Anemia of Prematurity 

Updated: Jan 08, 2016
Author: George Cassady, MD; Chief Editor: Ted Rosenkrantz, MD 

Overview

Background

All infants experience a decrease in hemoglobin concentration after birth. The transition from a relatively hypoxic state in utero to a relatively hyperoxic state with increased tissue oxygenation after birth leads to a decline in erythropoietin (EPO) concentration. For the term infant, a physiologic and usually asymptomatic anemia is observed 8-12 weeks after birth.

Anemia of prematurity (AOP) is an exaggerated, pathologic response of the preterm infant to this transition. AOP is a normocytic, normochromic, hyporegenerative anemia characterized by a low serum EPO level, often despite a remarkably reduced hemoglobin concentration. Nutritional deficiencies of iron, vitamin E, vitamin B-12, and folate may exaggerate the degree of anemia, as may blood loss and/or a reduced red cell life span.

AOP spontaneously resolves in many premature infants within 3-6 months of birth. In others, however, medical intervention is required. Although the physiology and pathophysiology for AOP are well studied, controversy surrounds the timing, method, and effectiveness of therapeutic interventions for AOP. This article reviews the pathophysiology of AOP, the means of reducing its impact on premature infants, and its treatment through blood transfusion or recombinant EPO therapy.

Go to Anemia, Pediatric Chronic Anemia, Anemia and Thrombocytopenia in Pregnancy, and Emergent Management of Acute Anemia for complete information on these topics.

Patient Education

It is important to discuss with parents the normal course of anemia, the criteria for and risks associated with transfusions, and the advantages and disadvantages of erythropoietin (EPO) administration.

Etiology

The three basic mechanisms for the development of anemia of prematurity (AOP) include (1) inadequate RBC production, (2) shortened RBC life span, and (3) blood loss.

Inadequate RBC production

The first mechanism of anemia is inadequate RBC production for the growing premature infant. The location of EPO and RBC production changes during gestation. EPO synthesis initially occurs in the fetal liver but gradually shifts toward the kidney as gestation advances. By the end of gestation, however, the liver remains the major source of EPO.

Fetal erythrocytes are produced in the yolk sac during the first few weeks of embryogenesis. The fetal liver becomes more important as gestation advances and, by the end of the first trimester, has become the primary site of erythropoiesis. Bone marrow then begins to take on a more active role in producing erythrocytes. By about 32 weeks' gestation, the burden of erythrocyte production in the fetus is shared evenly by liver and bone marrow. By 40 weeks' gestation, the marrow is the sole erythroid organ. Premature delivery does not accelerate the ontogeny of these processes.

Although EPO is not the only erythropoietic growth factor in the fetus, it is the most important. EPO is synthesized in response to anemia and consequent relative tissue hypoxia. The degree of anemia and hypoxia required to stimulate EPO production is far greater for the fetal liver than for the fetal kidney. EPO production may not be stimulated until a hemoglobin concentration of 6-7 g/dL is reached. As a result, new RBC production in the extremely premature infant, whose liver remains the major site of EPO production, is blunted despite what may be marked anemia. In addition, EPO, whether endogenously produced or exogenously administered, has a larger volume of distribution and is more rapidly eliminated by neonates, resulting in a curtailed time for bone marrow stimulation.

Erythroid progenitors in premature infants are quite responsive to EPO, but the response may be blunted if iron or other substrate or co-factor stores are insufficient. Another potential problem is that while the infant may respond appropriately to increased EPO concentrations with increased reticulocyte counts, rapid growth may prevent the appropriate increase in hemoglobin concentration.

Shortened RBC life span or hemolysis

Also important in the development of AOP is that the average life span of a neonatal RBC is only one half to two thirds that of an adult RBC. Cells of the most immature infants may survive only 35-50 days. The shortened RBC life span of the neonate is a result of multiple factors, including diminished levels of intracellular adenosine triphosphate (ATP), carnitine, and enzyme activity; increased susceptibility to lipid peroxidation; and increased susceptibility of the cell membrane to fragmentation.

Blood loss

Finally, blood loss may contribute to the development of AOP. If the neonate is held above the placenta for a time after delivery, fetal-placental transfer of blood may occur. Conversely, delayed cord clamping may lessen the degree of AOP[1] (although a study by Elimian et al did not find this to be true[2] ). More commonly, because of the need to closely monitor the tiny infant, frequent samples of blood are removed for various tests. These losses are often 5-10% of the total blood volume.

Taken together, the premature infant is at risk for the development of AOP because of limited RBC synthesis during rapid growth, a diminished RBC life span, and an increased loss of RBCs.

Epidemiology

The risk of anemia of prematurity (AOP) is inversely related to gestational maturity and birthweight. As many as half of infants of less than 32 weeks gestation develop AOP. AOP is not typically a significant issue for infants born beyond 32 weeks' gestation.

Race and sex have no influence on the incidence of AOP.

Testosterone is believed to be at least partially responsible for a slightly higher hemoglobin level in male infants at birth, but this effect is of no significance with regard to risk of AOP. The nadir of the hemoglobin level is typically observed 4-10 weeks after birth in the tiniest infants, with concentrations of 8-10 g/dL if birthweight was 1200-1400 grams, or 6-9 g/dL at birth weights of less than 1200 grams.

Prognosis

Spontaneous recovery of mild anemia of prematurity (AOP) may occur 3-6 months after birth. In more severe, symptomatic cases, medical intervention may be required.

 

Presentation

History and Physical Examination

Many clinical findings have been attributed to anemia of prematurity (AOP), but they are neither specific nor diagnostic. These symptoms may include the following:

  • Poor weight gain despite adequate caloric intake

  • Cardiorespiratory symptoms such as tachycardia, tachypnea, and flow murmurs

  • Decreased activity, lethargy, and difficulty with oral feeding

  • Pallor

  • Increase in apneic and bradycardic episodes, and worsened periodic breathing

  • Metabolic acidemia - Increased lactic acid secondary to increased cellular anaerobic metabolism in relatively hypoxic tissues

 

DDx

Diagnostic Considerations

Conditions to consider in the differential diagnosis of anemia of prematurity (AOP) are those which diminish red cell production, increase red cell destruction, or cause blood loss.

Conditions that diminish RBC synthesis are as follows:

  • Bone marrow infiltration

  • Bone marrow depression (eg, pancytopenia, drugs)

  • Diamond-Blackfan anemia

  • Substrate deficiencies (eg, iron, vitamin E, folic acid)

  • Congenital fetal infections (eg, cytomegalovirus, parvovirus, syphilis)

Conditions that cause hemolysis are as follows:

  • Congenital fetal infections (eg, cytomegalovirus, parvovirus, syphilis)

  • Acute systemic infections (leading to disseminated intravascular coagulation)

  • Abnormal red blood cells (spherocytosis, elliptocytosis)

  • Nonspherocytic hemolytic anemias (eg, G-6-PD deficiency, kinase and isomerase deficiencies)

  • Hemolytic disease of the newborn (Rh, ABO, other major blood-group incompatibilities between mother and fetus)

Conditions that reduce blood volume are as follows:

  • Twin-to-twin transfusion syndrome (donor twin)

  • Iatrogenic (eg, excessive blood sampling)

  • Hemorrhage (eg, gastrointestinal, central nervous system, subcutaneous tissues)

Differential Diagnoses

 

Workup

Approach Considerations

The following are useful laboratory studies:

CBC count - White blood cell (WBC) and platelet values are normal in AOP. Low hemoglobin values, below 10 g/dL, are found. They may descend to a nadir of 6-7 g/dL. Lowest levels are generally observed in the smallest infants. Red blood cell indices are normal (eg, normochromic, normocytic) for age.

Reticulocyte count - The reticulocyte count is low when the degree of anemia is considered, as a result of the low levels of erythropoietin (EPO). Conversely, an elevated reticulocyte count is not consistent with the diagnosis of AOP.

Peripheral blood smear - Red blood cell morphology should be normal. Red blood cell precursors may appear to be more prominent.

Maternal and infant blood typing; direct antibody test (Coombs) - The direct Coombs test result may be coincidentally positive. Despite this, it is important to ensure an immune-mediated hemolytic process related to maternal-fetal blood group incompatibility (hemolytic disease of the newborn) is not present.

Serum bilirubin - An elevated serum bilirubin level should suggest other possible explanations for the anemia. These would include hemolytic entities, such as G-6-PD deficiency or other kinase/isomerase/enzyme deficiencies, or more common causes such as infection or hemolytic disease of the newborn.

Lactic acid - Elevated lactic acid levels have been suggested by some to be useful as an aid to determine the need for transfusion.

 

Treatment

Approach Considerations

Medical treatment options are blood transfusion(s), recombinant erythropoietin (EPO) treatment, and observation.

Go to Anemia, Pediatric Chronic Anemia, Anemia and Thrombocytopenia in Pregnancy, and Emergent Management of Acute Anemia for complete information on these topics.

Observation and Supportive Care

Observation may be the best course of action for infants who are asymptomatic, not acutely ill, and are receiving adequate nutrition. Adequate amounts of vitamin E, vitamin B-12, folate, and iron are important to blunt the expected decline in hemoglobin levels in the premature infant. Periodic measurements of the hematocrit level in infants with AOP are necessary after hospital discharge. Once a steady increase in the hematocrit level has been established, only routine checks are required.

Blood Transfusion Considerations and Concerns

Packed red blood cell (PRBC) transfusions

Packed red blood cell (PRBC) transfusions are the mainstay of therapy for anemia of prematurity (AOP). The frequency of blood transfusion varies with gestational age, degree of illness, and, interestingly, the hospital evaluated. Unfortunately, there is considerable disagreement about the indication, timing, and efficacy of PRBC transfusion.

There is agreement, however, that the decision to give a transfusion should not be made lightly, because significant infectious, hematologic, immunologic, and metabolic complications are possible. Late-onset necrotizing enterocolitis has been reported in stable-growing premature infants electively transfused for AOP.[3, 4] Transfusions also transiently decrease erythropoiesis and EPO levels. There is also agreement that the number of transfusions, as well as the number of donor exposures, should be reduced as much as possible.

Reducing the number of transfusions

Studies from individual centers have documented a marked decrease in the administration of PRBC transfusions in the past decades, even before the use of EPO became more frequent. This decrease in transfusions is almost certainly multifactorial in origin. Adoption of standardized transfusion protocols that take various factors into account, including hemoglobin levels, degree of cardiorespiratory disease, and traditional signs and symptoms of pathologic anemia, are acknowledged as an important factor in this reduction. A restricted transfusion protocol may decrease the number of transfusions while also decreasing the hematocrit at discharge.[5]

A 2011 study evaluated 41 preterm infants with birth weights of 500-1300 g who were enrolled in a clinical trial that compared high and low hematocrit thresholds for transfusion. A rise in systemic oxygen transport and a decrease in lactic acid after transfusion was noted in both groups; however, oxygen consumption did not change significantly in either group. In the low hematocrit group only, cardiac output and fractional oxygen extraction fell after transfusion, which shows that these infants had increased their cardiac output to maintain adequate tissue oxygen delivery in response to anemia. The results demonstrate that infants with low hematocrit thresholds may benefit from transfusion, while transfusion in those with high hematocrit thresholds may provide no acute physiological benefit.[6]

The Premature Infant in Need of Transfusion (PINT) study showed that transfusing infants to maintain higher hemoglobin level (8.5-13.5 g/dL) conferred no benefit in terms of mortality, severe morbidity, or apnea intervention compared with infants transfused to maintain a low hemoglobin levels (7.5-11.5 g/dL).[7]

These findings differ from the Iowa study, which found less parenchymal brain hemorrhage, periventricular leukomalacia, and apnea in infants whose transfusion criteria was not restricted and whose hemoglobin level was higher. Clearly, no universally accepted guidelines for transfusion in infants with AOP are available at this time, and clinicians must determine their individual standardized transfusion practices.

As an example, note the Children's Hospital of Wisconsin Transfusion Committee guidelines for consideration:

  • An infant with a hemoglobin (Hb) level of less than 8 g/dL may be transfused at the discretion of the attending physician

  • A stable infant with an Hb level of 8-10 g/dL without clinical symptoms or other exceptions listed below may be transfused

  • An infant with an Hb level of 11-13 g/dL without a supplemental oxygen or continuous positive airway pressure (CPAP) requirement, apnea/bradycardia, significant tachycardia or tachypnea, or other exceptions listed below should not be transfused

  • An infant with an Hb level of more than 13 g/dL without an oxygen requirement of more than 40% by hood, CPAP, or ventilator; hypotension that requires pressor medication; major surgery; or other exceptions listed below should not be transfused

  • An infant with an Hb level of more than 15 g/dL without cyanotic heart disease, extracorporeal membrane oxygenation (ECMO) therapy, regional oxygen saturations less than 50%, or hypotension that requires pressor medications should not be transfused

  • An infant with a history of massive blood loss may be transfused at the discretion of the attending physician

It is of obvious importance to discuss with the family their child’s need for transfusion and to obtain consent before the transfusion. It is also important to discuss with parents the normal course of anemia, the criteria for and risks associated with transfusions, and the advantages and disadvantages of erythropoietin (EPO) administration. Also necessary is consideration of the family's religious beliefs regarding transfusions.

Reducing the number of donor exposures

Reducing the number of donor exposures is also important. Preservatives and additive systems allow blood to be stored safely for as long as 35-42 days. This can be accomplished by using PRBCs stored in preservatives (eg, citrate-phosphate-dextrose-adenine [CPDA-1]) and additive systems (eg, Adsol). Infants may be assigned a specific unit of blood, which may suffice for treatment during their entire hospitalization and thus limit exposure to the single donor of that unit. Concerns that stored blood might increase serum potassium levels are unfounded if the transfused volume is low.

Complications

Potential complications of transfusion include the following:

  • Infection (eg, hepatitis, cytomegalovirus [CMV], human immunodeficiency virus [HIV], syphilis)

  • Fluid overload and electrolyte imbalances

  • Exposure to plasticizers

  • Hemolysis

  • Posttransfusion graft versus host disease

An important tool in reducing at least one of these transfusion risks is to use all available screening techniques for infection. The risk of cytomegalovirus (CMV) transmission can be dramatically reduced by use of CMV-safe blood. This can be accomplished by using CMV serology–negative cells, along with blood processed through leukocyte-reduction filters or inverted spin technique. These methods also reduce other WBC-associated infectious agents (eg, Epstein-Barr virus, retroviruses, Yersinia enterocolitica) by yielding a leukocyte-poor suspension of PRBCs. The American Red Cross now provides exclusively leukocyte-reduced blood to hospitals in the United States.

Efficacy

Clinical trials designed to determine the efficacy of blood transfusions in relieving symptoms ascribed to anemia of prematurity (AOP) have produced conflicting results.[8] Improved growth has been an inconsistent finding. While some studies have demonstrated a decrease in apneic episodes after blood transfusion, others have found similar results with simple crystalloid volume expansion.

Subjective improvement in activity, decreased lethargy, and improved feeding have been described in some studies. Blood transfusions have been documented to decrease lactic acid levels in otherwise healthy preterm infants who are anemic. Blood transfusions have reduced tachycardia in anemic infants who are transfused.

Some medical professionals have suggested using lactate levels as an aid in determining the need for transfusion.

Recombinant Erythropoietin Treatment

Multiple investigations have established that premature infants respond to exogenously administered recombinant human EPO and supplemental iron with a brisk reticulocytosis. Subcutaneous administration of EPO may be preferred, as intravenous administration has increased urinary losses. Although EPO cannot prevent early transfusions, modest decreases in the frequency of late PRBC transfusions have been documented. Additional iron supplementation is necessary during exogenous EPO treatment.

Trials have evaluated the impact of EPO treatment in populations of the most immature neonates. These studies likewise have demonstrated that infants with very low birth weight (VLBW) are capable of responding to EPO with a reticulocytosis.

Studies and a Cochrane Neonatal Systemic review suggest an association between exogenous EPO administration and retinopathy of prematurity.[9, 10, 11]

Yasmeen et al studied 60 preterm low birth weight infants and concluded that short-term recombinant human erythropoietin with iron and folic acid was effective in preventing anemia of prematurity.[12]

EPO with iron does not adversely affect growth or developmental outcomes, but the impact on the number of transfusions a premature infant receives ranges from nonexistent to small.

At this time, no agreement regarding the safety, timing, dosing, route, or duration of therapy has been established. In short, the cost-benefit ratio for EPO has yet to be clearly established, and this medication is not universally accepted as a standard therapy for an infant with AOP.

 

Medication

Medication Summary

Drugs used to treat anemia of prematurity (AOP) are those that stimulate erythropoiesis and provide nutritional substrate needs. Ferrous sulfate/iron dextran, vitamin E, and folic acid, along with epoetin alfa, which stimulates RBC production, are among those administered.

Growth Factors

Class Summary

These agents are hormones that stimulate the production of red cells from the erythroid tissues in the bone marrow.

Epoetin alfa (Epogen, Procrit)

This is used to stimulate erythropoiesis and decrease the need for erythrocyte transfusions in high-risk preterm neonates. Epoetin alfa stimulates the division and differentiation of committed erythroid progenitor cells. It induces the release of reticulocytes from bone marrow into the bloodstream.

Infants require supplemental iron. Some physicians also use vitamin E and folate.

Vitamins and Minerals

Class Summary

These are organic substances required by the body in small amounts for various metabolic processes. They are used clinically for the prevention and treatment of specific deficiency states.

Ferrous sulfate (PO)/iron dextran (IV)

This is a nutritionally essential inorganic substance. It is the mainstay treatment for patients with iron deficiency anemia.

Vitamin E (Aquasol E, Aquavit E)

Vitamin E protects polyunsaturated fatty acids in membranes from attack by free radicals and protects RBCs against hemolysis. It is available as PO liquid drops (15 IU/0.3 mL).

Folic acid (Folacin-800)

Folic acid is a water-soluble vitamin used in nucleic acid synthesis. Required for normal erythropoiesis, it is an important cofactor for enzymes used in production of RBCs.