INTRODUCTION — Erythropoiesis decreases markedly after birth. This occurs due to the onset of breathing and closure of the ductus arteriosus, which increase tissue oxygenation and reduce production of erythropoietin (EPO) . In healthy term infants, a mild anemia develops as hemoglobin (Hgb) levels decline over the first 8 to 12 weeks after birth (referred to as the "physiologic nadir") (figure 1). (See "Approach to the child with anemia", section on 'Age of patient'.)
Preterm infants have lower Hgb values at birth compared with term infants and the postnatal decline in Hgb occurs earlier and is more pronounced than the physiologic anemia seen in term infants. This is compounded by other factors that contribute to more severe anemia (blood loss from phlebotomy, reduced red blood cell [RBC] lifespan, depleted iron stores). Together, these processes are referred to as anemia of prematurity (AOP).
The pathogenesis, clinical features, and management of AOP will be reviewed here, including a summary of indications for RBC transfusion in preterm neonates. A more detailed discussion of RBC transfusion in neonates is proved separately. (See "Red blood cell (RBC) transfusions in the neonate".)
DEFINITIONS OF PREMATURITY — Definitions of different degrees of prematurity based upon gestational age (GA; which is calculated from the first day of the mother's last period) or birth weight (BW) are provided in the table (table 1).
CAUSES AND CONTRIBUTING FACTORS — The primary cause of AOP is the impaired ability to increase serum erythropoietin (EPO) appropriately in the setting of anemia and decreased tissue availability of oxygen [2,3]. Circulating and bone marrow red cell progenitors respond to EPO, if present, indicating that the impaired erythropoiesis is due to lack of EPO, not a failure to respond to the hormone [4-6]. Other hematopoietic growth factors (eg, granulocyte-macrophage colony-stimulating factor) are not affected.
While AOP is directly due to impaired EPO production, several other factors can contribute to anemia in preterm infants, including blood loss from phlebotomy, reduced red blood cell life span, and iron depletion.
Impaired erythropoietin production — EPO is produced by the fetal liver and the cortical interstitial cells of the kidney in response to hypoxia. Its production is regulated by the transcription factor hypoxia inducible factor-1 (HIF-1). Its primary function is to regulate erythrocyte production. EPO does not cross the placenta; fetal production increases with gestational age [7-10].
In preterm infants, EPO levels increase modestly in response to anemia and tissue hypoxia; however, the response is less than what is seen in older children and adults with the same degree of anemia [2,11]. (See "Regulation of erythropoiesis".)
In AOP, the specific mechanisms leading to the discrepancy between serum EPO concentration and the severity of the anemia are uncertain. Proposed pathogenetic pathways involve the site of EPO production and the developmental regulation of transcription factors in the liver versus the kidney.
●The liver is the principal site of EPO production in the fetus [12,13]. The feedback increase in hepatic EPO mRNA in response to anemia or hypoxia may be less than that of the kidney . EPO mRNA expression in the kidney is present in the fetus, and increases significantly after 30 weeks gestation, suggesting that the switch to the kidney as the main site of EPO production is developmentally regulated.
●The fetal or neonatal environment may alter the response to hypoxic signals by the liver. Support for this hypothesis comes from the observation that hepatic transplantation from fetal and neonatal lambs into adult sheep increased EPO production by the transplanted liver .
●Transcriptional regulatory factors, such as HIF-1, may contribute to low levels of EPO in preterm infants. These factors activate target genes, including those encoding EPO, in response to decreased cellular oxygen concentration [16,17]. They appear to be developmentally regulated in some fetal tissues, which might account for the decreased expression of EPO in response to anemia in preterm infants [1,18].
Blood loss from phlebotomy — Iatrogenic blood loss due to phlebotomy for blood tests is a major contributor to anemia in preterm neonates. There is a strong correlation between the amount of blood lost from phlebotomy and the number of transfusions preterm neonates require . The volume of blood loss increases with illness severity and decreasing gestational age since critically ill, extremely preterm neonates tend to require more frequent laboratory tests [20,21]. Phlebotomy-related blood loss in preterm infants may be greater than is necessary for the care of the neonate .
Strategies to reduce iatrogenic blood loss include:
●Limiting blood sampling to essential testing only
●Using microtechniques (sampling and testing with very small volumes of blood)
●Using point-of care devices that can perform testing on small blood volumes
●Using noninvasive methods for monitoring when possible (eg, pulse oximetry and transcutaneous carbon dioxide monitors [TCOM] rather than frequent blood gas sampling)
In studies involving extremely low birth weight (ELBW; <1000 g) infants, total phlebotomy-related blood loss reached approximately 40 to 50 mL/kg by the end of the second week of the neonatal intensive care unit (NICU) stay and 80 mL/kg after 10 weeks [19,21]. In one study, approximately 50 percent of iatrogenic blood loss was related to sampling for blood gas analysis .
These studies emphasize the need for NICU policies to ensure that only the minimal volume required for testing is drawn, and unnecessary tests are avoided.
Reduced red blood cell life span — Red blood cell survival in newborn term infants is approximately 60 to 80 days, but decreases with decreasing gestational age to a range of 45 to 50 days in extremely low birth weight infants (ELBW) (BW below 1000 g) . The reduced red cell life span contributes to the severity of anemia. Increased susceptibility to oxidant injury may contribute to shortened red cell survival in the neonate [24,25]. (See "Red blood cell survival: Normal values and measurement".)
Iron depletion — Although it is not involved in its pathogenesis, iron depletion may impair recovery from AOP. Because of their rapid growth rate, preterm infants have increased utilization and depletion of iron stores and, as noted above, blood loss from phlebotomy. The administration of iron does not inhibit the fall in hemoglobin concentration due to AOP. However, in term infants, it reduces the incidence of iron deficiency anemia in the first year of life . (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis".)
Low levels of other nutrients, such as vitamin B12 or folate, do not appear to contribute to neonatal anemia . However, limited clinical trial data suggest that in preterm neonates receiving erythropoietin therapy, supplementation with folate and B12 may enhance erythropoiesis [26,27].
PHYSIOLOGIC CONSEQUENCES — The main physiologic consequence of anemia is impaired oxygen delivery. Oxygen delivery is the rate at which oxygen is transported from the lungs to the tissues. It depends upon the following (see "Oxygen delivery and consumption"):
●Oxygen carrying capacity (affinity) of hemoglobin
●Arterial oxygen saturation and oxygen tension
In preterm infants with anemia, compensatory physiologic changes that attempt to maintain adequate oxygen delivery include increases in heart rate and stroke volume, which improve cardiac output . These are similar to compensatory changes that occur in older children and adults with anemia.
However, anemic preterm infants may be less able to maintain oxygen delivery because of the following:
●Higher levels of hemoglobin F (HbF) – HbF-containing red cells in the preterm infant have a considerably higher oxygen affinity than adult red blood cells, resulting in reduced release of oxygen to tissues (figure 2). HbF binds poorly to 2,3 diphosphoglycerate (2,3-DPG), a potent modulator that diminishes the affinity of hemoglobin for oxygen. Decreased binding increases oxygen affinity and shifts the oxyhemoglobin dissociation curve to the left, resulting in decreased peripheral oxygen delivery (figure 2). The proportion of HbF increases with decreasing gestational age, and is regulated developmentally so that HbF levels are similar at the same postmenstrual age [29-31]. The concentration of HbF in an infant born at 28 weeks gestation is approximately 90 percent, and decreases to approximately 60 percent at 10 weeks after birth, a value that is similar to that of an infant newly born at 38 weeks gestation . (See "Structure and function of normal hemoglobins".)
●Concomitant respiratory disease – Many preterm neonates have hypoxia due to respiratory disorders, such as respiratory distress syndrome and bronchopulmonary dysplasia. (See "Respiratory distress syndrome (RDS) in the newborn: Clinical features and diagnosis".)
●Limitations on target oxygen saturation – For preterm infants requiring respiratory support, standard practice is to avoid hyperoxia due to its harmful effects (eg, risk of bronchopulmonary dysplasia and retinopathy of prematurity). (See "Bronchopulmonary dysplasia (BPD): Clinical features and diagnosis" and "Retinopathy of prematurity (ROP): Risk factors, classification, and screening", section on 'Risk factors'.)
Timing of onset — AOP typically occurs at 3 to 12 weeks after birth in infants <32 weeks gestational age (GA). The onset of AOP occurs earlier in more premature infants [1,32,33]. The anemia typically resolves by three to six months of age.
In a study of 40 very low birth weight (VLBW) infants, average hemoglobin (Hgb) concentrations fell from 18.2 g/dL at birth to a mean nadir of 9.5 g/dL at six weeks of age . Values of 7 to 8 g/dL were common even in the absence of significant phlebotomy losses. Hematocrit values were lowest in the smallest infant with average nadirs of 21 percent in infants with birth weights (BW) less than 1000 g, and 24 percent in infants with BW between 1000 and 1500 g.
Signs and symptoms — Many infants are asymptomatic despite having Hgb values <7 g/dL [35,36]. However, other infants with AOP are symptomatic at similar or even higher Hgb levels because of a reduced capacity to compensate for the degree of anemia. (See 'Physiologic consequences' above.)
Symptoms associated with AOP may include:
●Tachycardia that is otherwise unexplained
●Poor weight gain
●Increased oxygen or respiratory support requirement
●Increased episodes of apnea or bradycardia
In a prospective study of preterm infants with BW <1500 g, apneic episodes increased with decreasing hematocrit values and improved after red blood cell transfusion .
Laboratory features — The following laboratory findings are characteristic of AOP:
●Normocytic and normochromic anemia.
●Low reticulocyte count.
●While not routinely performed, bone marrow examination would show reduced red blood cell precursors .
●While not routinely measured in clinical practice, serum erythropoietin levels are low in preterm infants during the first postnatal month compared with normal values in older children and adults (<10 versus 15 mU/mL) and remain inappropriately low through the second postnatal month .
MANAGEMENT — Clinicians who care for preterm infants should anticipate the development of AOP, particularly in very low birth weight (VLBW; <1500 g) and extremely low birth weight (ELBW; <1000 g) infants. Optimal nutrition (including iron supplementation) should be provided and patients should be monitored for signs of anemia. Blood sampling should be limited to essential testing, and microtechniques should be used to minimize blood loss due to phlebotomy [22,38]. (See 'Blood loss from phlebotomy' above.)
Routine iron supplementation — The iron content at birth is lower in preterm infants than in term infants, and the iron stores of preterm infants often are depleted by two to three months of age. As a result, all preterm infants require iron supplementation. The target for daily intake is approximately 4 mg/kg per day.
●Breastfed infants – Breastfed infants should receive iron supplementation of 2 to 4 mg/kg per day through the first year of life. (See "Breastfeeding the preterm infant", section on 'Vitamin D and iron supplements'.)
●Formula-fed infants – Iron-fortified formulas have higher iron concentrations compared with breast milk and therefore formula-fed preterm infants require less additional iron supplementation compared with exclusively breastfed infants. The amount of supplemental iron required varies depending on the specific formula used, but it is typically 1 to 3 mg/kg per day. Low iron-containing preterm formulas should not be used as they do not adequately provide the necessary iron required for these patients. (See "Nutritional composition of human milk and preterm formula for the premature infant".)
Although iron supplementation does not prevent AOP, iron supplementation allows for greater iron substrate when erythropoiesis is stimulated . Iron supplementation does not necessarily prevent development of iron-deficiency anemia later in the first year of life. Thus, all preterm and term infants should undergo routine screening, as discussed separately. (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis".)
Neonates who are treated with erythropoiesis stimulating agents (ESAs) require additional iron supplementation, as discussed below. (See 'Additional iron supplementation' below.)
Laboratory monitoring — The hematocrit (HCT) or hemoglobin (Hgb) concentration should be monitored on a weekly basis in ELBW infants in the first weeks of life. Thereafter, it is generally not necessary to routinely monitor HCT/Hgb in healthy growing preterm infants. Infants with persistent illness (eg, bronchopulmonary dysplasia) or surgical issues may require ongoing monitoring.
Measuring the reticulocyte count is not routinely necessary but may occasionally be useful. Examples include:
●If there is concern for another etiology of anemia besides AOP (eg, hemolytic anemia), measuring the reticulocyte count may be warranted. (See "Overview of hemolytic anemias in children", section on 'Reticulocyte count'.)
●In patients with borderline HCT/Hgb values (ie, values that are approaching thresholds for transfusion), the reticulocyte count can occasionally help guide decisions about RBC transfusion, as discussed separately. (See "Red blood cell (RBC) transfusions in the neonate", section on 'Transfusion thresholds'.)
●In neonates who are receiving ESAs, reticulocyte indices (if available) can help guide the management of iron supplementation. (See 'Monitoring' below.)
Transfusion — RBC transfusion is the most rapidly effective treatment for AOP. However, transfusion is a temporary measure, it has well-established risks (eg, transfusion-transmitted infections, immune-mediated transfusion reactions, graft-versus-host disease, toxic effects of anticoagulants or preservatives), and has the disadvantage of further inhibiting erythropoiesis. (See "Red blood cell (RBC) transfusions in the neonate", section on 'Risks'.)
RBC transfusion is generally warranted when the degree of anemia causes symptoms or compromises oxygen delivery. Guidelines for RBC transfusion are based upon the degree of anemia (ie, the HCT/Hgb) and the patient's clinical status (ie, hemodynamic stability, respiratory support requirement, degree of symptoms). Signs and symptoms of anemia in preterm neonates may include otherwise unexplained tachycardia, poor weight gain, increased requirement of supplemental oxygen, and/or increased episodes of apnea or bradycardia. (See 'Signs and symptoms' above.)
For most preterm neonates with AOP, we recommend using a restrictive transfusion strategy (ie, transfusing at a lower Hgb level) rather than a liberal strategy (transfusing at a higher Hgb level). The thresholds we use to trigger transfusion are based chiefly upon HCT/Hgb levels, postnatal age, and clinical status (table 2). Additional details regarding RBC transfusion, including selection of RBC products and guidance on administration of transfusions are provided separately. (See "Red blood cell (RBC) transfusions in the neonate".)
The practice of using a restrictive transfusion approach in preterm neonates is supported by randomized clinical trials and meta-analyses demonstrating that using restrictive transfusion thresholds reduces exposures to transfusion without increasing mortality or serious morbidity [40-46]. Most of these trials involved ELBW neonates. In a meta-analysis of five trials (3325 neonates), patients assigned to restrictive versus liberal transfusion protocols had similar mortality rates (14 percent in both groups; relative risk [RR] 0.99, 95% CI 0.84-1.17) . Other neonatal morbidities (bronchopulmonary dysplasia, sepsis, necrotizing enterocolitis, retinopathy of prematurity, intraventricular hemorrhage) were also similar in both groups, as was hospital length of stay. In the two trials (1739 patients) that assessed neurodevelopmental outcomes at 18 to 24 months, rates of neurodevelopmental impairment were similar in both groups (39 versus 36 percent; RR 1.08, 95% CI 0.88-1.33) [40,42,46].
Most of these trials demonstrated that restrictive transfusion protocols reduce the number of transfusions given. For example, in one of the largest trials (the ETTNO trial, which included 1013 ELBW neonates), the restrictive threshold group had a lower incidence of any transfusion (60 versus 79 percent) and lower cumulative volume of transfused blood (median 19 versus 40 mL) . Similarly, in another large multicenter trial (the TOP trial, which included 1824 ELBW infants), patients in the restrictive threshold group on average received approximately two fewer transfusions compared with patients in the liberal threshold group (mean transfusions 4.4 versus 6.2) .
The transfusion thresholds used in the restrictive and liberal groups varied somewhat between the different trials. Most protocols were based upon postnatal age and respiratory support requirement. For example, in the ETTNO trial, the restrictive transfusion threshold for stable neonates ≤7 days old was HCT <28 versus <35 percent in the liberal transfusion protocol. For critically ill neonates ≤7 days old, transfusion thresholds were HCT <34 and <41 percent, respectively .
Erythropoiesis stimulating agents (ESAs) — The pathogenetic importance of impaired erythropoietin production in AOP provides the rationale for the therapy with erythropoiesis stimulating agents (ESAs) including recombinant human erythropoietin (epoetin alfa) and its longer-acting analog darbepoetin. Use of ESAs varies by institution.
Clinical use — The practice of using ESAs is not standardized and varies from center to center. ESAs may be used in neonates in the following settings:
●VLBW and ELBW infants whose parents/caregivers refuse blood transfusions for religious reasons. (see "Approach to the patient who declines blood transfusion", section on 'Erythropoiesis-stimulating agents (ESAs/EPO)')
●Infants with alloimmune hemolytic disease of the newborn. This is discussed separately. (See "Alloimmune hemolytic disease of the newborn: Postnatal diagnosis and management", section on 'Erythropoiesis stimulating agents'.)
●Infants with chronic kidney disease. This is discussed separately. (See "Chronic kidney disease in children: Complications", section on 'Erythropoiesis-stimulating agents'.)
●For routine prophylaxis in at-risk preterm neonates. This includes all ELBW infants and select VLBW infants (ie, those requiring frequent blood draws or who are undergoing surgery). There is considerable practice variation regarding use of ESAs in this setting. At the author's institution, ESAs are not routinely used in this setting; however, other centers routinely use ESAs in all ELBW neonates. (See "Red blood cell (RBC) transfusions in the neonate", section on 'Strategies to reduce RBC transfusion'.)
For ELBW and VLBW infants, the optimal approach is uncertain. The arguments for and against routine use of ESAs in this setting are as follows:
●The main argument against routine use is that when other strategies are used to reduce transfusion and donor exposure, the additional benefit of ESA therapy may be marginal. Other strategies include [47,48]:
•Providing optimal nutrition, including iron supplementation (see 'Routine iron supplementation' above and "Approach to enteral nutrition in the premature infant")
•Minimizing blood loss from phlebotomy by using microtechniques and limiting blood sampling to essential testing (see 'Blood loss from phlebotomy' above)
•Using a restrictive approach to RBC transfusion (see 'Transfusion' above)
•Using satellite packs (RBC units from a single donor that are divided into multiple smaller aliquots, allowing for repeated transfusions from the same donor to the individual infant) (see "Red blood cell (RBC) transfusions in the neonate", section on 'Administration')
In addition, the available clinical trial evidence suggest ESAs do not improve neurodevelopmental outcomes, as described below. (See 'Efficacy' below.)
●The main argument in favor of routine use of ESAs in this population is that they reduce transfusion rates and donor exposures. Limited data suggest they may be cost-saving . Data supporting the efficacy of ESAs are summarized below. (See 'Efficacy' below.)
●Darbepoetin alfa: 10 mcg/kg per dose given subcutaneously or intravenous (IV) once weekly.
●Subcutaneous epoetin alfa: 400 units/kg per dose given three times per week. For infants <1000 g, this is given as 0.2 mL/kg of the 2000 units/mL solution. As the infant grows, preparations with higher concentrations (up to 10,000 units/mL) can be used. An alternative regimen is 1200 units/kg per dose given subcutaneously once weekly .
●IV epoetin alfa: 200 units/kg per dose as an infusion over at least four hours given three times a week. Alternatively, IV epoetin can be given as a daily dose of 200 units/kg per dose as a continuous infusion over 24 hours (typically as an addition to total parenteral nutrition [TPN]). IV epoetin should be mixed in a protein-containing solution (5 percent albumin or TPN) .
●For infants tolerating enteral feeds, iron is given enterally. A typical initial regimen consists of ferrous sulfate 6 mg/kg of elemental iron once daily. Depending on the response, the dose can be increased if needed up to a maximum of 12 mg/kg per day (see 'Monitoring' below). When using doses ≥8 mg/kg, it should be divided into two daily doses.
●For infants not yet tolerating enteral feeds (ie, those receiving TPN), supplementation can be given intravenously (IV) with either iron sucrose or iron dextran (for the latter, a test dose is recommended prior to starting maintenance dosing). Various dosing regimens have been described, including 1 mg/kg per day, 1.5 mg/kg twice weekly, or 3 to 6 mg/kg once weekly [52,55-58]. At some centers, IV iron is added to the TPN .
Extremely low birth weight (ELBW) infants (birth weight <1000 g) receiving ESA therapy are at risk for iron deficiency even if they are receiving iron supplementation .
●Multivitamin once daily
●Folate 50 micrograms orally once daily
●Vitamin E 15 international units orally once daily
Monitoring — The reticulocyte count, central hematocrit or hemoglobin concentration, absolute neutrophil count (ANC), and ferritin level are measured before and one to two weeks after starting ESA treatment. If the ANC falls below 1000/microL, the ESA should be held.
The neonate's response to therapy can be monitored with either of the following tests:
●Reticulocyte hemoglobin content (ret-He; also called CHr) – If available at the center, the ret-He can be used to monitor adequacy of iron therapy during ESA treatment. Low ret-He values reflect early iron deficient erythropoiesis [61-64]. The ret-He is checked at two weeks of age and then every two to four weeks while on treatment. The goal is to maintain the ret-He in the range of 29 to 35 pg . If the ret-He falls below 29 pg, iron supplementation should be increased. Many automated hematology instruments routinely report ret-He and other reticulocyte parameters. However, the ret-He may not be available in all laboratories. (See "Automated complete blood count (CBC)", section on 'Reticulocytes'.)
●Serum ferritin – Ferritin levels can also be used to assess adequacy of iron supplementation. If this strategy is used, ferritin levels should be monitored every two weeks. If the neonate's ferritin level is <15 ng/mL, iron supplementation should be increased; if the level is >400 ng/mL, iron therapy should be discontinued .
Discontinuing therapy — We suggest discontinuing ESA therapy once the hematocrit is ≥50 percent or the neonate's corrected gestational age is ≥35 weeks, whichever is earlier. ESA therapy should be discontinued sooner if the neonate experiences adverse effects related to therapy (eg, neutropenia, hypertension, thrombosis). (See 'Adverse effects' below.)
ESA and iron therapy should generally not be held or discontinued following RBC transfusion except in the case of double exchange transfusion for alloimmune hemolytic anemia. (See "Alloimmune hemolytic disease of the newborn: Postnatal diagnosis and management", section on 'Exchange transfusion'.)
Adverse effects — Use of ESAs in preterm infants appears to be safe. In the available studies involving preterm neonates, the most common adverse effects were:
●Neutropenia, which is generally transient and resolves with stopping the agent [66,67].
●Iron deficiency, particularly if supplementation is inadequate [67-69].
Adverse effects that have been observed in other populations receiving ESAs (eg, patients with advanced kidney disease) include hypertension, seizures, rash, bone pain, and development of anti-erythropoietin antibodies. These have not been reported in preterm infants. Nevertheless, ESA therapy should be discontinued if the neonate experiences thrombotic complications, clinically significant hypertension, or seizures. (See "Treatment of anemia in patients on dialysis", section on 'Adverse effects of ESAs' and "Introduction to recombinant hematopoietic growth factors", section on 'Toxicity of colony-stimulating factors'.)
Efficacy — ESAs lower transfusion requirements in ELBW and VLBW infants. However, among transfused patients, ESAs may not reduce the number of blood donors to which the infant is exposed, regardless of whether the ESA is administered early (within the first week of life) or late (at or after eight days of life). In addition, based on the available data, ESAs do not appear to improve neurodevelopmental outcomes.
●Early (prophylactic) use – In a meta-analysis of 19 trials (1750 neonates), early ESA therapy (predominantly epoetin, started within the first eight days after birth) reduced the likelihood of needing a transfusion compared with no ESA therapy (52 versus 69 percent; relative risk [RR] 0.79, 95% CI 0.74-0.85) . In the two trials (n = 165 neonates) that provided information on donor exposures among transfused neonates, there was little to no difference in the number of donor exposures between infants treated with ESAs compared with placebo (mean difference 0.05, 95% CI -0.33 to 0.42). Rates of necrotizing enterocolitis and intraventricular hemorrhage were lower in ESA-treated infants compared with control. Rates of retinopathy of prematurity were higher in ESA-treated infants compared with control, but the difference was not statistically significant. Mortality rates were similar in both groups. Many of the trials included in the meta-analysis had important methodologic limitations (lack of blinding, incomplete or selective reporting of outcomes). Thus, the certainty of these findings is low.
●Late (therapeutic) use – In a meta-analysis of 21 trials (1202 neonates), late ESA therapy (predominantly epoetin, started 8 to 28 days after birth) reduced the likelihood of needing a transfusion compared with no ESA therapy (43 versus 60 percent; RR 0.72, 95% CI 0.65-0.79) . However, the total volume of blood transfused was similar in both groups (mean difference 1.6 mL/kg less in the ESA group, 95% CI 5.8 mL/kg less to 2.6 mL/kg more; based upon five trials [197 neonates]). In the two trials (n = 190 neonates) that provided information on donor exposures among transfused neonates, the number of donor exposures in ESA-treated neonates was slightly higher compared with placebo (mean difference 0.45, 95% CI 0.20-0.69). Mortality rates were similar in both groups, as were rates of necrotizing enterocolitis, intraventricular hemorrhage, sepsis, and bronchopulmonary dysplasia. Rates of retinopathy of prematurity were higher in ESA-treated infants compared with control, but the finding did not achieve statistical significance (RR 1.27, 95% CI 0.99-1.64).
●Impact on neurodevelopment – In the previously described meta-analysis of trials evaluating early ESA therapy, rates of neurodevelopmental impairment (NDI) at 18 to 22 months corrected age were lower in ESA-treated infants compared with control (13 versus 21 percent; RR 0.62, 95% CI 0.48-0.80; based on four trials [1130 neonates]) .
However, in two subsequent large multicenter trials that were not included in the meta-analysis, there was no apparent benefit of early ESA therapy on neurodevelopmental outcomes [55,72,73]. In the PENUT trial, which included 941 EPT infants who were randomized to epoetin or placebo starting within 24 hours after delivery, both groups had similar rates of moderate to severe NDI at age 22 to 26 months (38 percent in both arms; RR 0.97; 95% CI 0.79 to 1.18) . In a separate report from the PENUT trial, both groups had similar brain magnetic resonance imaging (MRI) findings at term equivalent, which correlated with neurodevelopmental outcome as assessed by the Bayley Scales . In the Swiss EPO trial, which included 448 preterm infants (GA between 26 weeks and 31 weeks and 6 days) randomized to epoetin or placebo starting at three hours after birth, both groups had similar mean scores on standardized developmental testing at age two years (mean Bayley MDI score 93.5 versus 94.5; difference -1.0, 95% CI -4.5 to 2.5]) . Neurodevelopmental outcomes at five years of age were also similar .
SUMMARY AND RECOMMENDATIONS
●Etiology, pathogenesis, and pathophysiology – Newborn infants have a fall in hematocrit soon after birth due primarily to impaired production of erythropoietin. Preterm infants have lower hemoglobin (Hgb) values at birth compared with term infants and the postnatal decline in Hgb occurs earlier and is more pronounced than the physiologic anemia seen in term infants. This is compounded by other factors that contribute to more severe anemia (blood loss from phlebotomy, reduced red blood cell [RBC] lifespan, depleted iron stores). Together, these processes are referred to as anemia of prematurity (AOP). (See 'Causes and contributing factors' above.)
Preterm infants are at particular risk for impaired oxygen delivery in the setting of anemia because they often have concomitant respiratory disease and have high levels of hgb F, which is less efficient in releasing oxygen to tissues. (See 'Physiologic consequences' above.)
•Timing of onset – AOP typically occurs at 3 to 12 weeks after birth in infants and it typically resolves by three to six months of age. (See 'Timing of onset' above.)
•Signs and symptoms – Many infants remain asymptomatic despite having Hgb levels <7 g/dL. However, other infants may be symptomatic at similar or even higher hgb levels. Symptoms may include tachycardia, poor weight gain, increased requirement of supplemental oxygen, and/or increased frequency of apnea or bradycardia. (See 'Signs and symptoms' above.)
•Laboratory features – The laboratory findings characteristic of AOP include normocytic and normochromic red blood cells, low reticulocyte count, and low erythropoietin levels. (See 'Laboratory features' above.)
●Management – Key components of managing AOP include:
•Optimal nutrition, including iron supplementation. (See 'Routine iron supplementation' above and "Approach to enteral nutrition in the premature infant".)
•Monitoring for signs of anemia.
•Limiting blood loss from phlebotomy by performing only essential tests and using microtechniques. (See 'Blood loss from phlebotomy' above.)
•Restrictive transfusion strategy – RBC transfusion is generally warranted when the degree of anemia causes symptoms or compromises oxygen delivery. For most preterm neonates with AOP, we recommend using a restrictive transfusion strategy (ie, transfusing at a lower Hgb level) rather than a liberal strategy (transfusing at a higher Hgb level) (Grade 1B). The thresholds we use to trigger transfusion are based chiefly upon HCT/Hgb levels, postnatal age, and clinical status (table 2) (see 'Transfusion' above). Additional details regarding RBC transfusion in neonates are provided separately. (See "Red blood cell (RBC) transfusions in the neonate" and "Red blood cell (RBC) transfusions in the neonate", section on 'Indications for transfusion'.)
●Role of erythropoiesis stimulating agents (ESAs) – The practice of using ESAs is not standardized and varies from center to center (table 3). ESAs may be used in neonates in the following settings (see 'Erythropoiesis stimulating agents (ESAs)' above):
•VLBW and ELBW infants whose parents/caregivers refuse blood transfusions for religious reasons. (See "Approach to the patient who declines blood transfusion", section on 'Erythropoiesis-stimulating agents (ESAs/EPO)'.)
•Infants with alloimmune hemolytic disease of the newborn. This is discussed separately. (See "Alloimmune hemolytic disease of the newborn: Postnatal diagnosis and management", section on 'Erythropoiesis stimulating agents'.)
•Infants with chronic kidney disease. This is discussed separately. (See "Chronic kidney disease in children: Complications", section on 'Erythropoiesis-stimulating agents'.)
•For routine prophylaxis in ELBW infants. There is considerable practice variation regarding use of ESAs in this setting and the optimal approach is uncertain. The advantages and disadvantages are discussed above. (See 'Clinical use' above.)
ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge Joyce M Koenig, MD, who contributed to an earlier version of this topic review.
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