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Anemia of prematurity (AOP)

Anemia of prematurity (AOP)
Author:
Joseph A Garcia-Prats, MD
Section Editor:
Steven A Abrams, MD
Deputy Editor:
Laurie Wilkie, MD, MS
Literature review current through: Dec 2022. | This topic last updated: Sep 21, 2022.

INTRODUCTION — Erythropoiesis decreases after birth as a result of increased tissue oxygenation due to the onset of breathing and closure of the ductus arteriosus, and a reduced production of erythropoietin (EPO) [1]. 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 sores). 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 transfusions in the newborn".)  

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).

PATHOGENESIS — 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.

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 in humans, and fetal production increases with gestational age [7-10].

Production of EPO in adults depends on the oxygen saturation of hemoglobin and tissue oxygen delivery, and is inversely proportional to central venous oxygenation. Although EPO levels in preterm infants with AOP increase slightly with hypoxia, they are lower than those seen in older children and adults with the same level 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 [14]. 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 [15].

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].

Other factors — Although 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.

Blood loss from phlebotomy — Preterm infants frequently develop an early anemia that is primarily due to iatrogenic blood loss due to phlebotomy for blood tests. The volume of blood loss increases with illness severity and decreasing gestational age. In one report, withdrawal of blood in excess of that required for laboratory studies contributed to iatrogenic blood loss by 2 to 4 mL/kg per week [19]. However, efforts to reduce blood loss from phlebotomy have resulted in changes in clinical practice to limit blood sampling for essential testing and the use of microtechniques, which have reduced iatrogenic blood loss.

The impact of clinical practice on phlebotomy and blood testing was illustrated in a study of very low birth weight (VLBW) infants (BW <1500 g) cared for in two neonatal intensive care units (NICUs) [20]. Phlebotomy losses increased with decreasing gestational age and increasing illness severity, as measured by the Score for Neonatal Acute Physiology (SNAP). The average losses due to phlebotomy differed between the two NICUs and resulted in increased average blood transfusion requirements in the NICU with the greater volume of blood loss. However, this difference was not associated with differences in the days of oxygen therapy or mechanical ventilation, risk of bronchopulmonary dysplasia, or growth rate by day 28 of life. These findings suggest that the additional use of blood in one of the NICUs was discretionary rather than necessary, as clinical outcomes did not differ.

These studies indicate that blood loss due to phlebotomy in preterm infants may be greater than is necessary for the care of the neonate. They emphasize the need for nursery 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) [21]. 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 [22,23]. (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 [2]. (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 [1]. However, limited clinical trial data suggest that in preterm neonates receiving erythropoietin therapy, supplementation with folate and B12 may enhance erythropoiesis [24,25].

Oxygen delivery — Oxygen delivery is the rate at which oxygen is transported from the lungs to the tissues. It is dependent upon the following (see "Oxygen delivery and consumption"):

Cardiac output

Hemoglobin concentration

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 [26]. 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 [27-29]. 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 [27]. (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.

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: Definition, pathogenesis, and clinical features", section on 'Oxygen toxicity' and "Retinopathy of prematurity: Pathogenesis, epidemiology, classification, and screening", section on 'Risk factors'.)

CLINICAL FEATURES

Timing of onset — AOP typically occurs at 3 to 12 weeks after birth in infants <32 weeks gestational age (GA). The onset of AOP is inversely proportional to GA [1,30,31]. 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 [32]. 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 [33,34]. 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 'Oxygen delivery' 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 less than 1500 g, the risk of apnea that lasted for more than 10 seconds rose with decreasing hematocrit values for both infants greater and less than 32 weeks gestation [35]. In addition, the frequency of apneic events detected by continuous monitoring of chest impedance and oxygen saturation decreased 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 [2].

While not routinely measured, serum erythropoietin levels are low in preterm infants during the first postnatal month compared with adults (9.7 versus 15.2 mU/mL) and remain inappropriately low for the extent of anemia through the second postnatal month [3].

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 [19,36]. (See 'Blood loss from phlebotomy' above.)

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 therefor 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.

Although iron supplementation does not prevent AOP, the use of iron-fortified formula compared with nonfortified formula allows for greater iron substrate when erythropoiesis is stimulated [37]. Iron supplementation does reduce iron-deficiency anemia, which both preterm and term infants are at high risk for developing in the first year of life. (See "Nutritional composition of human milk and preterm formula for the premature infant" and "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis".)

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, in healthy, growing preterm infants, it is not necessary to routinely monitor HCT/Hgb. 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. For example, if there is concern for another etiology of anemia besides AOP (eg, hemolytic anemia), measuring the reticulocyte count may be warranted. In addition, the reticulocyte count can occasionally help guide decisions about RBC transfusion in patients with borderline HCT/Hgb values (ie, values that are approaching thresholds for transfusion), as discussed below. (See 'Transfusion' 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 disadvantages of further inhibiting erythropoiesis. (See "Red blood cell transfusions in the newborn".)

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. Additional details regarding RBC transfusion, including selection of RBC products and guidance on administration of transfusions are provided separately. (See "Red blood cell transfusions in the newborn".)

The practice of using a restrictive transfusion approach for AOP is supported by randomized clinical trials and meta-analyses demonstrating that using a restrictive transfusion threshold reduces exposures to transfusion without increasing mortality or serious morbidity [38-44]. 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) [38]. 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) [38,40,44].

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) [40]. 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) [44].

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 percent versus HCT <35 g/dL in the liberal transfusion protocol. For critically ill neonates ≤7 days old, transfusion thresholds were HCT <34 percent and HCT <41 percent, respectively [40].

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. However, routine use of ESAs has not been widely adopted because ESA therapy is costly and appears to have limited efficacy in decreasing the number of blood donors to which the infant is exposed via transfusion, regardless of whether it is administered early (within the first week of life) or late (at or after eight days of life). Data on the outcome of early and late EPO administration are presented later in this section.

Our approach – We suggest not routinely using ESAs to prevent or treat AOP. A more effective and less costly approach to reduce the number of donor exposures for preterm infants consists of [45,46]:  

Providing optimal nutrition, including iron supplementation (see '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 transfusions in the newborn").

When these strategies are used, the additional benefit of ESA therapy is marginal.

In our practice the use of ESAs for management of AOP is a limited to the following settings:

VLBW and ELBW infants whose parents/caregivers refuse blood transfusions for religious reasons (see "The approach to the patient who declines blood transfusion", section on 'Erythropoiesis-stimulating agents (ESAs/EPO)')

Infants with chronic kidney disease (see "Chronic kidney disease in children: Complications", section on 'Erythropoiesis stimulating agents')

Dose – When the decision is made to give an ESA (eg, for a patient whose parents/caregivers refuse blood transfusions), different agents and dosing regimens can be used [47-49]:

Subcutaneous epoetin: 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.  

Darbepoetin (a longer acting ESA): 10 mcg/kg per dose given subcutaneously once weekly.

Intravenous (IV) epoetin: 200 units/kg per dose as an infusion over at least four hours given three times a week.

Alternatively, IV epoetin can be given at a dose of 300 units/kg per dose as a continuous infusion over 24 hours (typically as an addition to total parenteral nutrition [TPN]) given three times a week.

IV epoetin should be mixed in a protein-containing solution (5 percent albumin or TPN) [50].

In a small clinical trial, preterm infants who received 1200 units/kg once a week and control infants who received the standard three times a week dosing (400 units/kg) had similar increases in absolute reticulocyte counts and hematocrits at the end of the four-week trial period [51]. However, further studies are needed to confirm that weekly dosing provides the same benefit as more frequent administration.

Iron supplementation – Infants treated with ESAs require iron supplementation. A typical regimen is a daily elemental iron dose of 6 mg/kg for infants on full enteral feedings, and 3 mg/kg for those taking at least 60 mL/kg per day [47]. For infants receiving TPN, IV iron can be added to the TPN [47].

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 [52].

Monitoring – The reticulocyte count, central hematocrit or hemoglobin concentration, and absolute neutrophil count (ANC) are measured before as well as one to two weeks after starting ESA treatment. If the ANC falls below 1000/microL, the ESA should be held.

In addition, testing for adequate iron stores should be obtained for ELBW infants and those who fail to adequately respond to ESA therapy [47,52].

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 [53,54].

Iron deficiency, particularly if supplementation is inadequate [54-56].

Adverse effects that have been observed in other populations receiving ESAs (eg, patients with advanced kidney disease) include hypertension, seizure, rash, bone pain, and development of anti-erythropoietin antibodies. These have not been reported in preterm infants. (See "Treatment of anemia in patients on dialysis", section on 'Adverse effects of erythropoiesis-stimulating agents' and "Introduction to recombinant hematopoietic growth factors", section on 'Toxicity of colony-stimulating factors'.)

Efficacy – ESAs lower transfusion requirements in ELBW infants, but the effect appears to be modest with limited efficacy in decreasing 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. As a result, ESAs should not be given prophylactically as a neuroprotective measure.  

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) [57]. 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) [58]. 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 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]) [57].

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 [59-61]. 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) [59]. 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 [62]. 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]) [60]. Neurodevelopmental outcomes at five years of age were also similar [61].

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 sores). Together, these processes are referred to as anemia of prematurity (AOP). (See 'Pathogenesis' 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 'Oxygen delivery' above.)

Clinical features

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 '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 (see 'Transfusion' above). Additional details regarding RBC transfusion in neonates are provided separately. (See "Red blood cell transfusions in the newborn".)

No role for routine use of erythropoiesis stimulating agents (ESAs) – We suggest not routinely using ESAs (eg, epoetin alfa or its longer acting analog darbepoetin) to prevent or treat AOP (Grade 2C). While ESAs have been shown to modestly reduce transfusion requirements in preterm infants, they are costly and they appear to have limited efficacy in decreasing the number of blood donors to which the infant is exposed.

A more effective and less costly approach to reduce the number of donor exposures for preterm infants consists of limiting the amount of blood drawn, using a restrictive protocol for RBC transfusions, and using satellite packs, which allow for repeated transfusions from the same donor to the individual infant. (See 'Blood loss from phlebotomy' above and 'Transfusion' above and "Red blood cell transfusions in the newborn".)

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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