Appropriate transfusion in pediatric patients, especially in premature infants is very important to balance the benefits of transfusion against the risks. These transfusion risks include unpredictable acute transfusion reactions. Additional safety measures are in place for neonatal patients who are particularly vulnerable recipients due to their small size and immaturity of the organs.1

Very low birth weight (ELBW) babies, who weigh less than 1,000 g, about 90% of these babies will require at least one transfusion. The need for transfusion in this population has a number of causes, the most significant of which is anemia due to prematurity. Anemia of prematurity is a multifactorial effect of low body weight in the first few weeks after birth
India ranks first with 23.6% of premature births in the world. Premature neonates are the patient group requiring the most transfusions and approximately 85% of very low birth weight (ELBW) newborns receive transfusions at the end of the hospital stay. The reasons for increased transfusion in premature infants are immature hematopoiesis, poor hematological compensatory mechanisms, blood loss due to frequent laboratory tests, sepsis, necrotizing enterocolitis (NEC), bleeding, and consumptive coagulopathy. (Shanmugha Priya, 2018)

The standard definition of a neonate is that an infant with the age of newborn up to 28 days after birth and preterm is defined as an infant born alive before 37 weeks of gestation. There are 3 divisions of premature babies according to the time of birth, namely Extremely Preterm (<28 weeks), Very Preterm (28 – <32 weeks) and Moderate – Late Preterm (32 -36 weeks).1,2

Blood transfusion is the process of giving blood or blood-based products from one person to the circulatory system of another. Blood transfusions are associated with medical conditions such as large blood loss due to trauma, surgery, shock and malfunctioning of the red blood cell-forming organs.

Blood transfusion in premature babies
The trigger for transfusion for the neonate will vary depending on the clinical context, including gestational age at birth. General neonatal transfusion guidelines have been developed as a result of neonatal studies especially in very low birth weight (VLBW; <1.5 kg) infants. In neonatal intensive care units (NICUs) most transfusions are given to premature neonates (mostly <32 weeks’ gestation), some of whom will require transfusion after 28 days. In general, infants of all gestational and postnatal ages in the NICU will tend to be transfused using the same guidelines although there is little specific evidence associated with term infants. Thresholds for transfusion are usually based on hemoglobin (Hb) concentration, platelet count and/or coagulation test results.1,2
Overall from the 1990s to the present it has been reported that up to 90% of very low birth weight (ELBW) infants and 58% of premature infants <32 weeks of gestational age receive red blood cell transfusions (PRCs), mainly due to iatrogenic loss and ventilation requirements. .1

Red blood cell transfusion
The majority of very premature neonates (<28 weeks gestation) received at least one red cell transfusion because they were frequently anemic, partly due to loss of blood sampling (note: 0.5 ml blood sample in 500 g (1 ml/kg) infant, approximately equivalent to 70 ml of sample in a 70 kg adult), or sometimes with a larger sample volume than required. The use of cord blood for baseline blood testing for VLBW neonates has been advocated to reduce the need for transfusion. Neonatal transfusions are usually given as additional small volume transfusions to maintain Hb above a certain threshold or because of the presence of surrogate markers of anemia, such as increased episodes of apnea. 4
In general, PRC is beneficial for preterm infants who are ill and in intensive care by increasing circulating hemoglobin (Hb), increasing tissue oxygenation, and reducing cardiac output to maintain the same level of oxygenation. 4

Picture. 1. Fetal circulation scale

Picture. 1. Fetal circulation scale (A) and hemodynamic adaptations after birth (after direct cord clamping [B] or during delayed cord clamping [C]). OD: right atrium; OG: left atrium; DV: right ventricle; VG: left ventricle; AP: pulmonary artery; FO: foramen ovale; AD: ductus arteriosus; PA: arterial pressure; O: organs; yellow: vascular and / or tissue resistance; cross mark: clamping the umbilical cord; arrow direction: blood circulation direction; red arrow: blood is rich in oxygen; blue arrow: oxygen-poor blood; purple: oxygen-poor blood.

The potential benefits of transfusion in this group include increased tissue oxygenation and lower cardiac output to maintain the same level of oxygenation. These benefits need to be weighed against possible adverse outcomes. The major serious complications of prematurity including bronchopulmonary dysplasia, retinopathy of prematurity, intraventricular hemorrhage, and necrotizing enterocolitis can follow neonatal transfusion, all of which cause significant morbidity and mortality in premature infants. 4

Picture. 2. Pathophysiology of anemia

Picture. 2. Pathophysiology of anemia

Picture. 2. Pathophysiology of anemia due to prematurity as described by the interaction of physiological events, occurring late in pregnancy, which is “missed” by prematurely born infants plus premature complications that contribute to reduced red blood cell status and erythropoiesis.

One of the causes of anemia in premature infants is fetomaternal transfusion, which refers to the entry of fetal blood into the mother’s circulation before or during delivery. Antenatal fetomaternal hemorrhage is a pathological condition with a wide spectrum of clinical variations. Although there is no universally accepted definition of the fetal erythrocyte transfer rate that constitutes a fetomaternal transfusion, the range of blood volumes ranges between 10 and 150 mL. Massive fetomaternal transfusion is when a blood volume greater than 80 mL is transferred. Fetal bleeding is secondary to anemia that occurs, it may have adverse consequences for the fetus such as neurologic injury, stillbirth, or death of the newborn. Presentation is often without clear trigger factors. (Wylie, 2010)

. The effect of red blood cell unit preparation and storage on heme, iron, and oxidative status relates to the ability of premature infants to cope with these changes. Red blood cell units are a potential source of heme, iron and free radicals, and these increase with storage age. Hemolysis from red blood cell transfusions can add iron-free hemoglobin to the baby.4

The majority of red cell transfusions for neonates are supplementary small volume transfusions (usually 10-20 ml/kg, usually 15 ml/kg over 4 hours) given to replace losses in the context of premature anemia, especially for VLBW infants. There is very limited evidence to determine the optimal volume for red cell transfusion, particularly with regard to long-term outcomes. Volumes greater than 20 ml/kg may increase the risk of volume overload in patients who are not bleeding. Therefore, in the context of data supporting the restrictive transfusion threshold of patients of all age groups including neonates.5

Blood transfusion policies and methods to ensure their implementation have an impact in reducing the number of red blood cell transfusions. The Hb level is widely used as a marker of the need for transfusion despite its limitations. The specific threshold of Hb at which neonates are transfused varies according to cardiorespiratory status and age after birth, in part following the normal physiologic decline in Hb during the first few weeks of life.

Indications for red blood cell transfusion

Anemia becomes symptomatic when there is an imbalance between oxygen delivery and consumption that may not occur universally at the same Hb for every preterm infant. Symptoms of anemia (eg, desaturation, bradycardia, increased oxygen demand, and tachycardia) are nonspecific and may be due to other causes including sepsis, development of pulmonary conditions (including worsening of respiratory distress syndrome), or gastro-oesophageal reflux. Therefore, PRC transfusion may not result in such clinical improvement. Generally, PRC transfusions are given to keep the Hb level above a certain threshold depending on the level of cardiorespiratory support required. Nearly half of the PRC transfusions given to ELBW infants were administered during the first 2 weeks of life, when there was impaired cardiorespiratory and laboratory blood cell collection; blood loss due to weekly blood sampling during this period averages 10-30% of the total blood volume (10-25 mL/kg). PRC transfusions are also given because of acute blood loss (eg, maternal fetal haemorrhage or placental abruption) or because of clinical symptoms regardless of Hb level, or infants are breathing spontaneously, but with Hb below a certain threshold, with the aim of increasing their body weight1

Algorithm: PRC Transfusion Neonatal Guidelines for

Algorithm: PRC Transfusion Neonatal Guidelines for

Blood Transfusion Threshold
There is no consensus on the threshold at which premature infants should receive PRC transfusions. Hb levels are subjective and vary among different education centers despite recently published national guidelines. The British Committee for Standards in Hematology (BCSH) published revised guidelines in 2016 and a second edition of the American practice guidelines for PRC transfusion was published in 2007. This emphasizes the importance of defining poor cardiopulmonary status. A comparison of guidelines from different countries highlights how varied these thresholds are internationally.1

Blood Transfusion Threshold

Blood Transfusion Threshold

Benefits of Blood Transfusion
PRC transfusions are life saving when given to replace acute bleeding loss by replenishing circulating blood volume. The potential benefits of PRC transfusion for anemic premature infants include prevention of apnea and weight gain.3

Lack of Blood Transfusion
Complications of PRC transfusion include increased plasma free iron and possible iron overloading of the liver with iron in very low birth weight (VLBW) infants, which is a clinical implication of iron being removed from red blood cells during storage of red blood units as a result of oxidative damage to the RBCs. RBC membrane and hemoglobin. 7
Because of the physiological importance of iron and the potential toxic effects of free iron, the body is equipped with a very precise homeostatic mechanism to regulate iron bioavailability. The ability of albumin to bind iron appears to be of great importance as a defense mechanism against iron-induced oxidative damage. Serum albumin levels are lower in premature infants compared to term infants. Serum albumin in premature infants is highly susceptible to oxidative stress. Caeruloplasmin, which converts iron into the form required to bind to transferrin, may also be low in premature infants. Serum hepcidin concentrations are lower in preterm infants than in term infants. 7
Free heme has pro-oxidant and pro-inflammatory activities and many other potentially toxic activities. The potential toxicity of heme is limited by the presence of the heme-binding protein hemopexin. Thus adequate availability of hemopexin is required to prevent the toxic effects of heme. Premature infants have very low levels of hemopexin which makes them susceptible to the effects of excessive heme-mediated transfusion. 7

Figure 3. Hemolysis process

Figure 3. Hemolysis process

Storage of red blood cell units was associated with a gradual increase in malondialdehyde (MDA). MDA is a marker of lipid peroxidation. It is known that oxidative stress, normal aging and aerobic incubation lead to the release of free iron from Hb in erythrocytes. This suggests that lipid peroxidation in the RBC membrane may contribute to the loss of iron and Hb. Thus the evidence suggests that oxidatively mediated hemolytic changes in the RBC membrane and damage to iron-binding proteins lead to the release of iron from red blood cells into the extracellular medium during PRC storage. 7

There is evidence that iron released in erythrocytes can mediate oxidative damage to cell membranes, leading to hemolysis. It can be further oxidized to produce superoxide, methemoglobin and free iron. Methemoglobin is relatively unstable and will easily release the heme portion from the heme bag. Further oxidation of the heme molecule causes the release of free iron. Thus the lack of antioxidant protection contributes to oxidative damage to cell membranes and binds to proteins such as iron as Hb. The potential adverse effects of biochemical storage and the validity of stored erythrocytes are termed “storage lesions”.7

Many of these involve iron-mediated transfusion-induced factors such as infection and oxidative stress, changes in immune function and also other factors such as nitric oxide (NO)-mediated and responsive changes. 7

Figure 4. The process of formation of prooxidation and proinflammatory in hemolysis

Figure 4. The process of formation of prooxidation and proinflammatory in hemolysis

Perhaps the greatest controversy surrounding PRC transfusion in premature infants is its association with necrotizing enterocolitis (NEC). There are reports of a transient association between PRC transfusion and NEC occurring within 72 hours of this transfusion. 25–35% of NEC cases are transiently associated with RBCT and the terms “transfusion-associated NEC” or “transfusion-associated acute bowel injury”. 1, 7

Figure 5. The process of NEC in PRC . transfusion

Figure 5. The process of NEC in PRC . transfusion

Increased superior mesenteric artery blood flow and therefore impaired blood flow and organ perfusion are important etiologies in the development of NEC. In addition, the age of storage of blood units, the more likely the occurrence of NEC, and oxidative stress have been mentioned as potential factors. PRC transfusion induces a pro-inflammatory response that may support the pathogenesis of transfusion-associated NEC. 6

PRC transfusion volume is associated with retinopathy of prematurity (ROP) and most studies suggest that iron overload and oxidative stress may be major players in ROP. In addition, the increased delivery of O2 to the retinal vasculature after transfusion with adult RBCs may impair the function of growth factors that regulate retinal vasculature. Again low birth weight and respiratory distress were also independent risk factors for the development of ROP

Multivariate regression analysis found that gestational age and frequency of blood transfusions were independently associated with the risk of developing ROP (Cooke et al, 1993). They reported a 9% increase in the risk of ROP with each transfusion administered (95% CI 1.0–1.18). Hesse et al demonstrated by the same statistical method, that blood transfusion was an independent risk factor for ROP. In this study, the relative risk of developing ROP was 6.4 (95% CI 1.2-33.4) for infants who received 16-45 ml/kg, and 12.3 (1.6-92.5) for those who had received more of 45 ml/kg blood (reference, 0-15 ml/kg). (Mikaniki, 2012)

Figure 6. The process of ROP

Figure 6. The process of ROP

PRC transfusion given before the occurrence of intravascular hemorrhage (IVH) is an independent risk factor for the development of severe IVH. The association between IVH and blood receptivity may be related to volutrauma and damage to weak blood vessels in the germinal matrix. This may be further exacerbated by loss of NO from erythrocytes during storage which would impair capillary vasodilation. 6

In premature infants, red cell transfusion was found to be associated with bronchopulmonary dysplasia (BPD), and an increased number of transfusions was found to be associated with disease severity. Transfusion-associated iron overload and oxidative stress are potential mechanisms linking transfusion to the development of BPD. The association between blood transfusion and BPD may be related to the finding that infants with BPD are usually smaller, require more ventilator support and require more blood sampling, leading to iatrogenic anemia. As a result more blood transfusions will be required to replace the one taken by sampling. This suggests a potential consequence of very low birth weight rather than a direct cause of BPD. However, receiving a blood transfusion and the associated complications caused by it can exacerbate conditions developing from other causes. The main factor in the development of BPD is endotracheal infection. Recent studies in critically ill adults have shown that transfusions with blood stored for more than 14 days are associated with an increase in bacterial infections. Since iron availability is critical for bacterial colonization, and iron-mediated transfusion promoting bacterial infection may be involved in the development of BPD.
In a study conducted by Zhang et al in 2014, the incidence of BPD was significantly higher in the group of infants with transfusion than in the group without transfusion (37.2% vs. 2.1%, P < 0.00001). After adjusting for potential risk factors, the adjusted odds ratio for BPD was 9.80 (95% confidence interval, 1.70–56.36; P = 0.01). This study demonstrated an association between PRBC transfusion and BPD in premature infants.(zhang, 2014)

Neonatal platelet transfusion
Thrombocytopenia, generally defined as a platelet count less than 150 × 109/L, is the second most common (after anemia) haematological disorder in infants admitted to neonatal intensive care units (NICUs). It affects 18-35% of all patients admitted to the NICU and approximately 70% of very low birth weight (ELBW) infants with a birth weight of less than 1,000 grams.

The etiology of thrombocytopenia is very diverse. Clinically, a distinction is often made between “early onset” (≤3 days of life) and “late-onset” (≥4 days of life) neonatal thrombocytopenia. Impaired intra-uterine growth, pregnancy-induced hypertension or diabetes, perinatal infection, and transplacental passage of maternal allo- or autoantibodies are frequently associated with early-onset thrombocytopenia. Late onset neonatal thrombocytopenia is most often caused by bacterial infection or necrotizing enterocolitis

Hyporesponsiveness of neonatal platelet activation and aggregation to most agonists (including ADP, epinephrine, collagen, thrombin, and thromboxane analogues), compared with adult platelets. In particular, the lack of response to epinephrine is explained by the presence of fewer 2-adrenergic receptors on neonatal platelets, a reduced response to collagen likely a consequence of impaired calcium mobilization, and reduced neonatal thromboxane. Decreased expression of PAR-1 and PAR-4 receptors on neonatal platelets explains the decreased response to thrombin. While this platelet hyporeactivity is expected to produce a bleeding tendency. The presence of compensatory factors in the neonatal blood that promote clot formation and perfect balance of neonatal platelet hyporeactivity, leads to normal BT and CT. These compensatory factors include a high hematocrit in neonatal blood, neonatal red cells with a high MCV, and the predominance of the ultralong polymer von Willebrand Factor, which is also present at high concentrations in neonatal plasma. Thus, neonatal platelet hyporeactivity should not be considered as a deficiency of clotting factors or factors that lead to bleeding tendencies, but rather a part of a balanced and unique hemostatic system. 9

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