Transfusion reactions in neonates and pediatrics

How and why are they different?

Abstract

Neonates and children are physically as well as physiologically different from adults. They are immunologically vulnerable, and the effects of transfusion can be longstanding, including with respect to their development. The transfusion reactions in children differ from those in adults in the type of reactions, incidence, and severity. The incidence is more than that in adults for the common type of reactions noted in children. Transfusion reactions are most commonly associated with platelets, followed by plasma and red blood cell transfusions in children. Febrile, allergic, and hypotensive reactions or volume overload are the common types in children. Standardizing pediatric adverse transfusion reaction definitions and criteria are necessary to improve studies and reports. Several modifications are needed to be adapted for transfusing blood products in neonates and children to evade the reactions as much as possible and make transfusion safer in this vulnerable population. This article provides a brief articulation of the transfusion reactions in neonatal and pediatric populations describing how they are different from adults.

Introduction

A neonate is defined as an infant under 4 months of age for transfusion purposes.[¹] The upper limit for a “pediatric” patient is defined variedly as 14 or even 18 years. Transfusion reactions reported from India show a lower incidence in the neonatal and pediatric age group, as low as 10%–20% of the reported rate in adults.[²³] In contrast, there is a disproportionately high number of reports following pediatric transfusions compared to adults in the West. However, approximately two-thirds of these reports are related to errors, which should be preventable. These usually include incorrect blood component transfusions, specific requirements not met, and avoidable, delayed, or under/over transfusions.[⁴] Excess vulnerability to patient identification errors in this age group may be because they cannot confirm their details, share the same date of birth with other infants in the neonatal intensive care unit (ICU), or may not yet have a name.[⁵] Recognition and reporting of transfusion errors in neonates are hindered because age-appropriate adverse transfusion reaction (ATR) definitions and criteria are unavailable.

Immaturity of the immune system, particularly in extremely premature infants, and disorders of cellular immunity in children increase their susceptibility to transfusion-associated graft-versus-host disease (TAGVHD). In contrast, immunologically mediated reactions such as febrile or allergic hemolytic reactions are rare. Physiological differences lead to metabolic complications, which are more specific to this population. Blood product type, dose, infusion rate, monitoring, triggers, and complex administration processes such as warming and infusion through rate monitoring devices can lead to a new set of errors and complications. Specific blood components and indications for transfusion are also different in this group of patients. A child's long-term development, particularly neurocognitive development, also needs to be considered while monitoring long-term adverse events.

Transfusion reactions are generally classified based on pathogenesis into immunologically mediated reactions and those that are not. The classification is summarized in Table 1.

Table 1: Classification of transfusion reactions in neonates and children

Metabolic Complications

Hyperkalemia

Plasma K⁺ increases during storage of whole blood (WB) and red blood cells (RBCs) due to leakage of intracellular K⁺ associated with inhibition of the membrane Na⁺/K⁺ ATPase pump. The plasma of a unit of CPDA-1 WB contains approximately 25 mEq/L of K+ at day 35 and RBCs about 75–100 mEq/L, translating to about 8 mEq per unit. This would not pose a problem with low-volume transfusions (10–20 mL/kg), as the infant's daily requirement of K⁺ is 1–3 mEq/kg/day. However, large-volume transfusions or the infant's kidneys’ inability to excrete K⁺ may lead to dangerous hyperkalemia.[⁶] Transfusion at a faster rate or through central lines delivering a high K⁺ load directly to the heart may cause arrhythmias, including cardiac arrest.

Prevention

Using irradiated blood after 24 h of storage in neonates should be avoided. Care is to be taken to avoid mechanical lysis of cells during infusion. Blood transfusion tubing can be shielded with aluminum foil while the infant is under a radiant warmer or phototherapy lights. Inline potassium adsorption filters or washing have been shown to remove extracellular K⁺ from RBC units, but these may not be feasible on a routine basis.[⁷]

Hypothermia

The higher susceptibility of infants to hypothermia is due to decreased body fat, an immature epidermal barrier, and a higher surface area-to-weight ratio. At increased risk are infants on extracorporeal membrane oxygenation (ECMO), those undergoing exchange transfusions or cardiac surgery, and children with trauma. Blood products brought to room temperature before transfusion also have been shown to decrease an infant's core body temperature by 0.7°C–2.5°C.[⁸⁹]

Prevention

Usage of blood warmers designed explicitly for blood administration is recommended.[¹⁰] Counter-current technology for warming is the most effective.[¹¹]

Impaired glucose homeostasis

Both hypoglycemia and hyperglycemia are linked to blood transfusion. This is probably also because the infants at risk of developing hypoglycemia or hyperglycemia are also the ones most likely to receive a transfusion. Neonates have decreased glycogen stores and mucosal G-6-phosphatase. The proposed mechanisms for altered glucose homeostasis in infants are summarized in Table 2.

Table 2: Probable mechanisms for altered glucose homeostasis in infants during transfusion

Glucose concentrations are also known to decrease in stored units over time.[¹²] Glucose levels are reported to decrease after transfusion and are generally asymptomatic, but mild symptoms can be noted in infants, especially in children undergoing exchange transfusion. The incidence of hypoglycemia in infants with erythroblastosis fetalis ranged from 2% to 20%.[⁹]

Prevention

Infants at risk are to be recognised and monitored. Blood products should be transfused through a second iv line, with maintenance fluids being administered at a slower rate to avoid fluid overload. The glucose concentration of the fluid may need to be increased if the infusion rate is reduced.

Reduced 2,3-diphosphoglycerate

During storage, the amount of 2,3-diphosphoglycerate diminishes rapidly. This shifts the hemoglobin–oxygen dissociation curve to the left, thereby reducing the ability of RBCs to release oxygen into tissue. It takes between 3 and 8 h to be regenerated after one unit of RBCs has been transfused. Infants younger than 4-month-old cannot compensate as effectively as older patients that can compensate for the resulting hypoxia by increasing their heart rate.[¹³]

Prevention

For neonates undergoing large-volume transfusions, fresher blood units are preferred.

Hypocalcemia

The use of sodium citrate as an anticoagulant that binds ionized calcium is the cause of hypocalcemia in neonates. Small-volume transfusions are unlikely to cause it, but the load infused during exchange transfusion can reach high levels. Most citrate is metabolized in the liver, kidney, and skeletal muscles. The kidney and liver are not fully functional, and muscle mass is low in neonates. Hypothermia and acidosis, if present, can also reduce the clearance of citrate. Transient hypoparathyroidism relates to the gestational and postnatal age of the neonate. The presence of hypomagnesemia can also blunt the parathyroid hormone response. Early neonatal hypocalcemia has also been attributed to the presence of hypercalcitoninemia and inducing calciuria.[¹³¹⁴]

Prevention

Seizure activity during exchange transfusion where hypocalcemia is suspected should be treated with 10% calcium gluconate (2 ml/kg). Ionized calcium levels should be monitored in infants undergoing exchange transfusion.

Transfusion-associated circulatory overload

The available definitions of the Centers for Disease Control and Prevention/International Society of Blood Transfusion do not define cutoffs for age-adapted vital sign values. These definitions also ignore the effect of critical illness that can influence vital signs. Transfusion-associated circulatory overload is mentioned to be more frequent in children younger than 3 years.[¹⁵] The higher risk is probably because of comparatively fast infusion in the background of their smaller size.

Prevention

Identify patients at-risk such as premature infants, infants with cardiac and pulmonary conditions or on mechanical ventilation/vasopressors, and transfuse them at a rate as reasonably low as possible.

Transfusion-transmitted infections

Given their small size, neonates are often transfused with small-volume aliquots and could be exposed to multiple donors. On average, premature infants weighing <1 kg are exposed to more than five donors during a single hospital stay if an opened port system is utilized for aliquot production instead of multiple aliquot Pedi-pack systems.[¹⁶] There is a high risk of cytomegalovirus transmission for low-birth-weight infants born to seronegative mothers.[¹³]

Prevention

One strategy is to reduce multiple donor exposure, which can be achieved by using sterile collecting devices to use the same units for repeated transfusion for the infants, Pedi-packs with prior aliquoting, or a dedicated donor donates every time the patient wants.

Bacterial sepsis

It is more frequently associated with the transfusion of platelets than with any other blood product. The source of infection can be the donor or contamination of the product post collection, especially during manipulation for pediatric use and administration in open systems.[¹⁷]

Prevention

Appropriate usage of platelets and proper and reduced storage duration are beneficial in reducing these events.

Iron overload

Iron overload is observed in chronically transfused children with thalassemia major, congenital anemias, and sickle cell disease. Each milliliter of red cells contains roughly about 1 mg of iron. Transfusion-dependent patients usually require 200–300 ml/kg/year of blood, whereas an average nonmenstruating person absorbs and loses only about 0.01 mg Fe/kg/day.[¹⁸] With no physiologic means of excreting, iron overload is inevitable in this population.

Prevention

Iron chelation should be initiated in children who have received approximately ten transfusions or a total of about 180 ml/kg of packed RBCs or have a serum ferritin level over 1000 ng/ml.[¹⁹]

Immunological Transfusion Reactions

An infant's immune system is less mature; thereby, its lymphocytes are unable to present foreign antigens effectively. Hence, immunological transfusion reactions tend to be less common in this age group.

Hemolytic transfusion reactions

These are rare in neonates. Maternal isohemagglutinins are sometimes detected in the first 2 months of life. However, infant alloantibodies are rare before 6 months of age. There is a risk of a relatively large amount of incompatible blood being transfused in neonates before acute hemolysis is recognized.[²⁰]

Prevention

Pediatric antibody tests that include screening for clinically significant antibodies in the recipient can be done. Components should be screened for clinically significant blood group antibodies (including high-titer anti-A and anti-B), and an indirect antiglobulin test is performed.[⁵]

Alloimmunization

Alloimmunization to RBCs is particularly frequent in those with sickle cell disease receiving transfusions.[²¹] Incidence of alloimmunization and platelet refractoriness appears to be lower in children than in comparable adult populations.[²²] Posttransfusion purpura can develop due to platelet-specific alloantibody developing after blood transfusion, most commonly human platelet antigen-1a.

Prevention

Transfusion of phenotype matched and leukoreduced blood, especially for those needing regular transfusions.

Febrile and allergic reactions

This is the most common type of reaction reported in the neonatal and pediatric age groups. Storage-generated biological response modifiers (BRMs) and recipient antihuman leukocyte antigens (HLA) antibodies are the two well-described mechanisms for the causation of these reactions. A higher volume of blood product per kg body weight, a higher dose of pyrogenic cytokines or allergens in blood product, and undiagnosed IgA deficiency are the causes that put these groups at higher risk for the reaction. The most common product implicated is platelets.[¹³²³]

Prevention

Leukoreduction, washing, and fresher blood product administration are a few strategies. Premedication can help in repeated reactions.

T-antigen activation-induced hemolysis

T-antigen activation is reported in about 0.6% of all infants in ICU and in 9%–27% of the infants with necrotizing enterocolitis (NEC).[²⁴] The red cell membrane glycoproteins carry O-linked oligosaccharides that are disialylated tetrasaccharides. Bacterial neuraminidases released by anaerobic and aerobic organisms remove these sialic acid residues, exposing a T-antigen which is usually hidden (T cryptantigen). This T-antigen binds with anti-T immunoglobulin present in most adult plasma, and hemolysis can happen.[¹³²⁰]

Prevention

Infants with sepsis or NEC who need plasma-containing components should be minor crossmatched. Avoid transfusion of plasma or use low anti-T titres plasma. RBC products may be washed before transfusion.

Transfusion-associated necrotizing enterocolitis

The association between RBC transfusions and NEC in neonates is controversial, and severe anemia itself may predispose to the development of NEC. A recent meta-analysis of randomized controlled trials even suggested a protective effect of a recent RBC transfusion on the development of NEC, while another meta-analysis of observational data did not find any association.[²⁵²⁶] In theory, intestinal injury either from feeding, intestinal ischemia, or bacterial colonization in susceptible infants combined with exposure to biologically active mediators such as free hemoglobin, increased cytokines, and broken red cell fragments within the transfused blood may trigger an immunologic response within the intestinal mucosa. Altered angiogenesis within the intestine due to platelet-activating factor acetylhydrolase and reperfusion associated with transfusion has also been described as possible mechanisms for gut injury. Prematurity, low birth weight, and hypoxic-ischemic events are known to be risk factors for the development of transfusion-associated necrotizing enterocolitis.[²⁷²⁸]

Prevention

The traditional practice has been to withhold feeds during (or for a few hours after) RBC transfusion to reduce the risk of NEC, but a recent Cochrane review noted the paucity of evidence, and many units currently do not withhold feeds.[²⁹] Washed red cells may be provided to neonates with NEC to reduce complement-dependent antibodies that can cause hemolysis of neoantigen-labeled RBCs.

Transfusion-related acute lung injury

This condition is more challenging to differentiate from other pulmonary pathologies. The current definition is not suitable for the pediatric and neonatal population. There are two peaks noticed concerning its occurrence, one in infants <1 year and the other in those more than 14 years.[³⁰] Two events cause transfusion-related acute lung injury: the generation of biologically active compounds related to stress that activates the pulmonary vascular endothelium and primes the neutrophils, and the infusion of biological response modifiers and antibodies in stored blood components. Infants may be vulnerable because a respiratory injury has already happened in many hospitalized ones.

Prevention

Avoid using plasma products from multiparous women donors. Rational use of plasma products is to be practised.

Transfusion-associated graft-versus-host disease

The population at risk are immunocompromised patients, extreme preterm infants, infants who receive intrauterine transfusions, those with neonatal alloimmune thrombocytopenia, and those on ECMO. Many initial cases were reported in severe combined immunodeficiency or Wiskott–Aldrich syndromes, newborns with erythroblastosis fetalis, sepsis, or ARDS. The inability of these recipients to mount an immune response against donor T-lymphocytes is fundamental to the pathogenesis of TAGVHD.[²⁰]

Prevention

Avoid blood from blood relatives. If absolutely necessary to be used then irradiate those blood products. Pathogen inactivation has also been known to reduce the risk.

Transfusion-related immunomodulation

The development of immunity in premature infants is not complete, and they generally have complicated clinical conditions. Hence, transfusion-related immunomodulation is difficult to define in premature patients than in adults. Effects like increased risk of short-term mortality (up to 3 months), increased risk of postoperative bacterial infections, and recurrence of resected malignancies have been described. More studies are required to elucidate this issue.[³¹³²]

Prevention

Prestorage leukoreduction and pathogen reduction have some preventive benefits as leukocytes, and their soluble mediators mediate these effects. Washing also helps by removing soluble HLA molecules, autoantibodies, and factor concentrate.

Conclusion

Due to the numerous difficulties in classifying and studying transfusion reactions in children, standardizing pediatric ATR definitions and criteria is necessary to improve studies and reports. Several modifications are needed to be adapted for transfusing blood products in neonates and children to evade the reactions as much as possible and make transfusion safer in this vulnerable population.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.