Neonatal Transfusion

Components of Red Blood Cell Transfusion

Red blood cells (RBCs) are the most commonly transfused component of whole blood. They are produced by centrifugation from whole blood or, less frequently, acquired directly from a donor by apheresis. Various storage solutions, such as citrate–phosphate–dextrose–adenine (CPDA-1) and additive–glucose–mannitol (e.g., AS-1, AS-3), containing anticoagulants and preservatives are used to maintain RBCs at 4°C during storage. AS-1 and AS-3 units contain mannitol and adenine, which are associated with diuresis and renal toxicity, respectively. Therefore, RBCs stored in AS-1 and AS-3 should not be used for large-volume (≥20 mL/kg) transfusions.

Preparation of Red Blood Cell Transfusion

Preparation of RBCs for transfusion begins with donor assessment and ends with transfusion into the neonate. The goal is to assure blood safety and maximize efficacy and response to transfusion. Accurate RBC component and recipient identification are imperative for safety. More than 300 blood group antigens, from 35 blood group systems, have been discovered on RBCs. Among these, the ABO and D (also known as rhesus [Rh]) blood groups are the most important in determining the compatibility of allogenic RBC transfusion. Infants can have four ABO blood types containing the corresponding A or B antigens on the RBC surface: group A, group B, group AB, or group O (no A or B antigens). In addition, infants can be D antigen positive or D antigen negative. Testing of the plasma or serum from either the infant or the mother must include ABO and D typing of their RBCs and a screen for unexpected RBC antibodies (indirect antiglobulin test). Before non–group type O RBCs are issued, the infant's plasma or serum is tested to detect passively acquired maternal anti-A or anti-B isohemagglutinins, which usually do not develop until more than 4 months of age. Importantly, crossmatch compatibility testing and repeated ABO and D typing, as is required for all patients older than 4 months, may be omitted during any hospitalization for an infant younger than 4 months, as long as any of the following criteria are met:

• 1.

  Antibody screen is negative

• 2.

  Transfused RBCs are group O, ABO identical, or ABO compatible

• 3.

  RBCs are either D negative or the same D type as those of the patient

Testing for the isohemagglutinins must also include the antiglobulin phase of testing at 37°C (body temperature). In the presence of an immunoglobulin G (IgG) antibody, crossmatched, ABO-compatible RBCs are administered until the acquired antibody is no longer detected. Once RBC units have been properly selected, sterile aliquots from the parent unit are produced to more accurately provide volumes of RBCs dosed based on the patient's weight. This can reduce the risk of transfusion-associated circulatory overload and also limit donor exposure–related infectious risks by repeatedly using the same RBC unit. Data suggest that 20 mL/kg transfusions in very low birth weight (VLBW) infants, compared with 10 mL/kg transfusions, lead to a greater increase in hematocrit without respiratory compromise. Although the optimal dose and duration of RBC administration are not known, transfusions should not run for longer than 4 hours. There is substantial variability in how blood centers and blood banks prepare RBCs ( Fig. 70.1 ). This includes strategies to prevent cytomegalovirus (CMV) transmission, how and when RBCs are irradiated, when RBCs are washed, and what age of RBC units are used.

The exclusive use of RBC transfusions from CMV-seronegative donors in VLBW infants has been associated with a very low risk of transfusion-transmitted CMV infection: between 0.0% and 0.3% per unit of CMV-seronegative and leukoreduced blood. Historically, the risk of transfusion-transmitted CMV (TT-CMV) infection from leukoreduced transfusions from CMV-untested donors has been reported to be higher than that from approaches using both CMV-negative donors and leukoreduction. In the opinion of the authors, the safest approach for transfusion of VLBW infants is to use leukoreduced RBCs from CMV-negative donors. However, given the low risks of TT-CMV infection with improvements in modern leukoreduction techniques, use of leukoreduced blood from CMV-untested donors is an acceptably safe and low-risk alternative. Importantly, RBC transfusion should not be delayed if CMV-negative blood is unavailable, and CMV-untested blood should be used given the relatively low risk of TT-CMV infection.

Many centers limit the storage time of RBCs transfused into neonates and infants. The maximum storage duration depends on the type of storage solution, with 35 days for CPDA-1 units and 42 days for AS-1 and AS-3 units. Recent randomized trials have provided high-level evidence regarding the safety of using stored, older RBC units. The Age of Red Blood Cells in Premature Infants (ARIPI) trial randomized VLBW infants to receive fresh blood (mean 5 days) versus standard issue blood (mean 15 days) and found no difference in a composite of mortality or morbidity between groups. Similar trials in adults and children have produced concordant findings. However, the age of RBC units may not account for other donor RBC characteristics, such as storage solutions and irradiation. A recent observational study suggests that characteristics of blood donors may influence outcomes in transfused VLBW infants, with red cell transfusions from older female blood donors associated with the lowest risk of adverse short-term outcomes, although additional study is needed before selection of donors based on age and sex can be recommended.

Indications for Red Blood Cell Transfusion

Common indications for RBC transfusion include anemia, bleeding, and cardiorespiratory compromise. Extremely preterm infants are among the most highly transfused populations in medicine, with 64% of extremely low birth weight infants weighing 1000 g or less at birth receiving at least one RBC transfusion during their neonatal intensive care unit (NICU) stay.

Studies of RBC transfusion approaches in preterm infants suggest it is safe to practice a conservative approach. Four clinical trials enrolling at least 100 subjects each have compared the efficacy of RBC transfusion using liberal (high hemoglobin threshold) versus conservative (low hemoglobin threshold) transfusion strategies ( Table 70.1 ). In the Prematures in Need of Transfusion (PINT) trial, a lower hemoglobin transfusion threshold resulted in a nonsignificant increase in neurodevelopmental impairment at 18 to 21 months (odds ratio [OR] 1.74, 95% confidence interval [CI] 0.98 to 3.11), which was significantly higher in a post hoc analysis with a more inclusive measure of neurodevelopmental impairment. The Transfusion of Prematures (TOP) trial enrolled 1824 infants and found that a higher hemoglobin threshold, compared to a lower threshold, did not improve survival without neurodevelopmental impairment at 22 to 26 months (relative risk 1.00; 95% CI 0.92 to 1.10). In addition, there was no difference in survival or other common morbidities. Similar findings were reported in another multicenter trial from Germany, where no difference in death or disability at 24 months was noted between more liberal (higher) versus restrictive (lower) thresholds for RBC transfusion (risk difference 1.6%; 95% CI −4.8% to 7.9%). Both of these more recent trials support use of RBC thresholds within the ranges studied and favor the use of lower hemoglobin thresholds, given the lack of benefit with more liberal thresholds. However, the safety of thresholds below those evaluated in the aforementioned trials is uncertain and should be avoided.

RBC transfusions are sources of parenteral iron, and fewer RBC transfusions using lower hemoglobin transfusion thresholds without appropriate enteral iron supplementation may increase the risk of iron-deficiency anemia. Iron-deficiency anemia is associated with adverse long-term neurodevelopmental outcomes and higher amounts of enteral iron supplementation is associated with better cognitive outcomes at 2 years of age. Recent trends suggest an increasing use of conservative transfusion thresholds to decrease RBC exposure, mirroring patient blood management approaches in adults designed to minimize blood exposure. However, there is wide variation in pretransfusion thresholds among US centers.

For more mature preterm and term infants, transfusion approaches are largely based on expert opinion, owing to the lack of randomized trials. In select populations of infants, such as those undergoing surgery, hematocrit values of 40% or higher may be desired. By contrast, asymptomatic preterm infants may tolerate a hematocrit of 21% before needing RBC transfusion (see Table 70.1 ). In neonates without an ongoing source of blood loss, iron supplementation or erythropoiesis-stimulating agents may be sufficient to help restore RBC volume. However, a multicenter trial of high-dose erythropoietin did not show a reduction in death or severe neurodevelopmental impairment at 2 years of age with the use of erythropoietin (relative risk 1.03; 95% CI 0.81 to 1.32). Additional studies are needed to guide appropriate thresholds in term infants, particularly among neonates undergoing surgery, including cardiac surgery and those receiving extracorporeal membrane oxygenation support, given the association between higher transfusion rates and increased mortality in this population.

Risks of Red Blood Cell Transfusion

The risks of blood component therapy, specifically RBC transfusion, are reviewed here. However, many of the immunologic and nonimmunologic risks discussed are based on studies in adult transfusion recipients and have not been adequately studied in the neonatal population.

Immunologic Complications

Historically, the primary risk of blood transfusion has been infection. However, current estimates of the risk of transfusion-transmitted infections suggest that modern donor selection and post-donation diagnostic testing strategies reduce the risk to below 1 in 2,000,000 for most infections ( Table 70.2 ). Acute immunologic complications of transfusion include hemolytic transfusion reactions, immune-mediated platelet destruction, febrile nonhemolytic reactions, allergic reactions, anaphylaxis, and transfusion-related acute lung injury (TRALI). Formation of antibodies to ABO blood group antigens (anti-A and anti-B IgM and IgG types) typically occurs after 3 to 4 months of age. Therefore, transfusion reactions related to ABO blood group incompatibility are less likely to occur in neonates. Delayed immunologic complications include delayed hemolytic reactions, alloimmunization to white blood cells, RBCs, and platelet antigens in blood components, posttransfusion purpura, and transfusion-associated graft-versus-host disease. Transfusion-related immunomodulation (TRIM) is a potential entity described in adults that involves immunosuppressive effects of blood transfusion, which may be beneficial in solid-organ transplant but also can potentially increase the risk of infection and malignancy. However, many of the studies on TRIM were done in an era before leukoreduction, and TRIM has not been investigated in neonates.