Blood transfusions have shown adverse events (AEs) that augment morbidity and mortality.1 An adverse reaction or event is an undesirable response or effect in a patient, temporally associated with the administration of blood or blood component.2 Transfusion-related AEs increase morbidity and mortality and, therefore, the overall cost of their treatment. These AEs include fever, allergic reactions, viral and bacterial infections, edema and pulmonary injury, or heart damage, leading to emergency consultations, hospital admissions with diverse duration and even deaths.3

So that, the aim of this study was to assign, for the first time, a complete economic value, including social costs due to losses of productivity, of AEs attributed to blood transfusions in Spain. Secondary aim was to assess the trend in such costs during the last few years and, finally, to update the actual cost of the transfusion unit in Spain. AEs total costs’ information is crucial to update clinical trial-based cost-effectiveness analyses.

In year 2015, in Spain, 1,915,609 transfusions were performed, concerning a population of 46,439,864 inhabitants. Of these, 1,588 patients showed transfusion-related AEs with an imputability level equal to or greater than 2. This figure has increased 93% since the last five years. The total cost of these AEs for the NHS was 6,134,443€ calculated as a sum of healthcare cost (4,568,914€), social cost as a result of lost working days due to hospitalization (200,724€) and social cost of patient's death (1,364,805€).

The trend in costs analyzed for the period 2010-2015 show an increase in the healthcare cost of transfusion-related AEs of 42% and in the social cost due to loss of productivity of 83%. The number of patient's deaths (between 4 and 2) and patient's age at the time of the death (between 33 and 90 years old) in the period analysed present a high variability and therefore its associated social costs (range: 2.84-0.68M€). As a sum 33.8M€ of extra expenses, due to transfusion related AEs, were calculated for the period 2010-2015 for the NHS. In terms of AEs reported per 10,000 transfusions, the ratio has increased from 12.4 in year 2010 to 20.4 in year 2015. Results are shown in Table 2.

Our study calculates for the first time in Spain the total cost of transfusion-related AEs, including social costs. The number of transfusion related AEs show a 93% increase for the period 2010-2015 and their associated costs accounted for 6.13M€ in 2015. The study also describes a methodology for the calculation of the health care and social costs of morbidity and mortality associated to blood transfusion nationwide that can be easily conducted at the international level. All exploration objectives considered have been accomplished.

AEs in medicine represent a major problem for NHSs. Related to transfusions, both notifications of AEs and their associated costs, more specifically direct healthcare and social cost due to hospitalization, show a sharp upward trend during the last years. Post transfusion AEs in Spain accounted for 3.2€ per unitary packed red blood cell transfused, as a sum of healthcare costs and social costs due to such AEs. Cost-benefit studies should take into account all AEs’ related costs, including social ones, on behalf of accurate results and conclusions which could determine the adoption of cost-effectiveness new technologies and procedures.

In 2015, in the United Kingdom, over 2,577,276 transfusions, 3,965 AEs were reported, that is 0,154%.22 Compared to Spain, 3,043 AEs to transfusions (1,588 with imputability ≥2) were reported in the same year, representing a similar ratio of 0,159%. As mentioned in Table 2, in Spain, reported AEs ratio per 10,000 transfusions have grown from 12.4 in year 2010 to 20.4 in year 2015. In United Kingdom, in the same period, the ratio has increased from 11 to 15.4. Although showing similar prevalence between countries of the ratio of reported AEs, the difference may be due to the fact that the hemovigilance notification service in United Kingdom started in 1996, while in Spain the National Hemovigilance Unity was created in 2004 23 and serious AEs started to be notified in a regulated form in 2007.24

DRG and ICD-9 coding systems are in widespread use worldwide and the coding and clinical description of each category matches in every country.7,8 The present study describes a methodology that allows to know in a simple and explicit way the economic cost of transfusion-related AEs. DRG costs and their related ALOS vary each year. Every yearr's variations have been considered an accounted in the results.

It is of great importance to estimate not only the adeverse events¿ direct costs as recomended by Amin et al.25 and Agrawal et al.26 but also the social costs of blood transfusion-related AEs for an adequate economic assessment, as recommended by Neumann et al.27 In the present study, social costs, including loss of productivity and mortality associated to post-transfusion AEs, accounted for 4.4% and 29% respectively of all AEs’ costs.

In a similar way as the imputability of the AE associated to transfusions showed in Table 1, the hemovigilance report scores the severity of every AE. However, such severity scoring has not been considered for the calculation of the health costs associated to transfusion-related AEs, because the cost of each DRG is already a weighted average of several clinical episodes with different severity grouped by a similar clinical presentation.

The trend in the number of blood units transfused is decreasing during the last few years in Spain, as shown in Table 2, in part due to implementation of blood-saving policies,28 to the awareness of health care workers, the adaptation of surgical practices to less invasive procedures,29 and to the development of novel drugs and protocols.30 Demographically, Spanish population has descent 0.1% between years 2010 and 2015, while the population aging has increased. From 16.7% of Spanish population over 65 years of age in year 2010 to 18.1% in year 2015.31

However, it must be noted the steep increase in the actual healthcare cost associated to transfusion-related AEs in recent years. This increase is not due to a greater number of transfusions performed, but rather to a greater number of reported AEs, from 0.079% per blood unit transfused in year 2010 to 0.159% in year 2015, that is, increased by 100%. The likely reason to explain the increase in the number of AEs recorded is that it is becoming more common to notify them in recent years, rather than a true greater occurrence of post-transfusion-related AEs with respect to previous years. This notion is reinforced with progressive adherence of hospitals from the NHS to centralized information system of the Ministry of Health, together with a greater awareness of the importance of such notifications. Of course, the first step to be aware of its importance is to know the actual costs. In clinical practice, AEs are a serious problem with very important implications 32 that may represent more than 15% of the overall expenditure of a hospital.33

A limitation of this study is that it must be noted that not all social costs of the blood transfusion process have been fully considered. Besides the social costs computed in the present study, other minor blood donation-associated costs might be added. For example, the social donor's opportunity cost in terms of lost working days as reported by Amin et al.,25 the indirect cost associated with recruiting and retaining blood donors, as well as the healthcare cost of AEs associated to blood donation (bruising, urticaria, itching, nerve injury, vasovagal reactions, thrombophlebitis, etc.). Such complications are usually less frequent and milder than those assessed in the present study, and they likely contribute a much lower cost compared with the AEs recorded; although, they represent a true cost for the NHS. Moreover, not all patients get to work immediately when receiving hospital discharge. The average salary used in the calculation of the social cost due to ALOS does not include the social security contribution made by firms or autonomous workers, since there is no data available of a national average of social security payments that both enterprises and autonomous workers spend in social security coverage. Therefore, it is probable to have underestimated slightly the actual cost of the transfusion.

Post-transfusion morbidity and mortality costs account for 6.13M€ yearly in Spain and not only the healthcare cost, but also the number of AEs notified show an upward trend during recent years of 42% and 93% respectively. These costs and tendencies may alert health care providers and should be taken into account to update cost-effectiveness trials and for future studies regarding design and assessment of processes or techniques involving blood saving or transfusion activities. Finally, because there is a current trend for economic evaluations to consider the social costs and even patients’ health preferences,34 it is therefore concluded that the analysis of social costs described in this study may be of great use when making decisions in the field of public health.

NHS’ budget faces increasing pressure yearly. Sanitary decision makers need to deal constantly between adoption of innovative health technology, and the restricted economic resources that every Ministry manages. Future studies regarding AEs with a continuous update in costs are necessary to help NHS decision policies and a more rapidly adoption of cost-effectiveness technology.

David Epstein.

The corresponding author on behalf of the other authors guarantee the accuracy, transparency and honesty of the data and information contained in the study, that no relevant information has been omitted and that all discrepancies between authors have been adequately resolved and described.

All authors participated in the study design and revised and improved successive versions of the manuscript. B. Ribed Sánchez: first author. C.González Gaya: global reviewer, cost modelization and update. S. Varea Diaz: hemovigilance reports check, update and global review. C. Corbacho-Fabregat: global reviewer and technical consultant. I. Bule Farto: DRG, CIE-9 and CIE-10 expert. Contribution in cost assignment and review. J. Pérez de Oteyza: global transfusion adverse reaction check and review. All authors have approved the manuscript final version.

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