SYSTEMATIC REVIEW published: 03 February 2022 doi: 10.3389/fphar.2021.777498 Adverse Drug Reactions in Pediatric Oncohematology: A Systematic Review Kristopher Amaro-Hosey 1,2,3, Immaculada Danés 2,3,4* and Antònia Agustí 2,3,4 1 Clinical Pharmacology Service, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain, 2Department of Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona, Barcelona, Spain, 3Vall d’Hebron Research Institute, Barcelona, Spain, 4Clinical Pharmacology Service, Vall d’Hebron University Hospital, Barcelona, Spain Introduction: Adverse drug reactions (ADR) are an important cause of morbidity and mortality in pediatric patients. Due to the disease severity and chemotherapy safety profile, oncologic patients are at higher risk of ADR. However, there is little evidence on pharmacovigilance studies evaluating drug safety in this specific population. Methods: In order to assess the incidence and characteristics of ADR in pediatric patients with oncohematogical diseases and the methodology used in the studies, a systematic review was carried out using both free search and a combination of MeSH terms. Data extraction and critical appraisal were performed independently using a predefined form. Results: Fourteen studies were included, of which eight were prospective and half Edited by: focused in inpatients. Sample size and study duration varied widely. Different methods Eloisa Gitto, of ADR identification were detected, used alone or combined. Causality and severity were University of Messina, Italy assessed frequently, whereas preventability was lacking in most studies. ADR incidence Reviewed by: Ashwin Karanam, varied between 14.4 and 67% in inpatients, and 19.6–68.1% in admissions, mainly in the Pfizer, United States form of hematological, gastrointestinal and skin toxicity. Between 11 and 16.4% ADR were Evelyne Jacqz-Aigrain, considered severe, and preventability ranged from 0 to 74.5%. Institut National de la Santé et de la Recherche Médicale (INSERM), France Conclusion: ADR in oncohematology pediatric patients are frequent. A high variability in *Correspondence: study design and results has been found. The use of methodological standards and Immaculada Danés id@icf.uab.cat preventability assessment should be reinforced in order to allow results comparison between studies and centers, and to detected areas of improvement. Specialty section: This article was submitted to Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_ Obstetric and Pediatric Pharmacology, record.php?RecordID96513, identifier CRD42018096513. a section of the journal Frontiers in Pharmacology Keywords: pharmacovigilance, adverse drug reactions, pediatrics, hematology, oncology, neoplasms, systematic Received: 15 September 2021 review Accepted: 22 December 2021 Published: 03 February 2022 INTRODUCTION Citation: Amaro-Hosey K, Danés I and Agustí A Adverse drug reactions (ADR) have been defined by the World Health Organization (WHO) as “a response (2022) Adverse Drug Reactions in Pediatric Oncohematology: A to a drug which is noxious and unintended, and which occurs at doses normally used in man for the Systematic Review. prophylaxis, diagnosis, or therapy of disease, or for modification of physiological function” (WHO, 1972). Front. Pharmacol. 12:777498. ADR are an important cause of morbidity and mortality in patients of all ages, including pediatric doi: 10.3389/fphar.2021.777498 population, and are considered a public health problem worldwide (Impicciatore et al., 2001; Frontiers in Pharmacology | www.frontiersin.org 1 February 2022 | Volume 12 | Article 777498 Amaro-Hosey et al. Pharmacovigilance Studies in Pediatric Oncohematology Clavenna and Bonati, 2009; Thiesen et al., 2013; Durrieu et al., Systematic Literature Search 2014; Ramos et al., 2021). Children are more susceptible to ADR A systematic literature search was carried out in PubMed from owing to insufficient standardized information, unlicensed and inception to 31st December 2020, both using free search and the off-label use, unavailability of pediatric formulations, and combination of different MeSH terms (“Pediatrics,” physiological peculiarities inherent to age (Ramos et al., 2021). “Neoplasms,” “Hematology,” “Antineoplastic agents,” “Drug- Different systematic reviews and meta-analysis including ADR related side effects and adverse reactions,” “Iatrogenic disease,” observational studies have found an incidence of ADR in “Prevention and control,” “Medical oncology,” and “Primary pediatric inpatients ranging 0.6–16.8%, from 1.8 to 2.09% prevention”). References of the articles assessed for eligibility leading to hospital admission and 1.0–1.46% in outpatient were also reviewed and included if considered relevant. setting (Impicciatore et al., 2001; Clavenna and Bonati, 2009; Smyth et al., 2012). In addition, ADR prevention in outpatients Inclusion and Exclusion Criteria remains a public health and a patient safety challenge (Lombardi Studies that described the incidence and/or characteristics of ADR in et al., 2018). A systematic review including 102 articles assessed pediatric oncohematology patients or in pediatric population with a preventability in only 19, which ranged from 7 to 98%. This high differentiated oncohematology subgroup were included in this variability was explained due to a high heterogeneity in study systematic review. Articles describing infectious outbreaks related designs, methods and settings (Smyth et al., 2012). to immunosuppression, data from national or international clinical Risk factors for ADR in children are poorly characterized databases of spontaneous pharmacovigilance reporting systems and (Bellis et al., 2013; Lombardi et al., 2018). Age on admission, pharmacovigilance studies including one single drug or specific ADR number of drugs, off-label drug use, and oncology diagnosis and were excluded. No language or other search filters were applied. treatment have been described as ADR risk factors (Bellis et al., 2013; Thiesen et al., 2013). Moreover, one of these studies stated Screening and Data Extraction the risk in oncology patients and found an increased risk for ADR All articles were screened independently by two authors (KA-H, ID) (OR  1.89 [95% CI 1.36–2.63]) (Thiesen et al., 2013). to identify relevant studies based on titles and abstracts, and on full Chemotherapy toxicity is a common cause of morbidity and texts of potentially relevant papers if study relevance could not be mortality in most pediatric cancer patients, and a frequent cause determined from the titles and abstracts. For studies meeting of mid and long term sequel (Conyers et al., 2018). Even though inclusion criteria, data were extracted independently using a drugs used in cancer diseases are described as a risk factor of ADR standardized data collection form defined and agreed previously. occurrence, and that ADR are frequent in oncology and Data extracted included article identification, methodology hematology hospitalization wards, there are very few studies characteristics (study design, setting, study aim, ADR definition that have quantified or analyzed any of these aspects in and detection method, and causality, severity and preventability pediatric population. scales used), and relevant results (sample size, study duration, Oncohematological diseases have a high impact on children population characteristics, ADR frequency and description, and their families, and on their quality of life. Improving the severity and preventability). A third author (AA) participated in knowledge of ADR incidence, characteristics and preventability the review and in the data extraction in case of disagreement. can be useful to compare results between studies and centers and to detect improvement areas, as a way to offer quality Data Analysis and Quality Assessment healthcare. Our aim was to perform a systematic review in \This review focuses on both the incidence of ADR in a high-risk order to describe the incidence and characteristics of ADR in population and on the methodological characteristics of the studies pediatric oncology and hematology patients, to describe the included. Quality assessment was performed independently by two methodology used in the included studies and, if possible, to authors (KA-H, ID), using a scale designed and previously published identify preventive actions in order to minimize ADR (Laatikainen et al., 2017), available in the Supplementary Material. occurrence. The scale includes six questions related to study design, study population, ADR definition and identification, causality assessment and result description. Each question can be evaluated METHODS as 0 or 1, where 0 indicates the poor quality of the study regarding that item. A third author (AA) participated in the critical appraisal in case Study Design of disagreement. A systematic review of observational studies that evaluated the prevalence, incidence and/or characteristics of ADR in pediatric oncohematology was performed. This study was conducted in RESULTS accordance with the recommendations of the Joanna Briggs Institute (Munn et al., 2015) for systematic reviews of Using the research strategies defined previously, 7,712 studies were observational epidemiologic studies that evaluate prevalence retrieved from PubMed database. Forty articles were considered and incidence data, and the PRISMA recommendations for relevant for eligibility and finally, considering inclusion and systematic reviews (Tricco et al., 2018). This study was exclusion criteria, 14 studies were included in the systematic registered (CRD42018096513) at PROSPERO systematic review (Collins et al., 1974; Mitchell et al., 1988; Queuille et al., review database. 2001; Le et al., 2006; Gallagher et al., 2012; Posthumus et al., 2012; Frontiers in Pharmacology | www.frontiersin.org 2 February 2022 | Volume 12 | Article 777498 Amaro-Hosey et al. Pharmacovigilance Studies in Pediatric Oncohematology FIGURE 1 | Study flow chart. Barrett et al., 2013; Call et al., 2014; Langerová et al., 2014; hospitalized patients, four included admissions related to ADR Makiwane et al., 2019; Dittrich et al., 2020; Joseph et al., 2020; and three analyzed both settings. No studies assessing outpatient Morales-Ríos et al., 2020; Workalemahu et al., 2020). Due to the setting were found. Twelve studies evaluated ADR, characteristics of studies found, a meta-analysis was considered not predominantly using WHO or Edward and Aronson feasible to be carried out. Figure 1 shows the study flow chart. definitions, and two studies used adverse drug events (ADE). Study characteristics and main results are summarized in Causality was estimated in nine studies, using mainly Naranjo Tables 1–4. Of the 14 studies included, six were carried out in and WHO-UMC scales. Severity was assessed in 11 studies, pediatric oncology and hematology patients, and eight were carried mostly using Hartwig et al. scale and NCI CTCAE criteria. out in general pediatrics and included a clear pediatric Finally, preventability was only evaluated in five studies out of oncohematology subgroup. Four studies (Collins et al., 1974; 14, using Shumock and Thorton in two of them. Ten studies used Mitchell et al., 1988; Queuille et al., 2001; Le et al., 2006) were a single ADR detection method, and four studies used a published before 2010, and 10 studies (Gallagher et al., 2012; combination of them: intensive monitoring chart review Posthumus et al., 2012; Barrett et al., 2013; Call et al., 2014; method was used in seven studies, chart review was used in Langerová et al., 2014; Makiwane et al., 2019; Dittrich et al., four studies, and three studies based their results in triggers. 2020; Joseph et al., 2020; Morales-Ríos et al., 2020; Critical appraisal is summarized in the supplementary Workalemahu et al., 2020) were published later. material. Most of the studies defined adequately the study population and stated the causality assessment tool used Methodological Results (questions 2 [Q2] and 5 [Q5]). In contrast, results were Eight observational studies collected data prospectively, whereas considered not clearly described in half of the studies (Q6), as six were performed retrospectively. Seven studies focused on the information provided by the original articles on number of Frontiers in Pharmacology | www.frontiersin.org 3 February 2022 | Volume 12 | Article 777498 Amaro-Hosey et al. Pharmacovigilance Studies in Pediatric Oncohematology TABLE 1 | Methodology characteristics in pediatric oncohematology studies. References Design Setting Main ADR Detection Causality Severity Preventability study definition method scale scale scale aim Barrett et al. Retrospective Inpatients Assess the diversity of ADR (WHO) Single centre NS NCI Not evaluated (2013) toxicities, the association pharmacovigilance CTCAE v4 with drug pairs and to database compare the reported incidence of specific toxicities based on differences in dosing patterns Call et al. (2014) Retrospective Inpatients Investigate the effectiveness ADE Triggers + chart review NS NCI NS and efficiency of the use of a CTCAE v4 trigger tool for ADE detection NCC MERP MEI Collins et al. Prospective Inpatients Assess the incidence and ADR (WHO) Intensive monitoring chart NS NS Not evaluated (1974) Admission characteristics of ADR review + medical round + direct observation Joseph et al. Prospective Inpatients Determine the incidence and ADR Intensive monitoring chart Naranjo Hartwig Shumock and (2019) characteristics of ADR, drug (Edwards review et al et al Thornton interactions and drugs and involved Aronson) Queuille et al. Prospective Inpatients Evaluate ADE frequency and ADE Intensive monitoring chart Bégaud EORTC FAMC (2001) characteristics review et al tool Hartwig et al Workalemahu Retrospective Inpatients Evaluate ADR associated to ADR (WHO) Chart review WHO- Hartwig Not evaluated et al. (2020) chemotherapy and related UMC et al risk factors ADR, adverse drug reaction; ADE, adverse drug event; FAMC, factorial analysis of multiple correspondences; NCC MERP MEI, national coordinating council for medication error reporting and prevention medication error index; NCI CTCAE, National Cancer Institute common terminology criteria for adverse events; NS, not specified; WHO, World Health Organization; WHO- UMC, World Health Organization–Uppsala Monitoring Centre. patients or ADR was missing. In addition, study design (Q1), described was 11–16.4%, and preventability also varied ADR definition (Q3), and ADR detection method (Q4) were not from 0 to 74.5%. Only four studies reported fatal cases, clearly mentioned in three studies. shown at the results tables. Four studies included in this systematic review also assessed Clinical Results risk factors for an ADR. In general pediatric studies, Langerová Sample size varied from 52 to 10,297 patients, as well as study et al. described oncology patients as an independent risk factor duration, which ranged from 30 days up to 12 years. Age was (OR  9.8 [95% CI: 5.8–16.7]), as well as Makiwane et al. (OR  expressed in means in five studies, as median in four or with 7.3 [95% CI 3.0–18.9] and Gallagher et al., finding an even higher percentage of patients in an age range (2–12 years old) in risk (OR  29.7 [95% CI 17.4–50.9]). Workalemahu et al. three; age values can be found in Tables 3, 4. Gender varied described an increased risk for etoposide (OR  1.99 [95% CI from 44.1 to 61.3% of males, and was not stated in four 0.93–4.27]), mercaptopurine (OR  3.91 [95% CI 1.1–14.5), studies. Leukemia and solid tumors were the main cancer doxorubicin (OR  2.32 [95% CI 1.3–4.2]) and >4 diagnosis, stated in seven studies. ADR incidence varied chemotherapy agents (OR  2.7 [95% CI 1.5–4.7). depending on study setting: it ranged from 14.4 to 67% in hospitalized patients, 19.6–68.1% in admissions caused by an ADR, and 2.12–71% in studies evaluating both settings. DISCUSSION Chemotherapy toxicity described in the studies was related to hematological toxicity (anemia, febrile neutropenia), Even though ADR are an important cause of morbidity and gastrointestinal toxicity (nausea, vomiting, transaminases mortality, are frequent in oncology and hematology, and increase), and skin (alopecia, rash). Both chemotherapy chemotherapy is described as a risk factor, only 14 studies that agents such as methotrexate, doxorubicin or vincristine, assessed ADR were found. Incidence rates ranged from 14.4 to and antimicrobials were frequently related to ADR in 61.3% in hospitalized patients and 19.6–68.1% in ADR leading to oncohematology population. Severe ADR frequency admission. A high heterogeneity in methodological aspects Frontiers in Pharmacology | www.frontiersin.org 4 February 2022 | Volume 12 | Article 777498 Amaro-Hosey et al. Pharmacovigilance Studies in Pediatric Oncohematology TABLE 2 | Methodology characteristics in pediatric studies with oncohematology subpopulation. References Design Setting Main ADR Detection Causality Severity Preventability study definition method scale scale scale aim Dittrich et al. Retrospective Inpatients Identify if ADR are adequately ADR (WHO) Chart review WHO-UMC NCI Not evaluated (2020) documented and reported to CTCAE pharmacovigilance v5.0 databases Gallagher et al. Prospective Admission Identify ADR causing ADR Intensive monitoring LCAT Hartwig Hallas et al (2012) admission in order to quantify (Edwards chart review et al and characterise them, and to and determine their avoidability Aronson) Langerová Prospective Admission Ascertain the incidence and ADR Intensive monitoring Naranjo et al Not Not evaluated et al. (2014) characteristics of ADR related (Edwards chart review LCAT evaluated hospital admissions, and and Edwards determine drug groups Aronson) and involved Aronson Le et al. (2006) Retrospective Inpatients Evaluate the incidence and ADR (WHO) Spontaneous notification NS Hartwig Not evaluated Admission common types of ADR in + triggers + medical et al hospitalized children round + drug monitoring Makiwane et al. Prospective Inpatients Describe the prevalence of ADR (WHO) Intensive monitoring Naranjo et al Hartwig Not evaluated (2019) ADR in pediatric inpatients chart review et al Mitchell et al. Prospective Admission Provide information regarding ADR (NS) Intensive monitoring NS Not Not evaluated (1988) pediatric hospital admissions chart review evaluated prompted by ADR Morales-Ríos Retrospective Inpatients Estimate the frequency of ADR (WHO) Single centre Naranjo et al NOM-220- Not evaluated et al. (2020) Admission ADR and their characteristics pharmacovigilance SSA1- in hospitalized patients, as database 2012 well as drugs related Posthumus Prospective Admission Investigate the incidence and ADR Triggers + chart review Naranjo et al Hartwig Schumock and et al. (2012) characteristics of hospital (Edwards et al Thornton admissions related to ADR and Aronson) Seriousness was evaluated in three studies using the following tools: ICH CIOMS definitions (Makiwane et al., 2019), ICH E2A guidelines (Dittrich et al., 2020) and NOM-220-SSA1-2012 guidelines (Morales-Ríos et al., 2020) ADR, adverse drug reaction; ADE, adverse drug event; LCAT, Liverpool ADR, causality assessment tool; NCI CTCAE, National Cancer Institute common terminology criteria for adverse events; NS, not specified; WHO, World Health Organization; WHO-UMC, World Health Organization–Uppsala Monitoring Centre. reviewed was also described and has likely influenced on the most of the studies used a combination of methods, which might observed results. To our knowledge, this is the first systematic indicate a growing concern in ADR care in hospitalized children. review on pharmacovigilance regarding pediatric oncology and This improvement in combined methods for ADR detection was hematology. previously suggested (Gonzalez-Gonzalez et al., 2013). As mentioned previously, a high variability regarding To our knowledge, there is no reference quality assessment tool methodology was found in almost every aspect of study design: for observational studies with other designs than cohort or case- sample size, study duration, study setting, population of interest, control studies. A systematic review (Katrak et al., 2004) pointed ADR detection method, the assessment of severity and out the variability in 121 published critical appraisal tools, preventability, and the different scales used. These findings could regarding its intent, components and construction; this finding be explained by the different aim of each study, the effort to adapt the was later confirmed in another systematic review (Page et al., 2018), study to each local environment and available resources, research which concluded that there are several limitations of existing tools experience of the team and the moment in which they were designed for assessing risk of reporting biases. STROBE statement (von Elm and carried out, since methodology has evolved over time. These et al., 2007) or Johanna Briggs Institute (Munn et al., 2015) critical methodological differences have probably influenced on the clinical appraisal checklists are the most known tools, but their application results found. A systematic review on ADR detection methods in was complex and troublesome. Therefore, the choice of the hospitalized children was carried out (Ramos et al., 2021) and found checklist used in this systematic review (Laatikainen et al., 2017) that methods such as intensive monitoring chart review or trigger was agreed by the research team due to the lack of a standardized tools are more effective but time consuming, whereas spontaneous tool, its suitability to the type of studies included in the systematic notification showed the lowest rate of detection. They concluded that review and to the aim of the critical appraisal analysis, and its easy Frontiers in Pharmacology | www.frontiersin.org 5 February 2022 | Volume 12 | Article 777498 Amaro-Hosey et al. Pharmacovigilance Studies in Pediatric Oncohematology TABLE 3 | Clinical results in pediatric oncohematology studies. References Sample Duration Population ADR frequency ADR description Severity (%) Preventability size characteristics (%) Barrett et al. 1,713p 6.5 y Age: 64% (2–12 y) Incidence per year: Frequent ADR were neutropenia, NS Not evaluated (2013) 14.4–23.5% increased ALT and febrile neutropenia Gender: 53.1% 326p, ADR NS (especially G3-4). The most toxic drug male pair was methotrexate—vincristine. Dx: 52.1% leukemia, Twelve deaths were reported 28.5% neuroblastoma Call et al. (2014) 390p 4y Mean age: 11 y Incidence: NS Sodium polystyrene sulfonate and 21 ADE (G3-4) 63.6% Gender: 55% male Patients NS, 38 ADE naloxone were the triggers most Dx: 54% leukemia, frequently related to an ADE 24% solid tumor Collins et al. 63p 15 w Mean age: 8.9 y Incidence: 71% CT and antimicrobials were the drugs 11% severe Not evaluated (1974) (45p/63p) most frequently related to ADR. during Gender: 51% male 154 ADR: 63 Gastrointestinal and hematologic ADR hospitalization Dx: 44.4% leukemia (admission) and 91 were the most frequently described (during during hospitalization. ADR most hospitalization) frequent during admission were nausea and vomiting with cyclophosphamide (9), cytosine arabinoside (6) and/or vincristine (6) Joseph et al. 176p 18 m Age: 66.1% (2–12 y) Incidence: 67% The most frequent ADR was rash (19), 16.4% severe 74.5% (2019) (118p/176p) itching (10), anemia and gastrointestinal Gender: 55.9% 131 ADR complaints (8). The most frequent drugs female were vincristine (19) and methotrexate Dx: 67.9% leukemia (16). Rashes were related to co- trimoxazole, allopurinol, dexamethasone, methotrexate and vincristine. Cases of itching were related to dexamethasone Queuille et al. 52p 50 d NS Prevalence: 65% Allergic reactions and medication errors 16% severe 53% (2001) (34p/52p) were the most preventable ADE. CT was 155 ADE involved in >50% ADE Workalemahu 287p 25 m Mean age: 7.1 y Prevalence 41.5% Most frequent ADR were vomiting 74.1% moderate Not evaluated et al. (2020) (119p/287p) (16.3%), alopecia (15%) and febrile Gender: 61.3% 147 ADR neutropenia (10.2%). Vincristine male (85.4%), doxorubicin (61.7%) and Dx: 23.3% leukemia, cyclophosphamide (57.8%) were the 22.6% Wilms tumor most frequently prescribed drugs. Concomitant medication, etoposide, mercaptopurine, doxorubicin and >4 CT agents were identified as risk factors ADR, adverse drug reaction; ADE, adverse drug event; CT, chemotherapy; d, day; Dx, diagnosis; G3-4, grade 3–4; m, month; NS, not specified; p, patients; y, year. application. The main area of improvement was the presentation of profile and ADR risk factors, such as cancer diagnosis or number results, as results were insufficient or missing in half of the studies, of concomitant drugs. Moreover, it is likely that the use of and therefore it was considered to be the aspect most susceptible to different scales in causality and severity assessment has introduce bias. Moreover, an adequate study design statement, influenced on the results observed too. ADR definition and identification clearly mentioned would likely Hematological, gastrointestinal and skin toxicities are the reduce the risk of bias and improve study quality. Ten studies were most frequently described ADR in the articles included, which published after the STROBE statement, which suggests a need to are in tune with the expected safety profile of conventional reinforce the use of these tools both during study design and chemotherapy. No studies with novel drugs such as manuscript drafting. monoclonal antibodies or tyrosine kinase inhibitors were Incidence described in oncohematology pediatric patients was found up to 2020. A recently published study (Amaro-Hosey higher, in contrast with studies in pediatrics, which described an et al., 2021) prospectively assessed drug safety with some specific overall rate of ADR of 9.53 and 2.09% (hospitalized and therapies, including novel drugs and conventional chemotherapy. admission, respectively) (Impicciatore et al., 2001). This The most frequent ADR were hematological, infections and finding is expectable and consistent with chemotherapy safety gastrointestinal. Incidence using days at risk was calculated Frontiers in Pharmacology | www.frontiersin.org 6 February 2022 | Volume 12 | Article 777498 Amaro-Hosey et al. Pharmacovigilance Studies in Pediatric Oncohematology TABLE 4 | Clinical results in pediatric studies with oncohematology subpopulation. References Sample size Duration Population ADR frequency ADR description Severity Preventability characteristics (%) (%) Dittrich et al. T: 301p; 1m Median age (T): 5 y Gender T: 26.9%; 81p; All patients suffering multiple T: 12.1% Not evaluated (2020) POH: 31p (T): NS; Dx: NS 132 ADR ADRs received CT. Cytostatics G3-4 POH: % NS; p NS; was the drug group most POH: NS 56 ADR frequently associated to ADR (28.8%). Leukopenia and febrile neutropenia were the most common ADR Gallagher et al. T: 6,821p; 1y Median age (T): 3 y and 1 m T: 2.9% (240adm/ The most common ADRs were T: 6.8% T: 22% (2012) POH: 74p (IQR: 9 m, 9 y) Gender (T): 8,345adm); 178p; oncology related neutropenia (≥G4) POH: 6.7% 58.1% male; Dx: NS 249 ADR (89), thrombocytopenia (55) and POH: NS POH: NS; 41p, anemia (38); and 120 ADR immunosuppression (74) occurring in both oncology and non-oncology patients. The most frequent drugs were dexamethasone (68), vincristine (51) and doxorubicin (38). Oncology patients were much likely to have an ADR Langerová T: 2.405p, 9m Mean age (T): 7.1 ± 5.7 y; T: 2.2% (64adm/ The most frequent ADR were Not Not evaluated et al. (2014) 2,903adm Gender (T): 57.1% male 2,903adm); p NS; infections (16), febrile neutropenia evaluated POH: p NS, Dx: NS ADR NS (12) and mucositis (5). Cancer 143adm POH: 19.6% (28 was described as a risk factor adm/143 adm); p NS; ADR NS Le et al. (2006) T: NS 9y Mean age (T): 7.0 ± 6.2 y; T: 1.6%/10 y (per ADR with antibiotics were usually T: 11% Not evaluated POH: NS Gender (T): 52% male Dx: year: 0.4–2.3%); mild; anticonvulsants and CT POH: NS 31.5% had hematologic 1,009p; were associated more commonly malignancies or disorders, or 1,087 ADR with severe reactions. solid tumors POH: % NS; Asparaginase was associated 318p; ADR NS with 3% of ADR. One death in an oncohematological patient was reported Makiwane et al. T: 282p 3m Median age (T): 1.4 y Gender T: 18.4%; 52p; ADRs were associated with CT T: 11.5% Not evaluated (2019) POH: 23p (T): NS; Dx: NS 61 ADR (44.3%). ADR in POH included POH: NS POH: 56.5%; 13p; febrile neutropenia (6), anemia (4) ADR NS and pancytopenia (3). Drugs related were doxorubicin, etoposide, vincristine, carboplatin and asparaginase. Oncology patients had an increased risk of an ADR Mitchell et al. T: 10,297p 12 y NS T: 2.85%; 294p; The most frequent ADR in POH Not Not evaluated (1988) POH: 725p ADR NS were neutropenia (41%), fever evaluated POH: 22%; 157p; (38%) and leukopenia (29%). CT ADR NS was involved in 94% of POH admissions. Three deaths were reported in oncohematological patients Morales-Ríos T: NS 4y Age (T): 56.9% (2–11 y) T: 2.12–8.07% 91.9% ADR led to admission and T: 14.4% Not evaluated et al. (2020) POH: NS Gender (T): 52% female; Dx per year; 1,649p; 94.5% required treatment in POH: (T): 72.2% neoplasms 2,166 ADR POH. Serious ADR were 14.2% POH: % NS; frequently related to 1,190p; antineoplastic drugs (81.2%), 1,494 ADR being febrile neutropenia (52.4%) the most common serious ADR. Cancer patient deaths were drug- related in 1.4% cases (febrile neutropenia commonly (Continued on following page) Frontiers in Pharmacology | www.frontiersin.org 7 February 2022 | Volume 12 | Article 777498 Amaro-Hosey et al. Pharmacovigilance Studies in Pediatric Oncohematology TABLE 4 | (Continued) Clinical results in pediatric studies with oncohematology subpopulation. References Sample size Duration Population ADR frequency ADR description Severity Preventability characteristics (%) (%) associated to death). Seventeen deaths were reported in oncohematological patients Posthumus T: 258p 5m Median age (T): 3 y and 6 m T: 18.2%; 47p; 21 febrile neutropenia cases T: 0% T: 13% et al. (2012) POH: 47p Gender (T): 56.6% male; ADR NS related to 20 different CT drugs (6 POH: 0% POH: 0% Dx: NS POH: 68.1%; 32p; cases due to vincristine) ADR NS Adm, admissions; ADR, adverse drug reaction; CT, chemotherapy; d, day; Dx, diagnosis; G3-4, grade 3–4; m, month; NS, not specified; p, patients; POH, pediatric oncohematology subgroup; T, total population; y, year. regarding novel therapies: 1.1 and 5.3 ADR/100 days at risk for blood In conclusion, ADR in oncohematology pediatric patients are disorders and 0.8 and four ADR/100 days at risk for infections, more frequent than in general pediatric population, as expected. related to pegaspargase and thioguanine respectively; and 0.6 ADR/ A high variability in study design and results has been found, 100 days at risk for infections attributed to rituximab. Only four out which indicates a need to reinforce the use of methodological of 14 studies included in the systematic review reported fatal cases, standards both in study design and manuscript drafting, in order and the global incidence of fatal cases could not determined because to allow comparability between studies and to identify areas of the total population was not specified in two studies (Le et al., 2006; prevention and improvement. Preventability assessment should Morales-Ríos et al., 2020). This finding has been previously described be strongly encouraged in order to provide a high quality and could either suggest that fatal ADR are very rare in children or are healthcare and to improve patients’ quality of life. frequently underreported or not suspected (Bouvy et al., 2015). ADR preventability is a key aspect to analyze, in order to identify areas of improvement to reduce ADR occurrence and improve DATA AVAILABILITY STATEMENT patients’ life quality. A systematic review (Smyth et al., 2012) identified that preventability was only assessed in 19 out of 102 The original contributions presented in the study are included in studies, and ranged from 7 to 98%. This finding is similar to result the article/Supplementary Material, further inquiries can be obtained in the current systematic review, which evidences that it’s an directed to the corresponding author. aspect poorly evaluated in pharmacovigilance studies and therefore should be encouraged. This systematic review tries to add some evidence on an important AUTHOR CONTRIBUTIONS health problem insufficiently studied that affects a fragile population. Summarized data on characteristics and incidence of ADR in this KA-H and ID contributed to the conception and design of the population is provided, as well as a methodological description in study, and contributed to the recording of the data. Substantial order to find areas of improvement. Defined inclusion and exclusion contribution to the analysis or interpretation of data for the work criteria, the selection of studies in pediatrics with an oncohematology was made by KA-H, ID and AA. KA-H wrote the first draft of the subgroup, the lack of non-standardized critical appraisal tool that manuscript. All authors substantially contributed to fitted the study characteristics and the use of a selected/concrete the manuscript revision, read, and approved the submitted critical appraisal tool may have introduced bias, but was agreed and version. considered appropriate to enrich the results and the discussion. Great heterogeneity makes it difficult to compare results, but can also be interpreted as a need to establish methodology standards or to SUPPLEMENTARY MATERIAL reinforce their use during study design and manuscript drafting, such as STROBE statement. 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Adverse Drug Reactions Causing Conflict of Interest: The authors declare that the research was conducted in the Hospital Admissions in Childhood: a Prospective, Observational, Single-centre absence of any commercial or financial relationships that could be construed as a Study. Basic Clin. Pharmacol. Toxicol. 115, 560–564. doi:10.1111/bcpt.12264 potential conflict of interest. Le, J., Nguyen, T., Law, A. V., and Hodding, J. (2006). Adverse Drug Reactions Among Children over a 10-year Period. Pediatrics 118, 555–562. doi:10.1542/peds.2005-2429 Publisher’s Note: All claims expressed in this article are solely those of the authors Lombardi, N., Crescioli, G., Bettiol, A., Marconi, E., Vitiello, A., Bonaiuti, R., et al. (2018). and do not necessarily represent those of their affiliated organizations, or those of Characterization of Serious Adverse Drug Reactions as Cause of Emergency the publisher, the editors and the reviewers. Any product that may be evaluated in Department Visit in Children: a 5-years Active Pharmacovigilance Study. BMC this article, or claim that may be made by its manufacturer, is not guaranteed or Pharmacol. Toxicol. 19, 16. doi:10.1186/s40360-018-0207-4 endorsed by the publisher. Makiwane, M., Decloedt, E., Chirehwa, M., Rosenkranz, B., and Kruger, M. (2019). Adverse Drug Reactions in Paediatric In-Patients in a South African Tertiary Copyright © 2022 Amaro-Hosey, Danés and Agustí. This is an open-access article Hospital. J. Trop. Pediatr. 65, 389–396. doi:10.1093/tropej/fmy067 distributed under the terms of the Creative Commons Attribution License (CC BY). Mitchell, A. A., Lacouture, P. G., Sheehan, J. E., Kauffman, R. E., and Shapiro, S. The use, distribution or reproduction in other forums is permitted, provided the (1988). Adverse Drug Reactions in Children Leading to Hospital Admission. original author(s) and the copyright owner(s) are credited and that the original Pediatrics 82, 24–29. doi:10.1542/peds.82.1.24 publication in this journal is cited, in accordance with accepted academic practice. Morales-Ríos, O., Cicero-Oneto, C., García-Ruiz, C., Villanueva-García, D., No use, distribution or reproduction is permitted which does not comply with Hernández-Hernández, M., Olivar-López, V., et al. (2020). Descriptive Study these terms. Frontiers in Pharmacology | www.frontiersin.org 9 February 2022 | Volume 12 | Article 777498