Adverse drug reactions (ADR) have been defined by the World Health Organization (WHO) as “a response to a drug which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis, or therapy of disease, or for modification of physiological function” (WHO, 1972).

ADR are an important cause of morbidity and mortality in patients of all ages, including pediatric population, and are considered a public health problem worldwide (Impicciatore et al., 2001; Clavenna and Bonati, 2009; Thiesen et al., 2013; Durrieu et al., 2014; Ramos et al., 2021). Children are more susceptible to ADR owing to insufficient standardized information, unlicensed and off-label use, unavailability of pediatric formulations, and physiological peculiarities inherent to age (Ramos et al., 2021).

Different systematic reviews and meta-analysis including ADR observational studies have found an incidence of ADR in pediatric inpatients ranging 0.6–16.8%, from 1.8 to 2.09% leading to hospital admission and 1.0–1.46% in outpatient setting (Impicciatore et al., 2001; Clavenna and Bonati, 2009; Smyth et al., 2012). In addition, ADR prevention in outpatients remains a public health and a patient safety challenge (Lombardi et al., 2018). A systematic review including 102 articles assessed preventability in only 19, which ranged from 7 to 98%. This high variability was explained due to a high heterogeneity in study designs, methods and settings (Smyth et al., 2012).

Risk factors for ADR in children are poorly characterized (Bellis et al., 2013; Lombardi et al., 2018). Age on admission, number of drugs, off-label drug use, and oncology diagnosis and treatment have been described as ADR risk factors (Bellis et al., 2013; Thiesen et al., 2013). Moreover, one of these studies stated the risk in oncology patients and found an increased risk for ADR (OR = 1.89 [95% CI 1.36–2.63]) (Thiesen et al., 2013).

Chemotherapy toxicity is a common cause of morbidity and mortality in most pediatric cancer patients, and a frequent cause of mid and long term sequel (Conyers et al., 2018). Even though drugs used in cancer diseases are described as a risk factor of ADR occurrence, and that ADR are frequent in oncology and hematology hospitalization wards, there are very few studies that have quantified or analyzed any of these aspects in pediatric population.

Oncohematological diseases have a high impact on children and their families, and on their quality of life. Improving the knowledge of ADR incidence, characteristics and preventability can be useful to compare results between studies and centers and to detect improvement areas, as a way to offer quality healthcare. Our aim was to perform a systematic review in order to describe the incidence and characteristics of ADR in pediatric oncology and hematology patients, to describe the methodology used in the included studies and, if possible, to identify preventive actions in order to minimize ADR occurrence.

Using the research strategies defined previously, 7,712 studies were retrieved from PubMed database. Forty articles were considered relevant for eligibility and finally, considering inclusion and exclusion criteria, 14 studies were included in the systematic review (Collins et al., 1974; Mitchell et al., 1988; Queuille et al., 2001; Le et al., 2006; Gallagher et al., 2012; Posthumus et al., 2012; Barrett et al., 2013; Call et al., 2014; Langerová et al., 2014; Makiwane et al., 2019; Dittrich et al., 2020; Joseph et al., 2020; Morales-Ríos et al., 2020; Workalemahu et al., 2020). Due to the characteristics of studies found, a meta-analysis was considered not feasible to be carried out. Figure 1 shows the study flow chart.

Study characteristics and main results are summarized in Tables 1–4. Of the 14 studies included, six were carried out in pediatric oncology and hematology patients, and eight were carried out in general pediatrics and included a clear pediatric oncohematology subgroup. Four studies (Collins et al., 1974; Mitchell et al., 1988; Queuille et al., 2001; Le et al., 2006) were published before 2010, and 10 studies (Gallagher et al., 2012; Posthumus et al., 2012; Barrett et al., 2013; Call et al., 2014; Langerová et al., 2014; Makiwane et al., 2019; Dittrich et al., 2020; Joseph et al., 2020; Morales-Ríos et al., 2020; Workalemahu et al., 2020) were published later.

Even though ADR are an important cause of morbidity and mortality, are frequent in oncology and hematology, and chemotherapy is described as a risk factor, only 14 studies that assessed ADR were found. Incidence rates ranged from 14.4 to 61.3% in hospitalized patients and 19.6–68.1% in ADR leading to admission. A high heterogeneity in methodological aspects reviewed was also described and has likely influenced on the observed results. To our knowledge, this is the first systematic review on pharmacovigilance regarding pediatric oncology and hematology.

As mentioned previously, a high variability regarding methodology was found in almost every aspect of study design: sample size, study duration, study setting, population of interest, ADR detection method, the assessment of severity and preventability, and the different scales used. These findings could be explained by the different aim of each study, the effort to adapt the study to each local environment and available resources, research experience of the team and the moment in which they were designed and carried out, since methodology has evolved over time. These methodological differences have probably influenced on the clinical results found. A systematic review on ADR detection methods in hospitalized children was carried out (Ramos et al., 2021) and found that methods such as intensive monitoring chart review or trigger tools are more effective but time consuming, whereas spontaneous notification showed the lowest rate of detection. They concluded that most of the studies used a combination of methods, which might indicate a growing concern in ADR care in hospitalized children. This improvement in combined methods for ADR detection was previously suggested (Gonzalez-Gonzalez et al., 2013).

To our knowledge, there is no reference quality assessment tool for observational studies with other designs than cohort or case-control studies. A systematic review (Katrak et al., 2004) pointed out the variability in 121 published critical appraisal tools, regarding its intent, components and construction; this finding was later confirmed in another systematic review (Page et al., 2018), which concluded that there are several limitations of existing tools for assessing risk of reporting biases. STROBE statement (von Elm et al., 2007) or Johanna Briggs Institute (Munn et al., 2015) critical appraisal checklists are the most known tools, but their application was complex and troublesome. Therefore, the choice of the checklist used in this systematic review (Laatikainen et al., 2017) was agreed by the research team due to the lack of a standardized tool, its suitability to the type of studies included in the systematic review and to the aim of the critical appraisal analysis, and its easy application. The main area of improvement was the presentation of results, as results were insufficient or missing in half of the studies, and therefore it was considered to be the aspect most susceptible to introduce bias. Moreover, an adequate study design statement, ADR definition and identification clearly mentioned would likely reduce the risk of bias and improve study quality. Ten studies were published after the STROBE statement, which suggests a need to reinforce the use of these tools both during study design and manuscript drafting.

Incidence described in oncohematology pediatric patients was higher, in contrast with studies in pediatrics, which described an overall rate of ADR of 9.53 and 2.09% (hospitalized and admission, respectively) (Impicciatore et al., 2001). This finding is expectable and consistent with chemotherapy safety profile and ADR risk factors, such as cancer diagnosis or number of concomitant drugs. Moreover, it is likely that the use of different scales in causality and severity assessment has influenced on the results observed too.

Hematological, gastrointestinal and skin toxicities are the most frequently described ADR in the articles included, which are in tune with the expected safety profile of conventional chemotherapy. No studies with novel drugs such as monoclonal antibodies or tyrosine kinase inhibitors were found up to 2020. A recently published study (Amaro-Hosey et al., 2021) prospectively assessed drug safety with some specific therapies, including novel drugs and conventional chemotherapy. The most frequent ADR were hematological, infections and gastrointestinal. Incidence using days at risk was calculated regarding novel therapies: 1.1 and 5.3 ADR/100 days at risk for blood disorders and 0.8 and four ADR/100 days at risk for infections, related to pegaspargase and thioguanine respectively; and 0.6 ADR/100 days at risk for infections attributed to rituximab. Only four out of 14 studies included in the systematic review reported fatal cases, and the global incidence of fatal cases could not determined because the total population was not specified in two studies (Le et al., 2006; Morales-Ríos et al., 2020). This finding has been previously described and could either suggest that fatal ADR are very rare in children or are 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 patients’ life quality. A systematic review (Smyth et al., 2012) identified that preventability was only assessed in 19 out of 102 studies, and ranged from 7 to 98%. This finding is similar to result obtained in the current systematic review, which evidences that it’s an aspect poorly evaluated in pharmacovigilance studies and therefore should be encouraged.

This systematic review tries to add some evidence on an important health problem insufficiently studied that affects a fragile population. Summarized data on characteristics and incidence of ADR in this population is provided, as well as a methodological description in order to find areas of improvement. Defined inclusion and exclusion criteria, the selection of studies in pediatrics with an oncohematology subgroup, the lack of non-standardized critical appraisal tool that fitted the study characteristics and the use of a selected/concrete critical appraisal tool may have introduced bias, but was agreed and 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 reinforce their use during study design and manuscript drafting, such as STROBE statement. Ultimately, our aim should be to provide a high quality research and healthcare to our patients and to improve their quality of life, regarding drug efficacy and safety.

In conclusion, ADR in oncohematology pediatric patients are more frequent than in general pediatric population, as expected. A high variability in study design and results has been found, which indicates a need to reinforce the use of methodological standards both in study design and manuscript drafting, in order to allow comparability between studies and to identify areas of prevention and improvement. Preventability assessment should be strongly encouraged in order to provide a high quality healthcare and to improve patients’ quality of life.