1351.6 (1.3, 1.9) 
 Over the counter (OTC)3 579 (24.7)140.4 (0.2, 0.7) 
 Other sources2 042 (14.1)80.4 (0.2, 0.8) 
 Total*14 470 (100)1571.1 (0.9, 1.3) 
Duration of use   <0.001
 <1 week7 984 (55.5)570.7 (0.6, 0.9) 
 1–4 weeks2 099 (14.6)361.7 (1.2, 1.4) 
 1–12 months2 431 (16.9)391.6 (1.2, 2.2) 
 ≥1 year1 869 (13.0)231.2 (0.8, 1.9) 
 Total*14 383 (100)1551.0 (0.9, 1.3) 
Frequency of use   0.019
 Regular9 588 (65.9)1111.2 (1.0, 1.4) 
 Irregular2 518 (17.3)140.6 (0.3, 0.9) 
 Other frequency2 441 (16.8)311.3 (0.9, 1.8) 
 Total*14 547 (100)1561.1 (0.9, 1.3) 

Medicines from the classes N00, J00, R00, G00, D00 and A00 (representing 82% of the total medicines) covered the vast majority of suspected drugs (Table 4). The proportion of suspected drugs in each of these medication classes varied from 0.4% for A00 to 5.7% for J00. The same was true for the medications in the subgroups. The highest proportion was recorded in psychoanaleptics (12.1%, particularly methylphenidate 11.9%), followed by antibiotics 6.0% and contraceptives 2.8%. Although P00 (antiparasitic products, insecticides and repellents) showed the highest proportion of 10%, the number of medicines in this class was very low, being only 20 (Table 4).

Table 4. 
Perceived ADRs among children in Germany by medication classes. German Health Interview and Examination Survey for Children and Adolescents (KiGGS), 2003–06
ATC-codesNumber of drugs usedSuspected drugsProportion
nn%95% CI
  1. A00, Alimentary system and metabolism; B00, Blood and blood-forming organs; C00, Cardiovascular system; D00, Dermatologicals; G00, Genito-urinary system and sex hormones; G03A, Oral contraceptives; H00, Systemic hormonal preparations excluding sex hormones and insulin;J00, Anti-infectives for systemic use; J01, Antibiotics;L00, Antineoplastic and immunmodulating agents; M00, Musculoskeletal system; N00, Nervous system; N06, Psychoanaleptics; N06BA04, Methylphenidate (Ritalin); P00, Antiparasitic products, insecticides and repellents; R00, Respiratory system; R05, Cough and cold medications; S00, Sensory organs; V00, Various; Z00, Homoeopathics.

N001 289372.872.1, 4.0
 -N061902312.18.2, 17.6
 -N06BA041601911.97.7, 17.9
J00475275.73.9, 8.2
 -J01434266.04.1, 8.7
R004 412310.70.5, 1.0
 -R051 864140.80.4, 1.3
G00507163.21.9, 5.1
 -G03A429122.81.6, 4.9
D001 956140.70.4, 1.2
A003 310120.40.2, 0.6
B008633.50.8, 10.3
L009033.30.8, 9.9
H0029831.00.2, 3.1
P0020210.01.8, 31.6
V0023420.90.1, 3.3
S0023620.90.1, 3.3
M0060220.30.0, 1.3
Z0095120.20.0, 0.8
C008211.20, 7.4
Missing400
Total14 5881571.11.0, 1.3

Most perceived ADRs were recorded in drugs acting on the nervous system (N00), followed by systemic anti-infectives (J00), drugs acting on the respiratory system (R00), and drugs acting on the genitourinary system and sex hormones (G00) (Table 5). According to MedDRA terminology, 40.4% of all perceived ADRs related to gastrointestinal disorders such as nausea, vomiting and diarrhoea, while 16.2% were skin and subcutaneous tissue disorders such as rashes and dry skin.

Table 5. 
Perceived ADRs among children in Germany by ATC classes and MedDRA SOC. German Health Interview and Examination Survey for Children and Adolescents (KiGGS), 2003–06
ATC-codesMedDRA-SOC
123456789101112Total
n%n%n%n%n%n%n%n%n%n%n%n%n%
  1. MedDRA SOC: 1 General disorders and administration site conditions; 2 Skin and subcutaneous tissue disorders; 3 Respiratory, thoracic and mediastinal disorders; 4 Reproductive system and breast disorders; 5 Gastrointestinal disorders; 6 Immune system disorders; 7 Nervous system disorders; 8 Infections and infestations; 9 Psychiatric disorders; 10 Metabolism and nutrition disorders; 11 Others; 12 Not classified.

  2. ATC Codes: A00, Alimentary system and metabolism; B00, Blood and blood-forming organs; C00, Cardiovascular system; D00, Dermatologicals; G00, Genito-urinary system and sex hormones; H00, Systemic hormonal preparations excluding sex hormones and insulin; J00, Anti-infectives for systemic use; L00, Antineoplastic and immunmodulating agents; M00, Musculoskeletal system; N00, Nervous system; P00, Antiparasitic products, insecticides and repellents; R00, Respiratory system; S00, Sensory organs; V00, Various; Z00, Homoeopathics.

  3. ATC, Anatomical-Therapeutic-Chemical; MedDRA, Medical Dictionary for Regulatory Activities; SOC, System Organ Class.

A00  10.5    105.1  10.5          126.1
B00        42.0              42.0
C00        10.5              10.5
D0010.5168.1                    178.6
G00  10.5  84.073.5  21.0  31.542.0    2512.6
H00  10.5        10.5        10.531.5
J0031.521.0  21.02613.110.510.5      21.0  3718.7
L00        31.5  10.5          42.0
M00  10.5    21.0              31.5
N00105.121.010.5  115.6  63.0  73.5126.121.0  5125.8
P00        31.5              31.5
R0063.063.031.5  126.1  21.010.510.5    10.53216.2
S00  10.5                10.5  21.0
V00        10.510.5            21.0
Z00  10.510.5                  21.0
Total2010.13216.252.5105.18040.421.0147.110.5115.6168.152.521.0198100.0

Discussion

In a population-representative sample of children aged 0 to 17 years, we found that 0.9% (1.7% of children who had used medications in the last 7 days) reportedly experienced an ADR. Similar findings have been reported in previous pharmacovigilance studies conducted among children in Germany and other European countries.

A 3 month German ADR monitoring project estimated the incidence of mild to moderate ADRs as about 1% in children who had been given medications [21]. An Italian active ADR monitoring program reported an ADR incidence rate of 15.1 per 1000 children [3]. A prospective 1 week monitoring study in France found that 1.53% of children consulted a regional hospital and 0.67% a private paediatrician because of ADRs [10]. Another French prospective pharmacovigilance survey of drug prescribing by office-based paediatricians reported an ADR incidence rate of 1.41% [32]. The results of two meta-analysis studies estimated that the ADR incidence rate was 1.0 (95% CI 0.3, 1.7) for outpatient children [16] and 1.46% (95% CI 0.7, 3.03) for children undergoing outpatient care [15]. Our finding on the prevalence of perceived ADRs was well below the 95% CIs of the two studies [15, 16]. However, the children in our study were non-institutionalized and sampled from the general child population; most of them were in good/very good health. Since most outpatient children were being treated for a specific condition and more likely to be given medications, there was a greater possibility of ADRs. This may be one of the reasons why the prevalence rates of perceived ADRs in the total sample and among drug users were close to the lower and upper 95% CIs, respectively, of the two meta-analysis studies [15, 16].

In the Italian ADR monitoring programme, the highest ADR incidence rate was found in the youngest infant group, the lowest among children aged 8 to 14 years [3]. In a retrospective study conducted in Singapore, in which age and sex were independent ADR risk factors among hospitalized children, ADRs were more likely to occur at higher ages and among boys [33]. Data from the Sweden Medical Products Agency on the mandatory reporting of ADRs also showed a higher ADR frequency among boys than among girls over the period from 1987 to 2001, particularly among children under 5 years of age [34]. Our study, however, found no difference between boys and girls, but a significant difference between age groups, which largely showed a J-shaped curve, the highest rate being found in the 14–17 year age group. This may be due to the fact that many ADRs reported in our study related to oral contraceptives and Ritalin, which were used mainly by older adolescents.

Polypharmacy was a well-established ADR risk factor in both adult and child patients [15, 35]. As the number of concomitantly used drugs increases, so does the likelihood of drug–drug interactions, leading to a greater possibility of ADRs. We found a significant correlation between perceived ADRs and the number of concomitantly used drugs. This finding has been consistently observed previously in a prospective study of spontaneous ADR reporting among hospitalized children in Spain [6], in an ADR monitoring study of outpatient infant and preschool children in the Zagreb region [11] and in a retrospective study in Singapore [33]. Self-rated health status was an important indicator of morbidity; a poor state of health may imply a greater possibility of medication use [36] and therefore be a predictive risk factor of ADRs.

In our study gastrointestinal disorders such as nausea, vomiting and diarrhoea accounted for 40% of perceived ADRs, followed by skin/subcutaneous tissue disorders and general disorders/administration site conditions. These ADRs accounted for two thirds of the total number of perceived ADRs. One reason for such a clustering may be that the ADRs in our study were reported by the children's parents or the children themselves. It may be easier for them, as non-professionals, to perceive such ADRs. Our study sample consisted of non-institutionalized children in outpatient care; serious ADRs needing hospitalization may therefore have been excluded in advance. In addition, ADRs such as hepatotoxicity and pathological laboratory abnormalities induced by drug use were less likely to be reported in such a survey. Though we did not assess the severity of perceived ADRs, we presumed that most of the patients-perceived ADRs were mild to moderate and possibly at the lower limits of the range usually reported. Intensified ADR monitoring may identify a higher number of ADRs and more severe ADRs. However, this would require personnel and involve the cost of medical examinations [20].

Perceived ADRs were reported most frequently in relation to drugs acting on the nervous system, systemic anti-infectives, drugs acting on the respiratory system, genito-urinary and sex hormones, dermatologicals, and drugs acting on alimentary system and metabolism. Medicines from these classes were also the paediatric medicines that accounted for the vast majority of all medicines used. The prevalence rates of perceived ADRs varied between these classes. The lowest rate was found in drugs acting on the alimentary system and metabolism; in our study most of the medicines in this class were hydrosoluble vitamins and mineral supplements. In the class of drugs acting on the nervous system, suspected drugs were mainly those of the psychoanaleptics subgroup (methylphenidate in particular). Analgesics aspirin and paracetamol were reported less often, even though they accounted for a substantial proportion of the medicines in this class (data not shown). As for drugs acting on the respiratory system, perceived ADRs were mostly recorded in the subgroup of cough and cold medicines, the safety of which was recently reviewed by the UK Medicines and Healthcare products Regulatory Agency (MHRA), which called for their rational use and intensive monitoring [37]. 5.7% of all systemic anti-infectives were involved in the occurrence of perceived ADRs (mainly the antibiotics subgroup). Similar findings were also reported previously in both prospective studies [6] and the analysis of data from ADR spontaneous reporting [38], as well as in the pilot study on ADR monitoring among children by community pharmacies in Aberdeen, UK [39].

Most medicines that were used regularly were prescription medicines, which, as found in our study, were more likely to cause an ADR than OTC medicines. Interestingly, we found that medicines that were used for a medium period of time were more likely to cause an ADR. Repeated use of medicines for a medium period (from 1 week to 12 months) meant rechallenges and dechallenges, so it was easy for parents/adolescents to perceive any ADR. Long-term use of medicines over 1 year, however, may induce tolerance. In addition, patients may choose not to report what they may think is ‘normal’ when it occurs repeatedly. As a matter of fact, the characteristics of perceived ADRs relating to the suspected medicines and symptoms found in our study were very similar to those found by means of the yellow card system in Spain [38], among outpatient children in the Netherlands [40] and in the US [41], and in the regional ADR monitoring study conducted in Brandenburg, Germany [21]. A recent review revealed that the quality of patient ADR reports seemed not to differ very much from that of reports by health professionals [42].

A major strength of our study is that we used population-representative data to collect and analyze the perceived ADRs among non-institutionalized children. The results provide a clear picture of the frequency and spectrum of perceived ADRs that were not necessarily related to medical treatment in hospitals or outpatient facilities. There are several limitations, however. First, the ADRs reported in this study were perceived by children's parents or the patients themselves. It may be difficult for them to distinguish between an ADR and a symptom of the disease being treated, resulting in over- or under-reporting. Second, although all perceived ADRs were documented and confirmed by medical professionals with medical knowledge, a standardized causality and severity assessment was not carried out. Nevertheless, since parents may understand their own children better and can observe their health status more closely and perceive any changes after the intake of medicines, parental reporting of perceived ADRs can be regarded as an effective method in paediatric pharmacovigilance [42, 43]. Finally, drug use was measured in the past 7 days before the medical interview. This method is less likely to capture ADRs following long-term medicine use.

In conclusion, the perceived ADRs in the generally healthy child population were clustered with gastrointestinal disorders and skin and subcutaneous tissue disorders. They appeared to be mild and at the lower limits of the range usually reported. This, however, should be interpreted in conjunction with methodological limitations. The results of the KiGGS survey on medicine use provided a significant contribution to the quantification of perceived ADRs in the general child population. A comparison of our findings with those of national and international studies suggests that health surveys covering a diverse range of drug use may be suitable for computing perceived ADR prevalence and identifying risk factors and should be taken into account together with other pharmacovigilance systems. This applies in particular to population-representative statements on drug use and potential hazards.

Competing interests

There are no competing interests to declare.

Acknowledgments

This study received financial support from the Federal Institute for Drugs and Medical Devices (Bundesinstitut für Arzneimittel und Medizinprodukte, BfARM). The German Health Interview and Examination Survey for Children and Adolescents (KiGGS) was funded by the Federal Ministry of Health and the Federal Ministry of Education and Research.

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