Autotransfusion in obstetrics: a narrative review

Introduction

Background: history of autotransfusion

British obstetrician-gynecologist, James Blundell, is credited with the successful introduction of allogeneic transfusion, the collection of one person’s blood and infusing it into a patient suffering from hemorrhage. Throughout his career, Blundell experimented with blood transfusion. He viewed those who experienced postpartum hemorrhage (PPH) as ideal candidates for transfusion which “may be performed with promptitude; for the human blood is always at hand and the instrument be easily provided, as the danger of uterine hemorrhages at least, may frequently be foreseen (1)”. He proposed a model in The Lancet in 1819, called the blood gravitator which allowed a man to directly donate blood to a hemorrhaging mother. Autologous transfusion, the collection and re-infusion of a patient’s own blood lost during a hemorrhage, was first reported by William Highmomre in The Lancet in 1874. Its use was, once again, first described in the setting of maternal hemorrhage (2).

In the 1960s, autotransfusion techniques and “cell saver” devices were refined and became more widely employed in cardiothoracic, orthopedic, and trauma surgery (3). However, the use of cell salvage in childbirth was considered hazardous for many decades due to theoretical concerns for contamination of blood products. While cell salvaged autologous blood transfusion is more readily available and used in obstetrics today, a lack of provider training and comfort as well as limited access to ancillary services such as a perfusionist team are barriers to implementing cell salvage during childbirth.

Rationale and knowledge gap: obstetrical hemorrhage

PPH is the leading cause of maternal mortality worldwide accounting for 7 million maternal deaths each year (4). In the United States, PPH remains the leading cause of death within 24 hours of delivery, accounting for 10% of all maternal deaths in the United States (5-7). The vast majority of these deaths are considered preventable (5,7-9).

Despite significant healthcare resources in the United States, the prevalence and severity of PPH has increased significantly. In a cross-sectional study of over 76.7 million delivery hospitalizations in the US from 2000–2019, the rate of PPH rose from 2.7% to 4.3% (10). The authors attribute rising PPH rates with an overall increase in hemorrhage risk factors in patients, for example fibroids, multiparity, history of cesarean, or history of hemorrhage (10).

Generally, autotransfusion is indicated in cases where >1,000 mL of blood loss is expected. In obstetrics this typically includes: placenta accreta spectrum, placenta previa, history of PPH and other pregnancies at high risk for bleeding (3,5). However, approximately 40% of PPH occur in patients considered low risk or without identifiable risk factors (11). Uterine blood flow at term is 750 mL/min, meaning hemorrhage >1,000 mL can happen quickly and during any delivery (12). The American College of Obstetrics and Gynecology recognizes cell salvage as safe and effective in obstetric patients, but acknowledges its use is limited by the availability of trained staff and equipment (5). The American Red Cross, further describes perioperative autologous cell salvage as ‘a key component of blood management’ and offers cell salvage services in eight states and Puerto Rico (13).

Allogeneic blood transfusions play an essential role in the management of severe PPH; however, their availability is not guaranteed over time (5,6,8,14). This is evidenced by critical blood supply shortages during the COVID-19 pandemic when social distancing interrupted the regular blood donation pathways (15,16). Currently, most donors are over age 50 years old and there is a lack of diversity in the donor pool (16,17). National trends indicate an overall decline in the number of blood units donated annually (18,19). Autotransfusion technology can be utilized to reduce stress on our blood bank system, especially when used in patient populations with high risk for hemorrhage. In some cases, salvaged blood may be the only means to adequately resuscitate and give blood volume back to a patient who cannot receive a blood transfusion due to a rare blood type, autoantibodies or religious objections to allogeneic transfusion (i.e. Jehovah’s Witnesses) (20,21).

Objective

The purpose of this review is to provide a narrative overview of autotransfusion in the obstetric patient to describe feasibility, safety, and efficacy data in both caesarean and vaginal birth, and to highlight opportunities for future research. We present this article in accordance with the Narrative Review reporting checklist (available at https://aob.amegroups.com/article/view/10.21037/aob-24-34/rc).

Methods

Peer-reviewed literature with keywords obstetrics, autotransfusion, operative cell salvage, postpartum hemorrhage, blood transfusion published in English in PubMed and Google Scholar from 1987–2024 was reviewed (Table 1). Given the paucity of research in this area, a wide variety of literature was surveyed including case series, case reports, retrospective and prospective cohort studies, randomized control trials, meta-analyses, and reviews. Separately, a broad search across PubMed and Google Scholar was conducted to summarize the history and the development of autotransfusion technology. No MeSH terms are available for the historical review.

Autotransfusion in cesarean delivery

Autotransfusion during cesarean delivery is feasible, safe and efficacious at reducing the need for allogeneic blood transfusion. Data suggest cell salvage may be more likely to result in adequate blood collection and reinfusion in patients who are actively bleeding or at high risk of bleeding during childbirth (22-24). Decreased rates of allogeneic blood transfusion are seen with both emergent and routine use of cell salvage (25-28). Further data are needed to understand how protocols and familiarity with cell salvage technology impacts both blood collection volume and patient outcomes.

Technique

Successful and safe autotransfusion in obstetrics requires prompt recognition of blood loss and attention to unique challenges in blood collection. Common challenges encountered during a cesarean birth include field contamination with amniotic fluid and the common practice to utilize laparotomy sponges rather than suction to manage field visualization.

To maximize the amount of blood collected and reduce contamination with bacteria, amniotic fluid or fetal blood, bacterial and amniotic fluid contaminants, a dual suction system is recommended but not required (29). The dual suction system includes two unique suction devices: (I) an anticoagulated suction line for collection of salvaged blood and (II) a standard wall suction for use during amniotomy and delivery of the baby and the placenta (26,30). The anticoagulated suction line is used both before and after amniotomy to maximize blood collection during the case. When suctioning shed blood, it is important to avoid skimming the surface of the blood as this can lead to red blood cell (RBC) damage or lysis, reducing the quality of the shed blood.

In addition to direct suctioning of blood, shed blood can be collected from laparotomy sponges. Laparotomy sponges are predominately used to clear the surgical field of blood to improve visualization during cesareans; these are an important blood source for autotransfusion. Blood is collected by rinsing the sponges in normal saline. The saline is then collected into the salvage reservoir and processed with the blood collected. With adequate rinsing techniques, approximately 90% of blood can be recovered from laparotomy sponges (30,31).

Processing of blood will not initiate until the minimum amount of shed blood is collected. In the event that the minimal volume to transfuse is not obtained, all collected products are discarded. If the minimum volume to transfuse is attained, processing begins (31). Of note, the minimum volume to transfuse depends on the collection bowl size. A standard 250 mL bowl requires approximately 500–750 mL of collected blood to produce an autologous product for reinfusion. Although the 250 mL size is more commonly used, a 125 mL bowl is available and only requires 250–300 mL of shed blood (32).

After collection, when using Cell Saver technology, shed blood is centrifuged and washed in normal saline to eliminate contaminants and particulate material including plasma, platelets, activated clotting factors and complement (33). Another technique, HemoClear (HemoClear by Zwolle, The Netherlands) uses gravity-driven microfiltration rather than centrifugation with the same wash efficacy as well as increased platelet recuperation (34-37). There are limited data on the use of HemoClear technology in obstetrics, but is an area of active research (36).

Although not required, some centers recommend a leukocyte depletion filter for blood processing during cesarean delivery. A leukocyte depletion filter, placed between primary and secondary reinfusion bags, removes approximately 99.9% of leukocytes from whole blood therefore reducing immunity reactions (37). Once processing is complete, the secondary reinfusion bag is removed from the cell salvage system and ready for autotransfusion (30,31). Waters et al. demonstrated that leukocyte depletion filters at time of cesarean delivery significantly reduced particulate contaminants, including squamous cell concentration, bacterial contamination and lamellar body concentration (29). Interestingly, centers that do not require a leukocyte depletion filter have not reported significant safety concerns or increased morbidity (25).

Supporting literature

Numerous studies demonstrate the feasibility of blood salvage during cesarean delivery. In a large retrospective review of 884 cases where intraoperative cell salvage was used at the discretion of the obstetric provider, sufficient blood was collected for reinfusion in only 21% of cases overall. In cases of routine cesarean delivery (n=748), only 13% of these patients received reinfusion due to high rates of insufficient blood collection. However, cell salvage was more likely to produce an autologous product in cases with active bleeding (69%) or cases of cesarean hysterectomy (73%) (31). In a maternity hospital in the UK where cell salvage is protocolized and standard practice for all cesarean deliveries, a 32% rate of blood collection sufficient for reinfusion was reported (26). Differences in patient populations, hospital practices and protocols, familiarity with cell salvage technology, and size of the collection bowl likely contribute to differences seen across studies.

An abundance of literature supports the use of cell salvage to reduce the need for allogeneic blood transfusion. The same UK hospital mentioned above with routine cell salvage use in all caesarean deliveries reported a significant reduction in the number of patients requiring allogeneic blood transfusion as well as a decrease in the total number of units transfused in deliveries spanning a decade [2008–2017] (26).

Alternatively, another maternity hospital in the UK used cell salvage routinely, but only processed collected blood once there was greater than 1,000 mL in the collection reservoir. Of the 6,656 patients who underwent cesarean section, 6.6% received autologous transfusion and only 0.7% required allogeneic transfusion. Furthermore, only 0.3% had inadequate red cell salvage requiring allogeneic red cell transfusion. The other 0.4% had severe hemorrhages necessitating additional blood products, such as fresh frozen plasma, platelets, or cryoprecipitate (25).

The SALVO trial (cell SALVage in Obstetrics) performed in the UK is the largest randomized control trial examining autotransfusion during cesarean section. Overall, this study found there was no significant reduction in allogeneic transfusion in patients randomized to cell salvage compared to those who received standard of care. However, only 51% of those who were randomized to the cell salvage group received reinfusion of autologous blood due to an insufficient amount of intraoperative blood collected. In a subgroup analysis of the SALVO trial stratified by elective versus emergent cesarean delivery, patients who received autologous blood were 42% less likely to require an allogeneic blood transfusion (23).

Finally, a recent meta-analysis of the five largest randomized control trials of cell salvage in cesarean section (including the SALVO trial), found patients randomized to receive cell salvage were 68% less likely to require allogeneic blood transfusion compared to standard of care controls (28). A sensitivity analysis demonstrated that even patients who were not at risk for PPH (routine or low risk patients) had a significant reduction in the need for allogeneic transfusion. There was no difference in postoperative hemoglobin levels, transfusion reactions, or hospital length of stay between groups (28).

Aside from decreasing the need for allogeneic blood transfusion, autotransfusion of salvaged blood may have additional benefits. Retrospective data indicates less hematocrit change and a 74% reduction in the development of new anemia. Patients who received autologous product had higher postoperative hematocrits, lower rates of postpartum anemia, and no increased risk of complications (38). A randomized controlled study in China found cell salvage utilization during cesarean was associated with significantly lower rates of wound infection, allergic reaction, hyponatremia, and perioperative adverse cardiovascular events (27). This highlights an important opportunity for further research as autotransfusion may have maternal benefits in addition to decreasing reliance on donor blood.

Cost

There are limited and mixed data evaluating cost effectiveness of cell salvage during cesarean birth (39,40). Importantly, due to a wide variety of protocols for cell salvage, of cost effectiveness comparisons between healthcare systems may not be reliable. On average, transfusion of a single unit of allogeneic RBCs costs approximately 300 USD. An autologous blood product collected using the cell salvage system is approximately 130 USD, excluding the cost of personnel (31). Value analysis of cell salvage technology depends on blood loss, blood collected and reinfused, and equipment costs. If the system is prepared and blood is collected but not used, equipment cost is lost in addition to personnel resources and time. However, the routine use of 125mL bowls during cesarean delivery could increase the re-infusion rate by lowering the threshold to process blood while reducing waste and cost (26,41).

Lim et al. published a cost-effectiveness analysis demonstrating cost-saving only occurred when the risk of transfusion was predictably high, as in the case of active bleeding, placenta previa, placenta accreta spectrum, repeat cesarean delivery or multiparity, chorioamnionitis, placental abruption, hypertensive disorders during pregnancy, and uterine rupture (42). This article concludes that the use of cell salvage for cases at high risk for obstetric hemorrhage is economically reasonable, but routine use of cell salvage in all deliveries is not. Most hospitals have a protocol to risk stratify patients according to hemorrhage risk, and cell salvage can be judiciously employed in those at higher risk of hemorrhage undergoing caesarean section (43).

Autotransfusion in vaginal delivery

There are limited data describing autologous transfusion for PPH during vaginal birth. Existing data suggests that collection and processing of vaginally shed blood is feasible and preliminary safety data indicate no increased risk of adverse events. Data from a single, small, retrospective matched cohort study suggest possible efficacy of improved postpartum hemoglobin values compared to controls. However, existing studies fail to adequately address important maternal outcomes such as allogeneic transfusion, impact on hemoglobin, and maternal morbidity.

Technique

There is currently no standardized protocol for blood collection for autotransfusion during vaginal obstetric hemorrhage. While blood processing and reinfusion is similar to intraoperative blood salvage during cesarean delivery, there are unique considerations for collection and reinfusion of vaginally shed blood.

A review by Phillips et al. proposed a novel technique for blood collection in a detailed algorithm (41). The first step is to separate vaginal blood from amniotic fluid in order to enhance the quality of salvaged blood and to minimize the presence of contaminants. Separation can be achieved by the utilization of a second under-buttocks drape, placed over the primary delivery drape after the delivery of the infant. A drape allows for passive collection while providers are busy actively evaluating and managing a PPH. The drape can be placed prophylactically for every vaginal delivery or, alternatively, can be placed only in cases where a patient is at high risk for PPH or when hemorrhage is identified after delivery.

The second step is to utilize a low-cost blood collection standby system, ideally installed in every delivery room, which includes setup of a suction reservoir and a suction line. The authors utilize the HEMAsavR^TM (Ecomed Solutions, Mundelein, IL, USA)—a sterile blood collection device with reusable hard-shell canister with a sterile, patient-specific, disposable liner that facilitates transfer of salvaged blood into a traditional autotransfusion collection reservoir. Approaches to anticoagulation include mixing collected blood with normal saline and/or adding a 10,000-unit dose of heparin to the blood.

Though most of the blood shed during postpartum vaginal hemorrhage will be collected in the second under-buttocks drape, sponges used in the delivery field may be a source of salvageable blood. As in the operating room, sponges can be rinsed in saline solution, which can subsequently be suctioned into the standby system (41). All previously described principles for optimization of blood quality should also be utilized in vaginal obstetric hemorrhage. Additionally, the postpartum hemorrhage autotransfusion (PPH AT) device was designed for use during vaginal deliveries in low-resourced settings. The blood is collected via under buttock drape where the pooled blood is processed through the device with filters and collected in a standard transfusion bag (44).

Of note, Phillips et al. discussed the possibility of blood collection from devices frequently utilized for PPH refractory to uterotonic agents, including balloon tamponade and vacuum-induced hemorrhage control devices (41). As an example, the standby cell salvage system previously described may be connected directly to the intrauterine Jada^® system (41).

Supporting literature

Current literature supports the feasibility, safety, and possible efficacy for cell salvage of vaginally shed blood (45-49). However, existing data are limited to feasibility studies, case series, and small retrospective analyses and fails to adequately address important maternal outcomes such as allogeneic transfusion, impact on hemoglobin, and maternal morbidity.

In a small case series by Lim et al., 36% (10/28) of cases with vaginal obstetric hemorrhage and attempted cell salvage resulted in adequate blood collection for reinfusion (49). Using the previously described protocol, a prospective pilot feasibility study demonstrated that 21.4% of a unit of blood could be salvaged in deliveries where vaginally shed blood could be collected (45).

The most robust study is a matched cohort comparing 36 patients who received autologous red cell transfusion to 144 unexposed controls (50). This study found that there was no significant difference in the allogeneic transfusion between groups. However, patients who received autologous product had a less drastic decline in hemoglobin compared to controls across all values of estimated blood loss. Importantly, there were no detectable differences in major morbidity markers, including venous thromboembolic events or rates of infectious, pulmonary, or renal complications. While robust, this study was flawed due to routine use of cell salvage for vaginal obstetric hemorrhage at the originating institution, making matching difficult and limited to patients with an estimated blood loss less than 2,400 mL. Additionally, there were signals that the autotransfusion (case) group was at higher risk for morbidity than the control group (50). These flaws limit the ability to critically analyze the impact of cell salvage technology during vaginal obstetric hemorrhage on maternal outcomes.

Cost

The cost-effectiveness of implementing a protocol cell salvage of vaginally shed blood is unstudied. Phillips et al. proposed utilization of a protocol with a standby system, which may improve cost-effectiveness in this patient population (41). In a feasibility study at a separate institution, implementation of the protocol proposed by Cabrera et al. suggested that the presence of a standby system (HEMAsavR^TM device) in delivery rooms allowed for its use only in settings where sufficient blood collection could be guaranteed (45).

Safety considerations

Intraoperative blood salvage in the obstetric patient was once considered contraindicated due to risk of contamination of blood with amniotic fluid, activated clotting factors, and other embolic debris. However, in a meta-analysis of five randomized-controlled trials (n=3,361) examining the use of autotransfusion during cesarean section, there were no cases of amniotic fluid embolism (28). A leukocyte depletion filter in particular removes fetal squamous cells and amniotic fluid-derived tissue factor which is thought to cause amniotic fluid emboli (51). Even when using a single suction device for both amniotic fluid and blood, Sullivan et al. concluded there was little to no possibility of clinically relevant events for reinfused blood while using a leukocyte depletion filter (52). Additionally, a study in the UK reported no clinical safety concerns in 1,170 patients who had a reinfusion of cell salvaged blood during cesarean section (26).

Within the field of obstetrics, there are specific safety considerations given the mixing of fetal and maternal blood when utilizing cell salvage systems. Rhesus alloimmunization during cell salvage remains a potential concern in Rh-negative patients. It is important, however, to note that on average, fetal RBCs account for only 1.5% of autologous blood retransfused during cesarean sections. Within a unit of cell salvaged blood, there is approximately 3 mL of pure fetal RBCs. Since a single dose of Rhesus-immunoglobulin will cover 15 mL of pure fetal RBCs, it can be assumed that a single dose of the immunoglobulin will cover up to 5 units of retransfused cell salvaged blood (40).

In addition to the overall safety considerations of cell salvage, autotransfusion of vaginally collected blood raises increased concern for infection, given potential for contamination with amniotic fluid, feces, urine, microorganisms, and vaginally administered medications. As previously mentioned, the existing data has not found any increased risk of infectious morbidity. This is likely attributable to the blood processing and wash protocol and effective removal of bacterial contaminants. Although bacteria were detectable in all post-wash and post-filter samples from vaginal collection, the median residual contamination was similar to that found with cell salvage in cesarean deliveries (47). If reinfused, the minimal bacterial contamination is estimated to be similar to that incurred during a routine dental cleaning thought to be clinically insignificant.

While there are potential risks, salvaged blood may decrease morbidity by avoiding the immunologic stress associated with donor blood. The red cell quality is also considered better as the blood is not stored for a prolonged period of time. Additionally, the risk of administering the incorrect blood type by error or acquiring an infectious disease from transfusion is eliminated (53).

Contraindications

Despite existing data suggesting that cell salvage is overall safe and effective in obstetric hemorrhage, there do exist some relative contraindications to blood collection for autologous use. Caution should be employed while using certain pharmacologic agents. Specific to obstetrics is misoprostol, a prostaglandin E1 analog commonly used for labor induction (placed vaginally) and in the management of PPH (placed per rectum). Though dependent on rate of vaginal absorption, if remnants of misoprostol are suctioned into salvaged blood, there is theoretical concern for maternal hemodynamic effects including hypotension, given its potency as a vasodilator (30). However, unless the tablets directly contaminate the salvaged blood, use of misoprostol is not an absolute contraindication to autotransfusion. Other pharmacologic agents to consider are topical clotting agents (Avitene, Surgicel, Gelfoam) and cleansing agents (betadine is often used for vaginal preparation in the operating room). In most cases, flushing the surgical site with irrigation solutions and utilizing a leukocyte depletion filter minimize this risk.

Other considerations include patient-specific medical history such as malignancy or hematologic disorders. Sickling of RBCs, as seen in sickle cell disease, can be increased with acidosis, hypothermia, and hypoxia—all potential stressors with blood collection and processing. Thalassemias similarly lend to increased red cell friability and therefore decreased quality of blood products. Case reports of autologous transfusion with these specific hematologic disorders have been reported (21,54,55).

Barriers to cell salvage in the obstetric patient

Despite feasibility, safety, and efficacy data that support the use of cell salvage in the obstetric patient, this intervention remains largely underutilized. Barriers to routine use of cell salvage include both provider training and comfort with cell salvage, lack of standardized cell salvage protocols, as well as hospital access to ancillary services such as a perfusionist team. Additionally, there are limited data in the obstetric patient with vaginal obstetric hemorrhage and more data are needed to describe both its safety and efficacy.

Availability of technology varies based on individual healthcare systems and local resources. Although this review focuses on the implementation of cell salvage in large tertiary care hospitals, there is autotransfusion technology available for use in low resource settings. For example, the souple-ladle technique has been described using a ladle (or other receptacle) to collect shed blood which is then filtered through 5–8 layers of gauze, treated with anticoagulant and reinfused via blood bag (56). The use of the Tanguieta funnel (a cone-shaped steel funnel with 1-mm holes punctured in lower two-thirds that can be submerged into pools of blood) was described in Benin and Burkina Faso, with 212 patients receiving re-infused blood without any adverse effects reported (57). The Hemafuse device was specifically designed for low resource settings and does not require electricity. It is a handheld mechanical device that collects shed blood and passes it through built-in filters prior to passing through an outlet valve into a standard blood bag ready for reinfusion (35,58). Although these techniques can be lifesaving, there are substantial risks to reinfusing improperly washed blood, and current guidelines support use of electric cell salvage technology to ensure blood is properly washed prior to reinfusion (59,60).

Developing universal cell salvage protocols in the obstetric patient and enhancing provider, nursing, and support staff education on cell salvage are initial steps toward improving and standardizing use of cell salvage during childbirth.

Conclusions

Allogenic product replacement is a life-saving medical intervention. Albeit rare, blood transfusion-related complications such as infection, allergic reaction and acute lung injury do occur (61,62). As rates of PPH hemorrhage, maternal mortality and blood bank shortages rise in the United States, it is imperative that obstetric hospitals and providers consider the role of autotransfusion via cell salvage as feasible, safe, and efficacious for patients at high risk for hemorrhage during childbirth. Additionally, autotransfusion could improve access to blood product replacement in rural settings where allogeneic blood units and products, such as platelets, may not be readily available.

Despite its safety profile and cost savings potential, autotransfusion is not commonly used in obstetrics. Cell salvage is indicated for obstetric patients who are actively bleeding or who are at increased risk of hemorrhage during childbirth, including but not limited to placenta previa, placenta accreta, multiple gestation, prior PPH, and other high-risk pregnancies. Critical next steps include facilitating additional clinical research in autotransfusion in the obstetric patient, as well as standardizing protocols, improving provider knowledge comfort with autotransfusion, and securing routine access to this technology on labor and delivery units. Protocol development and quality initiatives would help to make blood collection and conservation a routine process during childbirth. Standardization of blood collection techniques can improve blood collection and return, especially in the setting of severe PPH. Combined, these efforts would enhance the approach to blood management, conservation, and resuscitation in the obstetric patient and may help to address the rising rates of maternal morbidity and mortality.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://aob.amegroups.com/article/view/10.21037/aob-24-34/rc

Peer Review File: Available at https://aob.amegroups.com/article/view/10.21037/aob-24-34/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aob.amegroups.com/article/view/10.21037/aob-24-34/coif). S.S. reports consulting fees from Mirvie, payment or honoraria as ACOG District IV Speaker, support for attending meetings or travel from APGO CREOG Program Director School, APGO CREOG Retreat and SOGH Annual Meeting, and Voluntary DC Perinatal Quality Collaborative. J.W. reports consulting fees from Procell, and meeting cost of Society for the Advancement of Blood Management and Society for Thoracic Surgery provided by Procell. J.P. reports grants or contracts from NICHD, R01 HD110109 OPTIMUM and OB-TXA, consulting fees from Mirvie, and participation on NIH Maternal-Fetal Medicine Unit Network Medical Monitor. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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