Adverse Drug Reactions of Spontaneous Reports in Shanghai Pediatric Population
Malcolm Gracie Semple, Editor
Abstract
Background
Knowledge
of drug safety in the pediatric population of China is limited. This
study was designed to evaluate ADRs in children reported to the
spontaneous reporting system (SRS) of Shanghai in 2009.
Methodology and Principal Findings
Crude
ADR reports submitted to Shanghai SRS in 2009 for individuals aged from
birth to 17 years (including 17 years) were included. Data were
analyzed with respect to age, gender, category of ADR (System Organ
Class [SOC]), the severity of reports and type of reporter.
Results
A
male overrepresentation was observed regarding the total number of
reports. The most frequently reported group of drugs were vaccines
(42.15%). Skin rash and fever were the commonest symptoms reported in
the total pediatric dataset. The proportion of children that suffered
from a serious ADR was 2.16% and that for drug related deaths was 0.34%.
And we found that the multiple drug exposure experienced a high
proportion of serious ADRs compared with the single drug use (χ2
=15.99,
P<0.0001). Sixty-five percent of ADRs were for children less than 6
years of age. And more than half of reports were from doctors.
=15.99,
P<0.0001). Sixty-five percent of ADRs were for children less than 6
years of age. And more than half of reports were from doctors.Conclusions
In
our study, consumers were more likely to report new ADRs though they
appear to contribute a relatively small percentage of total reports. We
propose that patients would take an active role in reporting ADRs. More
researches are needed in order to achieve better understanding the
characteristics of ADRs in pediatric population of China.
Introduction
Adverse
drug reaction (ADRs) are defined as events related to a medication that
are noxious, unintended and occur at normal doses used in humans for
prophylaxis, diagnosis or therapy of disease, or for modification of
physiological function by World Health Organization (WHO). This
definition excludes accidental or deliberate excessive dosage or
maladministration [1]. ADRs are one of the leading causes of morbidity and mortality in many countries [2], [3].
In the UK a major study of hospital patients found that up to 6.5% of
admissions were due to ADRs, and 2.3% of those patients died after
admission in hospital [3].
A systematic review have shown that the incidence rates for ADRs
causing hospital admission ranged from 0.4% to 10.3% of all children
(pooled estimate of 2.9% (2.6%, 3.1%)) and from 0.6% to 16.8% of all
children exposed to a drug during hospital stay [4].
In addition, ADRs constitute a major cost factor in public health care.
Almost 5% of hospital admissions in the pediatric setting and 10% of
hospitalized pediatric patients are presumably due to drug related
problems [5], [6], [7]. A large variety of drugs are used in children now [8],
although many of them have been marketed without trials regarding the
efficacy and safety in this population. Little attention has been paid
to the safety of medicines in children [9], [10].
The ADRs resulting from the administration of a drug that has not been
test and proven in the pediatric population through proper clinical
trials may therefore lead to significant morbidity and death among
children [11], [12].
In a meta-analysis of 17 prospective studies performed in the United
States and Europe, the overall incidence of ADRs in hospitalized
children was estimated to be 9.53% (95% CI 6.8 to 12.6) and in pediatric
outpatients 1.46% (95% CI 0.7 to 3.3), and serious reactions accounted
for 12% of the total number of ADRs. The contribution of ADRs to the
hospitalization of children was estimated to be 2.09% (95% CI 1.02 to
3.77) [7].
Knowledge of drug safety is limited in the pediatric population,
especially for off-label drugs. Less than half of those specifically
intended for children are operated on the basis of clinical trials which
demonstrate specific features of risk-benefit balance in children [13].
Spontaneous reporting of ADRs has been shown to be an important method
of increasing such knowledge and the method could be considered
particularly important in children since drugs are not routinely test in
the pediatric population [14].
A major function of the spontaneous reporting system is early detection
of signals of new, rare or serious ADRs. The SRS covers a large number
of patients and a wide range of drugs. It is therefore a relatively
cost-effective method for drug safety monitoring [15]. However, few studies were conducted to investigate knowledge of drug safety in Chinese children.
The
Shanghai ADR SRS is a part of China ADR SRS and one of the major goals
of this system is the timely detection of possible new ADRs. There are
12000–16000 ADR reports submitted to the system annually now. Both urban
and rural areas in Shanghai are included in this ADR monitoring scheme,
covering more than 17,000,000 inhabitants. Pharmaceutical manufactures,
healthcare professionals (HCPs), and drug dealers are the main sources
of reports. This scheme is a voluntary reporting system without any
incentive. The monitoring scheme includes not only prescribed
medications, but also over the counter, traditional Chinese remedies,
etc. In this study, we demonstrated the characteristics of suspected
pediatric ADRs reported to the Adverse Drug Reaction Monitoring Center
of Shanghai.
Methods
Data Acquisition
The data was downloaded automatically from the system via http://www.adr.gov.cn,
which was developed by National Adverse Drug Reaction Monitoring Center
of China. We cannot get ADR incidence rates as the true extent of drug
use was unknown, so all the data in the manuscript were frequency of
reports. Personal information was excluded in our dataset, and
individual identify codes in SRS were marked with random numbers. The
study was approved by the Ethics Committee of the Second Military
Medical University, Shanghai, China. The ethics committee waived the
need of informed consent for the study because of its retrospective
nature and data were analyzed anonymously.
Data Coding
The
ADR names were coded according to MedDRA (Medical Dictionary for
Regulatory Activities, version 3.0.2b) terminology at SOC level. In
addition, generic names of drugs were standardized and coded according
to the catalogue of generic names for common prescription drugs issued
by the Ministry of Health of China in 2007. The website http://app1.sfda.gov.cn/datasearch/face3/dir.html and Chinese Pharmacopoeia were also used as materials for our work [16].
We classified each ADR as a general, serious, new general or new
serious reaction based on the Measures for the Reporting and Monitoring
of Adverse Drug Reactions definitions [17].
Serious Adverse Drug Reactions means one of the following harmful
situations caused by taking drugs: 1. Results in death; 2. Results in
cancer, a persistent of significant disability/incapacity; 3. Results in
life threatening; 4. A persistent of injury to organ function; 5.
Results in hospitalization or prolongs an existing inpatient
hospitalization. And new ADRs means adverse reactions that are not
recorded and explained on the drug package insert [17].
Age -specific groups were classified into newborn (0–1 month), infant
(1–23 months), preschool child (2–5 years), child (6–12 years), and
adolescent (13–17 years, including 17 years) [18].
When a suspected ADR is reported more frequently on the combination of
two drugs as compared with the situation where these drugs are used in
the absence of each other, this association might indicate the existence
of a drug-drug interaction (DDI) [19], [20].
By patient reporting we mean a slightly adapted version of the van
Grootheest definition: ‘users of drugs (or their parents or cares)
reporting suspected ADRs directly to a spontaneous reporting system [21].
Data Split
ADR
report may contain one or more drugs and ADRs. In this study, all
drug-event pairs, whether the role of the drug of interest was
considered ‘suspect’ or ‘concomitant’, was included and the calculation
was based on the counts of drug-event pairs in the analysis.
Data Analyses
Categorical
data were compared by Chi-square test, and ranked data by
Cochran-Mantel-Haenszel test. Fisher’s exact test was used when
numerators were small number. Odds ratios (ORs) and 95% confidence
intervals (CIs) between the rates of new ADRs report in different
reporters were calculated using Logistic Regression. Only two-tailed
tests were used. A P-value of 0.05 or less was considered to be
significant and statistical analyses were performed using SAS 9.3
software (SAS Institute, Cary, NC, USA).
Results
A
total of 24292 reports were submitted to Shanghai SRS in 2009, and 3945
reports concerning children 0–17 years (including 17 years) were
retrieved from the system. Of the 3945 reports, 97 were deleted from our
analyses for the following reasons: drug administration was to the
mother (n=1); out-of-range age (n=86); no suspected ADR (n=9); or no suspected drug (n=1).
In total, we examined 3848 reports of suspected pediatric ADRs that
were reported to the Adverse Drug Reaction Monitoring Center of Shanghai
during the study period.
=1); out-of-range age (n=86); no suspected ADR (n=9); or no suspected drug (n=1).
In total, we examined 3848 reports of suspected pediatric ADRs that
were reported to the Adverse Drug Reaction Monitoring Center of Shanghai
during the study period.
The 3848 reports
included 4430 suspected ADRs, with an average of over 10 reports per day
and 1.15 ADRs per child. There were 666 reports, which cited more than
one suspected drug (Table 1). The total number of suspected drugs in pediatric reports was 4619 with a mean number of 1.20 drugs per child.
Number of suspected drugs per ADRs report.
ADRs by Age and Gender
The age- and gender-specific prevalence of ADRs was presented in Fig. 1.
In general, a total of 1790 ADRs (40.41%) and 2640 ADRs (59.59%) were
reported for female and male patients, respectively. More ADRs were
reported for boys than girls except the 0–1 month group. When the data
were assessed in terms of age groups, almost two thirds of ADRs were
reported for children from birth to 5 years of age (65.01%) and 39.46%
concerned children aging 2 months-2 years (Fig. 1). Table 2
showed the number of serious ADRs report of different age groups. The
highest proportion (6.58%) of serious reports was reported for newborn
(0–1 month). A total of 110 serious ADRs were detected in our analysis
with 57 (2.16%) in male patients and 53 (2.96%) in female patients. No
statistically significant difference was observed between boys and girls
by Fisher exact test (P=0.095, two sided test of proportions).
=0.095, two sided test of proportions).
Age- and gender-specific prevalence of ADRs based on the data from Shanghai SRS (2009).
Number of ADRs reports by age and severity category.
ADRs by Vaccines and Non-vaccines
The single most common reaction was exanthema, followed by fever, application site reaction and vomiting (Table 3).
Regarding assessment of drugs, the most frequent reports were related
to vaccine use (1622 reports, 42.15%). When the non-vaccine related
reports were discriminated by excluding children that had been reported
to have a suspected ADR of a vaccination, the total number of children,
whom an ADR had been related to, were then reduced to 2649. Skin
reactions were still most frequently reported. The most commonly
reported drugs among serious reports were antibacterials for systemic
use (32.82%), nervous system (17.56%) and vaccines (13.74%). When drugs
were assessed, cefuroxime (382 reports), azithromycin (340 reports) and
cefotiam (130 reports) were the most frequently reported non-vaccine
related drugs. When assessing the serious ADRs, the frequency of the
non-vaccine related increased to 83.64%, the most frequently reported
non-vaccine drugs were ceftriaxone (9 reports), cefuroxime (7 reports)
and lamotrigine (7 reports).
Ten most frequently reported ADRs.
Multiple Drug Exposure and Serious ADRs
Among the total 3848 ADRs reports, there were 3182 single drug use and 666 multiple drug exposure reports (Table 1).
Two point forty-eight percent (110/4430) of the adverse drug reactions
were reported as serious reactions (48 new serious ADRs). The most
frequently reported serious reactions were Anaphylactic Shock (17
reports, 15.45%) followed by exanthema (11 reports, 10.00%). Fifty-five
(1.73%) and 28 (4.20%) reports in single drug use and multiple drug
exposure, respectively, were registered as serious. It seemed that
multiple drug exposure experienced a high proportion of serious ADRs
compared with the single drug use (χ2=15.99, P<0.0001, two sided test of proportions).
=15.99, P<0.0001, two sided test of proportions).Outcomes of ADRs Reports
Of
all 3848 children, 1176 (30.56%), 2655(69.00%), 4(0.10%), 13(0.34%)
children were reported to be cured, getting better, recovering with
sequelae, and death, respectively (Table 4).
Vaccine accounted for 50% of these cases, and others were central
nervous system agents. The fraction of non-vaccine related reports with
total recovery of the patients was 30.10% (670) and 69.45% (1546) of
children were getting better. Two children had recovered with sequelae
of non-vaccine related reports. There were 13 drug related deaths, with 8
of non-vaccine and 5 vaccine related reports (Table 5).
Outcomes resulting from ADR Reports.
Reported adverse drug reactions (ADRs) in children leading to death.
ADRs by Type of Reporter and Severity
Analysis
of the ADR reports for children received in 2009 of spontaneous
reporting system (SRS) of Shanghai showed that 9.68% (429) of the
suspected ADRs were described as new to the Agency, of which 381 ADRs
were general and 48 ADRs were serious. There were 52.03% (2002 reports),
24.27% (934 reports) and 15.46% (595 reports) of reports from
physicians, pharmacists and other HCPs, respectively. For the total 3848
reports, Spontaneous reports from consumers (like patients themselves
or their parents) appear to contribute a relatively small percentage of
total reports (2.52%, 97 reports). Nearly 5.72% (220) of reporters did
not give their occupations. The difference on distributions of severity
between different reporters was not statistically significant (χ2CMH=3.09, P=0.377). However, it was concluded that the sources of reports might have a difference between new and traditional ADRs (χ2CMH=22.45, P<0.0001). When compared with reports from other HCPs, consumers were more likely to report new ADRs (OR=5.06, 95% CI 1.84 to 13.94, Table 6).
=3.09, P=0.377). However, it was concluded that the sources of reports might have a difference between new and traditional ADRs (χ2CMH=22.45, P<0.0001). When compared with reports from other HCPs, consumers were more likely to report new ADRs (OR=5.06, 95% CI 1.84 to 13.94, Table 6).
The Logistic regression results of different reporters (new or traditional ADRs).
Discussion
In
our study, more than 50% of the ADRs were reported for children from
birth to 5 years of age and almost 40% concerned children between 2
months and 2 years of age. Similar findings were observed in other
studies [22], [23], [24].
Several reasons might contribute to the higher reporting rates in young
children. Firstly, young children are more closely monitored by
physicians and parents. Secondly, a large number of ADRs reported in
this age group may also be due to the widely use of off-label and
unlicensed drugs. Thirdly, Children under 5 were the most common age
group for vaccination. The ADR rate causes by vaccine is much higher
than other drugs, and this may be related to the types and number of
vaccination being used in China, as the types of routine immunization
vaccines in China reach up to 15 kinds, which is much higher than 7
kinds in India and Vietnam, 9 kinds in Thailand and 11 kinds in America,
and most of the vaccines in China are attenuated live vaccines, which
may bring greater potential safety hazard. In addition, previous studies
suggested an increased risk of ADRs for drugs used off-label [25], [26], [27].
This was an important issue regarding children’s health risk. Some
studies in adults demonstrated that female patients were more prone to
develop ADRs than male patients whereas other studies did not [28], [29]. However, a recent pediatric study published in 2011 found that a high proportion of ADR reports among children were for boys [30].
For our research, there seems to be an overrepresentation of male
patients in the ADR reports except the 0–1 month group, which is
consistent with Star’s finding [30].
This may be explained by more attention being paid to ADRs in males
than females in some parts of China or it is an indication that male
patients truly suffer more often from ADRs than female ones. Further
investigations are needed to explain this finding.
In
the present survey, skin reactions were the most frequently reported
ADRs, regardless of including or excluding of vaccine-related reports.
And this is consistent with previous findings [23], [31].
Antibiotics were the most frequently reported pharmacological group of
drugs in previous studies in contrast to our study where vaccines were
most commonly reported [31], [32], [33].
This difference might be due to the occurrence of Type A H1N1 influenza
in China this year, and HCPs or parents paid close attention to
children who got flu vaccine to prevent the influenza. Our study showed
that the majority of the children recovered without sequelae and about
1.04% recovered with sequelae. Vaccines were associated with the highest
number of Children that recovered with sequelae, followed by central
nervous system agents.
With the seemingly constant flow
of new therapeutic agents and new treatment indications for existing
medications, polypharmacy is increasingly common [34], [35].
Drug-drug interactions (DDI) occur when two or more drugs are taken in
combination and one drug influences the effects of another drug. This
may subsequently cause a change in the pharmacodynamic or
pharmacokinetic parameters which may lead to lack of efficacy, or to an
increase in the number of reported adverse drug reactions. The
association between multiple drug exposure and the incidence of ADRs has
been studied, consistently showing an exponentially increased risk with
the increase of the number of drugs taken [36], [37].
When assessing the severity of the reported ADRs, our study confirmed
that multiple drug exposure experienced a high proportion compared with
the single drug use. This finding indicate that in order to minimize the
risk of serious ADRs, HCPs should pay particular attention to children
who are prescribed two drugs or more.
The majority of
ADRs in children were reported by physicians, and equal shares of
serious ADRs were reported by physicians, pharmacists, other HCPs and
consumers. This was different with studies of other countries [22], [33]. Previous founding suggested that patients’ reports were more likely to be serious ADRs than health professional reports [38].
In our study, there were just a small proportion of reports from
patients themselves or their parents, but they might report more new
ADRs. The importance of patient reporting in not only contributing to
‘signal generation’ but also providing data on ‘adverse changes in the
quality of life which can be very important, real and distressing to the
medicine user yet are unlikely to be clear to a prescriber’ was also
highlighted [39].
Patient reporting of suspected ADRs in Shanghai should be encouraged
and their reports should be taken as seriously as reports from other
sources.
There is so little known of
ADRs in the Chinese population, especially for the children. Our study
analyzed information reported to Shanghai ADR database on ADRs in
pediatric population, and in conclusion, a male overrepresentation was
observed regarding the total number of reports, most ADRs were for
children less than 6 years of age, the multiple drug exposure
experienced a high proportion of serious ADRs, and consumers just
contributed a limited number of ADR reports. There were also several
limitations of this study. We just evaluated ADRs in children reported
to the SRS of Shanghai in 2009, in order to achieve better understanding
the characteristics of ADRs in pediatric population more researches are
needed. Substantial underreporting of ADRs is a well-known phenomenon,
which makes it difficult to estimate the ADR incidence for pediatric
patients. In this study, the results suggest that 2.16% of all ADRs were
severe, and 0.34% were fatal. However, the true proportion is likely to
be much lower than this because severe reactions are much more likely
to be reported. We recommend more prospective investigations in
outpatient and inpatient settings to better estimate the type and
incidence of ADRs in Chinese children.
Acknowledgments
We are indebted to the Adverse Drug Reaction Monitoring Center of Shanghai, who contributed the data.
Funding Statement
This
study was funded by three grants from the National Natural Science
Foundation of China (No. 81072388, No. 81202285, No. 81373105), the key
discipline construction of evidence-based public health in Shanghai (No.
12GWZX0602) and Natural Science Foundation of Shanghai (No.
12ZR1453700). The funders had no role in the study design, data
collection and analysis, decision to publish, or preparation of the
manuscript.
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