Drug-Related Problems of Children With Chronic Diseases in a Chinese Primary Health Care Institution: A Cross-Sectional Study

Introduction: Drug-related problems (DRPs) refer to events or circumstances involving drug therapy that actually or potentially interfere with desired health outcomes. DRPs might be severe for children with chronic diseases managed at primary health care institutions, but the relevant research is scarce. Objective: In this cross-sectional study, we aimed to explore the prevalence, types, causes, and influencing factors of DRPs in children with chronic diseases in a Chinese primary health care institution. Methods: We recruited children with chronic diseases who visited the pediatric outpatient department in a primary health care institution from July 1 to 12 October 2021. Clinical pharmacists identified DRPs through medication therapy reviews, classified the types and causes of DRPs, and distinguished the manifested DRPs that affected the outcome and potential DRPs that were going to affect the outcome. Results: A total of 188 children with chronic diseases was included, and 584 DRPs were identified in 89.89% of participants. The most common type of DRPs was “treatment effectiveness” (a manifested problem or potential problem with the effect of the pharmacotherapy; 83.56%), of which 67.29% were potential DRPs. The second common type was “treatment safety” (patient suffers or could suffer from an adverse drug event; 14.21%), of which 89.16% were potential DRPs. The most common cause of DRPs was related to the process of use (42.24%), such as “patient uses/takes less drug than prescribed or does not take the drug at all,” “patient stores drug inappropriately,” and “patient administers/uses the drug in a wrong way.” The second common cause was related to the process of dispensing (29.83%), such as “necessary information not provided or incorrect advice provided” and “prescribed drug is not available.” The third common cause was related to the process of prescribing (26.21%), such as “drug dose is too low” and “no or incomplete drug treatment despite an existing indication.” The number of combined medications was an influencing factor for the frequency of DRPs (p < 0.05). Conclusion: This cross-sectional study showed that the current situation regarding DRPs among children with chronic diseases managed in the primary health care institution was serious. The types of DRPs were mainly related to treatment effectiveness, and improper usage of medications was one of the main causes of DRPs. The number of combined drugs was the influencing factor for the frequency of DRPs. In the future, pharmacists should consider formulating pharmaceutical intervention strategies for this specific group according to the characteristics of DRPs.


INTRODUCTION
The Pharmaceutical Care Network Europe Association (PCNE) defined "drug-related problems" (DRPs) as events or circumstances involving drug therapy that actually or potentially interfere with desired health outcomes (Pharmaceutical Care Network Europe Association 2020). DRPs not only focus on the effectiveness and safety of drug therapy but also on the rationality and cost of drug therapy, involving the whole process of prescribing, dispensing, and medication use (Leape et al., 1991;Edwards and Aronson 2000;Morimoto et al., 2004).
As a special population, children may have a higher prevalence of DRPs than adults. A cohort study has shown that the prevalence of potentially harmful medication errors in children was 3 times higher than that in adults (Kaushal et al., 2008). A systematic review has also shown that the prevalence of medication errors was higher in children (53-67%) than in adults (12-59%) (Mira et al., 2015). Studies from Lebanon, Israel, and Australia have shown that pediatric hospital admissions due to DRPs represented 7.9-17.7% (Yosselson-Superstine and Weiss 1982;Easton et al., 1998;Major et al., 1998). Studies from Australia have shown that 4.3% of all hospitalizations were associated with DRPs in children, with an associated medical cost of approximately AUD $181,878.2 (Easton-Carter et al., 2003), while DRPs resulted in a 3.3% emergency visit rate for children, with an associated medical cost of approximately AUD $137,088.74 (Easton et al., 2004).
The prevalence of chronic diseases in children has increased since the 1980s and might further increase (van der Lee et al., 2007;Van Cleave et al., 2010). Chronic diseases usually have a long duration, are prone to relapse, and their therapeutic regimens are relatively complex, which might increase the risk of DRPs. A study using home visits has found that 22% of children with chronic diseases had medication errors when taking medicine at home, which caused manifested or potential harm to children (Walsh et al., 2011). Several studies have shown that the adherence of children and adolescents was usually less than 50% (Quittner et al., 2008). Also, children with complex chronic diseases were more likely to visit emergency departments due to adverse drug events (odds ratio [OR] = 4.76, 95% confidence interval [CI]: 4.45-5.10) (Feinstein et al., 2014). Therefore, compared to other pediatric patients, the risk of DRPs in children with chronic diseases might be increased.
The function of primary health care institutions (PHCIs) is mainly to provide primary public health services, including management and rehabilitation services for common chronic diseases (National Health Commission Of China 2020). In 1978, the international Conference on Primary Health Care set out the goal of health for all (International Conference on Primary Health Care 1978). However, existing studies have shown that PHCIs have some imperfections, such as poor medical quality, underdeveloped pharmaceutical care, and patients' absent awareness of diseases and medication (Sylvia et al., 2015;Su et al., 2017;Adisa and Omitogun 2019;Khalil and Huang 2020;Li et al., 2020). A systematic review has shown that the median (interquartile range, IQR) of DRPs prevalence among patients in PHCIs was 70.04% (59%), and the median (IQR) of DRPs frequency per patient was 3.4 (2.8) (Ni et al., 2021). Hence, compared to other children with chronic disease, the risk of DRPs among children with chronic disease in PHCIs might be further increased. However, per our systematic retrieval, in primary health care institutions, there are only two studies on the occurrence of DRPs in children without chronic diseases. Therefore, this cross-sectional study aimed to investigate the characteristics of DRPs among children with chronic disease in a PHCI, including the prevalence, types, causes, and influencing factors of DRPs. The results of this study might provide theoretical evidence to formulate pharmaceutical intervention strategies in the future to ensure the effectiveness and medications safety for children with chronic diseases in PHCIs.

Study Design
We conducted a prospective cross-sectional study.

Study Subjects
Study subjects comprised patients visiting the pediatric outpatient clinic of the Xihanggang Community Health Service Center from July 1 to 12 October 2021. Inclusion criteria were as follows: 1) patients younger than 18 years; 2) patients with at least one diagnosed chronic disease; and 3) patients who were prescribed at least 1 medicine for chronic diseases. Chronic diseases in children are defined in these terms (Mokkink et al., 2008): 1) the disease is not (yet) curable or is highly resistant to treatment, and 2) the disease has been present for longer than 3 months, it will probably last longer than 3 months, or it has occurred 3 times or more during the past year and will probably reoccur. Exclusion criteria were as follows: 1) patients with incomplete clinical data without which statistical analysis cannot be performed; and 2) a refusal to sign the informed consent by patients or their guardian.

Identification of Drug-related problems
Through the children's health management project of West China Women and Children's Alliance, the Xihanggang University led the graduate students majoring in clinical pharmacy to identify, classify, and double-check DRPs, but they did not intervene in physicians, pharmacists, and patients' behaviors in this PHCI. The identification of DRPs mainly was based on package inserts of drugs, authoritative guidelines, the latest editions of textbooks, and approved and documented off-label usage in the hospital. The researchers also used certain software and websites to identify DRPs, such as UpToDate, MCDEX, and Micromedex. At the first visit, for children who met the inclusion criteria and signed the informed consent, the researchers collected the basic information about children, caregivers, and doctors (such as the sex, age, quality of life, growth and development of children; sex, age, and education level of caregivers; and the working years, professional title, and education level of doctors), data on children's diseases and medications, including prescription and over-thecounter drugs, through interviews and medical records. In the prescribing process, the researchers compiled a comprehensive list of medications for each patient to identify DRPs in drug selection, form, dosage, and duration. The researchers identified DRPs of the dispensing process by observing the patients' visits to their doctors and picking up of their medicines at the pharmacy and conducting follow-ups on the eighth day after their first visit. In the dispensing process, the researchers mainly reviewed whether there were shortages of prescribed drugs, inadequate or incorrect medication information, or wrong drug or strength provision. In the use process, the researchers created a comprehensive list of medication therapy reviews for each patient; thus, possible DRPs could be reviewed item by item during the follow-ups. We formulated a unified follow-up record table in which the questions were designed based on the Pharmaceutical Care Network Europe (PCNE)-DRP classification system v9.1 to standardize the follow-ups (Pharmaceutical Care Network Europe Association 2020).

Outcomes
The following outcomes were investigated: 1) the prevalence of DRPs; 2) the types and causes of DRPs; 3) the influencing factors related to the frequency of DRPs. Regarding the types and causes of DRPs, the primary domain and subdomain types and causes of DRPs were classified according to the PCNE-DRP classification system v. 9.1. Also, the manifested DRPs (DRPs that affected the outcome) or potential DRPs (DRPs that were going to affect the outcome) were classified.

Sample Size
The sample size was calculated with the primary outcome "the prevalence of DRPs." and the calculation formula was n ( Z1−a/2 δ ) 2 × p × (1 − p) (Newcombe 1998;Fleiss 2003), where a = 0.05, Z 1-α/2 = 1.96. P is the expected prevalence of DRPs. According to the results of a systematic review (Ni et al., 2021), the prevalence of DRPs in PHCIs has been about 70.04%, and the allowable error δ = 0.07; therefore, the calculated n is 163. According to the preliminary investigation experience, the rate of loss to follow-ups was 15%; thus, 192 children should be recruited.

Data Statistics
Excel 2020 was used to organize the data, and SPSS 24.0 was used for statistical analysis. The continuous data were described by mean ± standard deviation (X ± s), and the categorical variables were described by frequency and percent of the total sample (%). Missing values were filled in based on central trends among the samples; for example, numerical variables were filled with the mean or median, and fractional variables were filled with the mode (Austin et al., 2021). Poisson regression analysis of potential factors that may affect the frequency of DRPs was performed. The outcome measure

Ethical Approval
This study obtained the approval of the Medical Ethics Committee of the West China Second University Hospital of Sichuan University before the formal implementation (identifier: MR 2021 ERA No.136).

Study Registration
This study was registered on the website of the Chinese Clinical Trial Registry (identifier: ChiCTR2100048235).

RESULTS
During the study period, a total of 234 children met the inclusion criteria, while 46 children among them met the exclusion criteria (26 children or their primary caregivers refused to sign informed consent forms, 13 children's medical records were missing critical information, 6 children were lost to follow-up, and 1 children visited the doctor repeatedly during the observation period). Finally, 188 children were included in the analysis.

Basic Characteristics
Of all participants, 52.66% (n = 99) were males, 121 children (64.36%) were aged 3-6 years, and 100 children (53.19%) were in kindergarten (n = 100, 53.19%). Most of participants had normal growth and development (n = 138, 73.40%), and quality of life score of ≥95 (n = 167, 88.83%). A total of 49.47% of children visited the doctor for the first time due to chronic disease. The participants' chronic diseases were mostly respiratory (n = 170, 90.43%), and most of them were complicated with two or more diseases (n = 119, 63.30%) and took two or more drugs simultaneously (n = 163, 86.70%). Furthermore, most participants lived in urban areas (n = 176, 93.62%), and most of the medical expenses were paid at their own expense (n = 183, 97.34%).
The detailed basic information on the participants, primary caregivers, and receiving doctors is shown in Table 1.

Occurrence of Drug-Related Problems
Among 188 children included in the analysis, there were 584 DRPs, with an average of 3.11 ± 2.19 DRPs. A total of 169 children had at least 1 DRP, with a DRP prevalence of 89.89%. The frequency distribution of DRPs is shown in Figure 1.

Poisson Regression of Potential Factors Associated With the Frequency of Drug-Related Problems
Poisson regression of factors that may influence the frequency of detected DRPs is shown in Table 4. The goodness-of-fit Chi squared test showed that the regression model fits reasonably well (deviance divided by degrees of freedom of 1.258). There was a significant 36.9% increase in the frequency of DRPs detected for each additional medicine added to a patient's treatment regimen.

Findings of this Study
In this study, we investigated the occurrence, types, causes, and influencing factors of DRPs in children with chronic diseases in a PHCI. The results showed that the prevalence of DRPs in children with chronic disease in the PHCI was 89.89%, with an average frequency of 3.11 ± 2.19 DRPs. Compared with the results of the systematic review of patients in PHCIs mentioned earlier (Ni et al., 2021), children with chronic disease, as a special population in PHCIs, might have a more difficult situation regarding DRPs, requiring more attention from pharmacists. Similarly, the prevalence of DRPs in children in non-PHCIs has ranged from 21 to 51.2% (Birarra et al., 2017;Rashed et al., 2013;Rashed et al., 2012;Easton-Carter et al., 2003), which might be not as bad as that in PHCIs. In this study, treatment effectiveness was the most common type of DRPs, mainly characterized by a poor treatment effect. Treatment safety was the second most common type of DRPs, including manifested or potential adverse drug events. The process of use was the main cause of DRPs in this study. In pediatric patients, their use of medications is greatly influenced by their primary caregivers (Solanki et al., 2017;Wang et al., 2020). From the basic characteristics of primary caregivers in this study, nearly half of primary caregivers' education levels was high school or below, with poor knowledge of the chronic diseases and medications, which might have aggravated the occurrence of DRPs. The process of dispensing was also one of the important causes of DRPs, mainly containing inadequate medication information provided by pharmacists and drug shortages. Considering these causes, continuing education for pharmacists in PHCIs will be important to reduce the occurrence of DRPs in the future. The problem of drug shortages in PHCIs is very common (Bawontuo et al., 2021). Drug shortage not only restricts patients from choosing the most appropriate treatment regimes and affects their treatment effect but also induces patients to purchase medications from private pharmacies by themselves, which might provide hidden risks to medication safety. Therefore, it is urgent to improve the accessibility of clinically essential medications in PHCIs. Although the diseases of patients in PHCIs are usually relatively common and simple, the process of prescription was still one of the common causes of DRPs in our research, probably because of the limited qualification level of receiving doctors. It is necessary to create a medical alliance or cooperation; therefore, doctors in PHCIs will be led by clinically experienced doctors in the upper-level hospitals to improve their diagnosis and treatment quality. This study also explored the influencing factors. Similar to several other studies on pediatric patients (Birarra et al., 2017;Rashed et al., 2012;Easton-Carter et al., 2003), the number of combined medications was an independent factor associated with the occurrence of DRPs, possibly because more complicated therapy regimen leads to more adverse drug reactions, drugdrug interactions, medication errors, and non-adherence.

Innovation of this Research
One of the responsibilities of PHCIs is to undertake the long-term management of patients with common chronic diseases. Through the previous systematic retrieval, we found that research on the DRPs in children with chronic diseases in PHCIs was lacking. Therefore, this was the first study to focus on this special population to explore the occurrence, types, causes, and influence factors of the DRPs, which would help formulate pharmaceutical intervention strategies to reduce the occurrence of DRPs.

Limitations of this Research
Firstly, this study is a single-center cross-sectional survey; thus, the results may lack universality. However, the PHCI selected as the research site is a community hospital designated by 16 communities, and in 2020, the number of pediatric emergency/ outpatient visits reached more than 120,000. Therefore, the sample of children is representative to a certain extent. Secondly, since this study is cross-sectional, the investigation of the influencing factors of DRPs is only a preliminary exploration, and the results still need to be verified by a large sample cohort study.

Future Research Direction
Firstly, to solve the defects of this study, large-sample multicenter studies can be conducted in the future to further explore the characteristics of DRPs in children with chronic diseases in PHCIs, which is conducive to the development of the DRPs risk assessment model. Secondly, the method to provide a pharmaceutical intervention aimed at DRPs in children with chronic disease patients in PHCIs will be an important direction for the next step of research to ensure that these children can obtain high-quality chronic disease management and rehabilitation services even if they are in PHCIs.

CONCLUSION
This cross-sectional study investigated the DRPs in children with chronic diseases in a PHCI and found that the prevalence of DRPs and the frequency of DRPs per capita were significantly high. The types of DRPs mainly involved treatment effectiveness, and improper usage of medications was one of the main causes of DRPs. The number of combined drugs was the influencing factor for the frequency of DRPs. In the future, it is urgent to formulate DRPs pharmaceutical intervention strategies for children with Frontiers in Pharmacology | www.frontiersin.org July 2022 | Volume 13 | Article 874948 chronic diseases in PHCIs according to the common types, causes, and influencing factors of DRPs in this population.

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding authors.

ETHICS STATEMENT
The studies involving human participants were reviewed and approved by This study obtained the approval of the Medical Ethics Committee of the West China Second University Hospital of Sichuan University before the formal implementation (identifier: MR 2021 ERA No.136). Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.

AUTHOR CONTRIBUTIONS
XN, CY and LZ designed the study, collected the data, performed the analysis, and interpreted the data. HL and SD designed the study and interpreted the data. DL, JW, ZJ, YL and GC designed the study. XN and CY wrote this manuscript. LZ checked this manuscript.

FUNDING
This study was supported by the Special Fund of Science and Technology Cooperation between Sichuan University and Zigong City (Grant number: 2020CDZG-25) and the Science and Technology Project of Sichuan Province (Grant number: 2020YFS0035).