CINAHL Plus, Embase, Scopus, MEDLINE, Web of Science and Cochrane Library, electronically to obtain relevant research studies published from 1st January 2011 to 31st April 2021. A second step was to manually check the reference lists of the currently qualified research to guarantee that no eligible studies were overlooked. The search technique will integrate just terms representing to and referring the participants and the intervention.

The search strategy follows the PICOTT framework [15] (Population, Intervention, Comparator, Outcome, Type of Question, Type of Study) to identify the keywords due to their suitability to assess clinical questions, especially to identify therapy/ intervention effectiveness [16] (Table 1).

Table 1. PICOTT framework

The search of databases found 4739 articles, and 6 papers were found by harvesting references (Figure 1). Boolean operators combinations and truncations were utilised to narrow down the search results. The MeSH browser was utilised to index articles. The keywords that were used to search the databases were: “Blood transfusion” and “Transfusion Safety” or “Adverse effects/Transfusion” or “Transfusion reaction” and “Whole blood transfusion” or “Red blood cell transfusion” or “Platelet transfusion” or “Plasma transfusion” or “granulocyte transfusion” and “Pediatrics” or “Children” or “Infants” either singly or in combination. With the implementation of search limitations, the scope of the search was narrowed to include only primary peer-reviewed papers that were available in the English language and full-text articles.

Study Selection

The inclusion and exclusion criteria are listed in Table 2:

Table 2. PICOTT framework

Before applying the inclusion and exclusion criteria, the duplicated papers were eliminated using the RefWorks tool and manually reviewed to ensure no bias caused by duplication. A total of 4349 publications were found in the literature search after the duplicate articles were removed, and a total of 06 studies were obtained through reference harvesting (Fig 1). 3963 records excluded after title screening. 386 reports were sought for retrieval.

Inclusion Criteria and Exclusion Criteria Implementation:

The papers found as an outcome of the search were screened for research design in the first step. After that, the title and abstract of each search result were screened using “P” “I” “C” “O” “T” “T” inclusion and exclusion criteria for sample and research designs that were limited to interventional and non-interventional studies and observational studies. From the literature search, it was found that in some articles, the population group was not children, and alternative therapies were used as intervention instead of blood transfusion. In the next phase of screening, 82 relevant articles on blood transfusion (I-intervention) in children (P-Population) resulted from the search. Their full-text articles were scanned for data collected from participants regarding Blood transfusion or not (C-Comparator) and searched for complications and mortality after blood transfusion (O-Outcome). Articles that provided insufficient or unfocused information regarding blood transfusion were excluded. After implementing the inclusion and exclusion criteria, 12 papers were chosen for the critical appraisal stage (Figure 1 & Table 2).

Critical Appraisal

Various evaluation techniques were used to evaluate the research. Twelve papers were assessed using two critical evaluation techniques to investigate the studies’ methodological strengths and flaws as well as their validity and reliability. It was also carried out to determine if the studies had been developed, conducted, and documented adequately and whether they produced a relevant answer to the systematic review issue in question. The cross-sectional study was evaluated using the Appraisal Tool for

Cross-Sectional Studies (AXIS) [17], specifically intended to assess this design. The prospective or retrospective study’s quality assessment was conducted using the CASP tool [18]. After the quality check, one study [19] was removed as no definitive conclusion was drawn.

Fig1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement¹⁴

Data Abstraction

Data were extracted from the selected studies in a standardised Microsoft Excel sheet. The following information was extracted: (i) reference (ii) study design (cross-sectional, prospective, retrospective; single centre or multicentre) (iii) study context (clinical setting in which the study was performed) (iv) study period (duration of the study) (v) characteristics of the study population (sample size, health condition) (vi) parameters related to blood transfusion (transfused blood product, primary and secondary outcomes) (vii) aim of the study (vii) results and limitations of the study.

Analysis

3. RBC transfusion safety

The transfusion of red blood cells (RBCs) is the most frequent blood product transfusion. This review examined six research for their findings on RBC transfusion in children. RBC transfusion has been associated with worse results in all of the studies. The findings of a study conducted to determine the adverse effects of RBC transfusion in a multidisciplinary PICU population revealed an independent association and a dose-effect relationship between RBC transfusion and increased morbidity [24]. It includes an increased risk of NPMODS, a more prolonged PICU stay, and an increased duration of mechanical ventilation [24]. RBC transfusion was identified as an independent risk factor for nosocomial infections in medical and surgical care centres that provided treatment to critically sick children in another research [27]. According to another study conducted among juvenile trauma patients, early pRBC transfusion was related to a 50% increase in death [21]. Compared to individuals who did not get pRBC transfusion, those who received it late had more extended ICU stays and more ventilator days [21]. When RBC transfusion is performed during surgery, there is an elevated risk of postoperative VTE in paediatric patients; however, this risk is still shallow [22]. A study [28] concluded that the administration of RBCs to ELBW newborns was shown to be related to an increased risk of neonatal mortality. It also established a relationship between RBC transfusion and a higher likelihood of ROP threshold [28]. However, this research found that RBC transfusion positively influenced late cognitive development in ELBW babies, as measured by the MDI score at 18-24 months corrected age in ELBW infants [28]. The frequency of TAH in children who had RBC transfusions was modest (0.93 percent, suggesting that 1 out of every 108 kids in the study developed TAH); nonetheless, the 1-day death rate was 20% in this group of children [29]. A multitude of circumstances caused TAH, and all of the patients in that study had comorbidities that might increase TAH and associated complications [29].

4. Oncology patients

The transfusion response profile of paediatric oncology patients was investigated in a study. 55.5% of patients with transfusion reactions were between the ages of 10 and 18, 94.4% were poly-transfused, and 62.3% had no previous history of a transfusion reaction [26]. The transfusion profile showed a high prevalence of urticaria, erythema, and fever, as well as acute allergic-type reactions associated with platelet transfusion [26]. The research also indicated that if they detect a transfusion response, they should promptly cease the transfusion and act to prevent the complication [26].

5. Critically ill children admitted to PICU

A study in severely ill children found a substantial and independent link between blood product (plasma) transfusions and higher morbidity [23]. One study [24] reported that RBC transfusions in severely sick infants were related to extended mechanical ventilation and PICU duration. The study further [24] doubts the capacity of preserved RBCs to enhance oxygenation in critically unwell infants. Outcomes such as mortality and NI has also shown an association with blood transfusion in two studies [27, 30].

6. Injured children

Among children younger than 15 years of age, three-year research looked into the relationship between transfusion and increased morbidity and mortality in wounded children [21]. A pRBC transfusion was given to 8% of the injured kids (43/512). Approximately one-half of injured children who had an early pRBC transfusion died; nevertheless, most deaths were caused by injuries to the central nervous system [21]. The number of days spent on the ventilator and in the critical care unit was higher in children who had pRBC transfusions than those who did not [21]. In this study, uncontrolled bleeding and coagulopathy were associated with early post-injury mortality following pRBC transfusion [21].

7. Children underwent surgery

According to the findings of one research, the use of perioperative RBC transfusions in paediatric surgical patients was related to an increased incidence of postoperative VTE [22]. This relationship remained significant despite accounting for other potential prothrombotic risk factors [22]. In children who have surgery and need RBC transfusions during the surgery, this study says they should be closely watched and given a lower threshold for mechanical and chemical prophylaxis [22]. Children younger than 1 year old who had heart surgery and received plasma had a higher risk of getting bloodstream infections, mediastinitis, and other infections in the hospital [25]. The study was only done at one location [25], making the findings less generalisable. The choice to deliver plasma transfusions in children who underwent cardiac surgery was left to the discretion of physicians on a patient-by-patient basis, and there was no standardisation in this regard [25].

8. Transfusion in infants less than one-year-old

Blood transfusion is frequently regarded as a life-saving intervention in highly sick neonates. Most blood transfusions are given to the tiniest and most immature newborns [28]. Hospital mortality and short-term morbidity have been linked to RBC transfusions in neonates [28]. However, in ELBW preterm newborns, the relationship was beneficial in later neurodevelopmental outcomes [28]. In another centre, plasma transfusion following heart surgery in babies younger than one year of age was shown not to affect the outcomes of the patients [25].

transfusion practices in children. The objective of this research was to provide a comprehensive overview of all documented concerns to understand better the clinical adverse reactions and associations linked to blood transfusions.

Paediatric patients’ reactions to blood products

The paediatric patient’s reaction to various blood products is different in different contexts. The transfusion outcome depends on the comorbidities and the patient’s current health condition. This review noted that the blood transfusion led to mortality, nosocomial infection, MODS, venous thromboembolism, NEC, ROP, BPD, and late-onset sepsis. TAH was seen in individuals who also had other concomitant conditions. In addition to these, intestinal and neurological complications, prolonged ICU stay and 28-day mortality, hypotension, systemic inflammatory response syndrome, and acute respiratory distress syndrome were noted as secondary outcomes.

Need of long-term studies in the vulnerable population

The review establishes an association between harmful outcomes and children exposed to RBC, platelet and plasma transfusion practices. On the contrary, two studies could not show an association (plasma and platelet) with the outcomes [20, 25]. There were no statistically significant differences in various adverse effects between children exposed to blood transfusion procedures and those not exposed to it [31]. However, the risks of bias revealed in many research and the lack of consistent reporting and definitions of occurrences restrict the conclusions that can be drawn from these investigations.

Blood transfusions are associated with worse outcomes in critically ill children. In severely ill children, plasma and platelet transfusions are related to increased organ failure and death. Despite the possibility of therapeutic advantages, haemostatic transfusions are accompanied by poorer clinical results in the long run. Platelet transfusions were the most often related to transfusion responses in adult and paediatric groups, followed by RBC transfusions and then plasma transfusions [6]. When comparing the paediatric population to the general adult population, there is an overall rise in transfusion responses.

The transfusion profile of oncology patients showed a high prevalence of urticaria, erythema, fever, and acute allergic-type reactions associated with platelet transfusion [26]. Other studies supported these findings. Allergic responses to platelets and RBCs were the paediatric group's most often testified reaction forms. A higher than threefold increase in the rate of allergic reactions to platelets was seen in children than in adults, and a greater than sevenfold increase in the incidence of allergic reactions to RBCs was observed in children compared to adults [7]. According to the findings of this investigation, critically ill children are more prone than adults to respond to blood products, with RBC and platelet transfusions being linked with the most significant magnitude of observed differences. Long-term studies in the vulnerable population (immune-compromised and critically ill children) should be encouraged to reduce the worst outcome.

Long-term effects of blood transfusion reaction in children

Metabolic complications of blood transfusion remain unnoticed on some occasions. Because young children may have difficulties communicating their symptoms to healthcare practitioners, this finding may be explained by the fact that the clinician must define the reaction solely based on physically visible signs. Transfusion-associated Hyperkalaemia may be more prevalent in juvenile populations, which fall into this category. The frequency of TAH in children who had RBC transfusions was modest, and a multitude of circumstances caused TAH [29]. It could also be a sign that medical staff would be too careful when giving RBC products to children, leading to a reaction report that doesn’t meet any case definition criteria [7].

According to the findings of one research, the use of perioperative RBC transfusions in paediatric surgical patients was related to an increased incidence of postoperative VTE [22]. Another study [32] confirmed by confirmed that children, infants, and neonates who get preoperative RBC transfusions are more likely to have new or worsening VTE after surgery [32]. Another study also observed various transfusion reactions over two years in a PICU in a study and noted increased mortality [33]. There are no studies with a well-developed follow-up or information on the long-term consequences of blood transfusions in children. Improvements in the observation of transfusions administered to patients in the PICU and improved understanding of these responses among healthcare workers should help to enhance the safety of transfusions in the PICU.

Various alterations to familiarise and standardise children’s adverse transfusion reaction

This review noted that post-surgical children who needed blood transfusion should be closely watched and given a lower threshold for mechanical and chemical prophylaxis [22]. An additional risk factor related to RBCT is the duration of the procedure, haemorrhage, and oxygen saturation levels. These considerations should be considered when planning paediatric treatments, particularly where exposure to RBCT is desired [34]. De Pascale, et al., reported that apheresis of platelet and RBC showed more excellent transfusion safety [35]. Other studies also supported blood product modification. Modifications to blood products can significantly reduce the dangers associated with transfusions [3]. They have also proposed leukoreduction, irradiation, washing, volume reduction, pathogen inactivation, and other treatments [3]. Alteration of the blood product can improve transfusion safety by reducing the risk of infection. More research, however, is needed to determine the safety of each alteration for each kind of blood product in question. Every alteration is unique, and it will behave uniquely with each and every blood product.

Develop new health data and strategies to increase the safety

A significant incidence of transfusion reactions in children is seen, which depends on the following variables: the kind of blood component administered, patient comorbidity, and the number of transfusions received; the sort of response is also connected with the type of blood component and the age of the patient [36]. The understanding of patients and the variables that contribute to transfusion responses serve as the foundation for the development of preventative measures, which ultimately contribute to improving the transfusion services and care provided to patients.

It is estimated that current transfusion practices partially comply with suggested transfusion standards. Guidelines for transfusions in children are based primarily on “professional opinion” instead of scientific proof. Likewise, to adult transfusion methods, present transfusion practises in children frequently do not reflect the application of existing knowledge about the necessity for transfusion. More extraordinary efforts to implement current evidence-based transfusion practices are needed. New health data and strategies should implement to increase the safety from adverse transfusion reactions in young children

Limitations of the study

Given several studies identified, the research quality that has provided primary and secondary outcomes has been low. Numerous studies were likely to have been compromised by confounding due to indication bias. More severely sick babies were more likely to have a blood transfusion than the rest of the population. Furthermore, the sample sizes in many research are from a single centre, which is insufficient for addressing damage comprehensively. This review included only articles published in English, which might give rise to selection bias. Some reports did not mention the age of the children and those articles were skipped from the review. Data from those articles might contribute to reasonable interpretations. This review included studies with the retrospective/prospective nature of the data analysis. These descriptive studies can reveal an independent association, but they cannot prove a cause-and-effect relationship between blood transfusions and outcomes in children. Only a randomised clinical trial can definitively prove the existence of a cause-and-effect relationship between blood transfusions and outcomes in children.

Declaration of competing interest
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Russell Kabir is an author of this paper. Therefore, the peer review process was managed by alternative members of the Editorial Board and the author had no involvement in the decision-making process.

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