AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

All infants experience a decrease in hemoglobin concentrations after birth, as the infant transitions from a relatively hypoxic state in utero to a relatively hyperoxic state in room air. Increased tissue oxygenation leads to a decline in erythropoietin (EPO) concentration and, for the term infant, a physiologic and usually asymptomatic anemia at age 8-12 weeks. Anemia of prematurity (AOP) is an exaggerated and pathologic response of the preterm infant to this transition. AOP is a normocytic, normochromic, hyporegenerative anemia that is characterized by the existence of a low serum EPO level in an infant who has what may be a remarkably reduced hemoglobin concentration.

While the physiology and pathophysiology for AOP are well studied, controversy exists regarding 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.

Pathophysiology

The 3 basic mechanisms for the development of AOP include inadequate red blood cell (RBC) production for a growing premature infant, shortened RBC life span or hemolysis, and blood loss.

Inadequate red blood cell 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 of the fetus. EPO synthesis initially occurs in the fetal liver, with production gradually shifting to the kidney. By the end of gestation, the liver remains a major source of EPO.

In the first few weeks of embryogenesis, fetal erythrocytes are produced in the yolk sac. This site is succeeded by the fetal liver, which, 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 approximately 32 weeks' gestation, the burden of erythrocyte production in the fetus is shared evenly between the 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 both anemia and hypoxia. The degree of anemia and hypoxia required to stimulate EPO production is far higher 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 eliminated more rapidly by neonates, resulting in a curtailed time for bone marrow stimulation. Erythroid progenitors of premature infants are quite responsive to EPO when that growth factor finally is produced or administered, but the response may be blunted if iron stores are insufficient. While the infant's response may produce increased EPO concentrations and reticulocyte counts, the infant's rapid growth may prevent the appropriate increase in hemoglobin concentration.

Shortened red blood cell life span or hemolysis

Secondly, the average life span of a neonatal RBC is only one half to two thirds that of the RBC life span in an adult. 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 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, a fetal-placental transfusion may occur. 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 synthesis, diminished RBC life span, and increased loss of RBCs.

Frequency

United States

Frequency of AOP is related inversely to the gestational age and/or birthweight of the population. Up to 50% of infants less than 32 weeks' gestational age develop symptoms as a result of AOP.

Mortality/Morbidity

Although a premature infant is unlikely to be allowed to become so severely anemic as to die, complications from necessary blood transfusions can ultimately be responsible for the death of a patient. Anemia is blamed for a variety of signs and symptoms, including apnea, poor feeding, and inadequate weight gain (see History).

Race

Race has no influence on the incidence of AOP.

Sex

Although the presence of testosterone in the male infant is believed to be at least partially responsible for a slightly higher hemoglobin level at birth, this effect is of no significance with regard to individuals with AOP.

Age

• The more immature the infant, the more likely the development of AOP. AOP typically is not a significant issue for infants born beyond 32 weeks' gestation.
• The nadir of the hemoglobin level typically is observed when the tiniest infants are aged 4-10 weeks, with concentrations of 8-10 g/dl if birthweight was 1200-1400 grams, or 6-9 g/dl if birthweight was less than 1200 grams.
• AOP spontaneously resolves by the time most patients are aged 3-6 months.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Few symptoms are universally accepted as attributable to AOP; however, the following are among the symptoms that clinicians attribute to anemia of prematurity (AOP):

• Poor weight gain/difficulty feeding
• Apnea
• Tachypnea
• Decreased activity
• Pallor
• Tachycardia
• Flow murmurs

Physical

Debate regarding the presence or absence of physical findings in the infant with AOP is ongoing. Clinical trials designed to determine the efficacy of blood transfusions in relieving these findings have produced conflicting results.

• Poor growth
• • Inadequate weight gain despite adequate caloric intake often is attributed to AOP.
  • The response of weight gain to transfusions has been inconsistent in the literature.
• Apnea
• • If severe enough, anemia may result in respiratory depression manifested by increased periodic breathing and apnea.
  • While some studies have demonstrated a decrease in frequency of these symptoms subsequent to blood transfusions, others have found similar results with simple crystalloid volume expansion.
• Decreased activity: Lethargy frequently is attributed to anemia, with subjective improvement subsequent to transfusion.
• Metabolic acidosis
• • Significant anemia can result in decreased oxygen-carrying capacity less than the needs of the tissue, resulting in increased anaerobic metabolism with production of lactic acid.
  • Blood transfusions have been documented to decrease lactic acid levels in otherwise healthy infants who are anemic and premature. Some medical professionals have suggested using lactate levels as an aid in determining the need for transfusion.
• Tachycardia
• • Infants with AOP may respond by increasing cardiac output through increased heart rates, presumably in response to inadequate oxygen delivery to the tissues caused by anemia.
  • Blood transfusions have been associated with a lowering of the heart rate in infants who are anemic.
• Tachypnea
• Flow murmurs

Causes

• AOP results from a combination of relatively diminished RBC production, shortened RBC life span, and blood loss (see Pathophysiology).
• Nutritional deficiencies of iron, vitamin E, vitamin B-12, and folate may exaggerate the degree of anemia.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Bone marrow infiltration
Diamond-Blackfan anemia
Disseminated intravascular coagulation
Elliptocytosis
G-6-PD deficiency
GI bleeding
Glucose kinase deficiency
Immune-mediated hemolysis
Iron deficiency
Pancytopenia
Spherocytosis
Twin-to-twin transfusion syndrome
Vitamin E deficiency

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• CBC count
• • The CBC count demonstrates normal white blood cell (WBC) and platelet lines.
  • The hemoglobin is less than 10 g/dL but may descend to a nadir of 6-7 g/dL; the lowest levels generally are observed in the smallest infants.
  • RBC 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 EPO. A rising reticulocyte count may not predict recovery from anemia of prematurity (AOP).
  • The finding of an elevated reticulocyte count is not consistent with the diagnosis of AOP.
• Peripheral blood smear: No abnormal forms are observed.
• Maternal and infant blood typing: In the evaluation of anemia, consider the possibility of hemolytic processes, such as the ABO blood group system and Rh incompatibility.
• Direct antibody test (Coombs): This test may be coincidentally positive; however, with such a finding, ensure that an immune-mediated hemolytic process is not ongoing.
• Serum bilirubin: With an elevated serum bilirubin level, consider other possible explanations for the anemia.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

The medical care options available to the clinician treating an infant with anemia of prematurity (AOP) are prevention, blood transfusion, and recombinant EPO treatment.

Prevention

• Reducing the amount of blood taken from the premature infant diminishes the need to replace blood. When caring for the premature infant, carefully consider the need for each laboratory study obtained. Hospitals with care for premature infants should have the ability to determine laboratory values using very small volumes of serum.
• Manufacturers are developing an array of technologies that require extremely small amounts of blood for a steadily increasing number of tests. Likewise, devices that allow blood gases and serum chemistries to be determined at bedside via an analyzer attached to the umbilical artery catheter without loss of blood have been developed. The impact of such devices on the development of anemia and/or the need for transfusions has yet to be determined.
• The use of noninvasive monitoring devices, such as transcutaneous hemoglobin oxygen saturation, partial pressure of oxygen, and partial pressure of carbon dioxide, may allow clinicians to decrease blood drawing; however, no data currently support such an impact of these devices.

Blood transfusion

• Packed red blood cell (PRBC) transfusions: Despite disagreement regarding timing and efficacy, PRBC transfusions continue to be the mainstay of therapy for the individual with AOP. The frequency of blood transfusions varies with gestational age, degree of illness, and, interestingly, the hospital evaluated. The decision to give a transfusion should not be made lightly, as significant infectious, hematologic, immunologic, and metabolic complications exist. Transfusions also transiently decrease erythropoiesis and EPO levels, but this effect is not sustained.
• Reducing the number of transfusions: Studies derived from individual centers document a marked decrease in the administration of PRBC transfusions over the past 2 decades, even before the use of EPO. This decrease in transfusions is almost certainly multifactorial in origin. One frequently mentioned component is the adoption of transfusion protocols that take a variety of factors into account, including hemoglobin levels, degree of cardiorespiratory disease, and traditional signs and symptoms of pathologic anemia.
• Recently, the Premature Infant in Need of Transfusion (PINT) study demonstrated that transfusing infants to maintain a high hemoglobin level (8.5-13.5 g/dL) confers no benefit in terms of mortality, severe morbidity, or apnea intervention compared with infants transfused to maintain a low hemoglobin level (7.5-11.5 g/dL). This differs from a study from Iowa, which found fewer brain injuries and less apnea in infants whose transfusion criteria was not restricted and whose hemoglobin level was higher (Strauss, 2006). Clearly, no set guidelines for transfusion in infants with anemia of prematurity are prescribed.
• Using various audit criteria and indications for transfusions suggested by Canadian, American, and British authorities, the Medical University of South Carolina has instituted the following transfusion guidelines:
• • Do not transfuse for phlebotomy losses alone.
  • Do not transfuse for hematocrit alone, unless the hematocrit level is less than 21% with a reticulocyte count less than 100,000.
  • Transfuse for shock associated with acute blood loss.
  • For an infant with cyanotic heart disease, maintain a hemoglobin level that provides an equivalent fully saturated level of 11-12 g.
  • Transfuse for hematocrit levels less than 35-40% in the following situations:
  • • Infant with severe pulmonary disease (defined as requiring >35% supplemental hood oxygen or continuous positive airway pressure [CPAP] or mechanical ventilation with a mean airway pressure of >6 cm water)
    • Infant in whom anemia may be contributing to congestive heart failure
  • In the following situations, transfuse for a hematocrit level that is 25-30% or less:
  • • The patient requires nasal CPAP of 6 cm water or less (supplemental hood oxygen of <35% by hood or nasal cannulae).
    • The patient has significant apnea and bradycardia (defined as >9 episodes in 12 h or 2 episodes in 24 h, requiring bag-mask ventilation while receiving therapeutic doses of methylxanthines).
    • The patient has persistent tachycardia or tachypnea without other explanation for 24 hours.
    • Weight gain of patient is deemed unacceptable in light of adequate caloric intake without other explanation, such as known increases in metabolic demands or known losses in metabolic demands (malabsorption).
    • The patient is scheduled for surgery; transfuse in consultation with the surgery team.
• Reducing the number of donor exposures: In addition to reducing the number of transfusions, reducing the number of donor exposures is important. This can be accomplished as follows:
• • Use PRBCs stored in preservatives (eg, citrate-phosphate-dextrose-adenine [CPDA-1]) and additive systems (eg, Adsol). Preservatives and additive systems allow blood to be stored safely for up to 35-42 days. Infants may be assigned a specific unit of blood, which may suffice for treatment during their entire hospitalization and limit exposure to a single donor. Concerns that stored blood might increase serum potassium levels are unfounded, as long as the transfused volume is low.
  • Use volunteer-donated blood and all available screening techniques. The risk of cytomegalovirus (CMV) transmission can be reduced dramatically (but not entirely) through the use of CMV-safe blood. This can be accomplished by using either CMV serology-negative cells or blood processed through leukocyte-reduction filters. This latter method also reduces other WBC-associated infectious agents (eg, Epstein-Barr virus, retroviruses, Yersinia enterocolitica). The American Red Cross now is providing exclusively leukocyte-reduced blood to hospitals in the United States.

Recombinant erythropoietin treatment

• Multiple investigations have established that premature infants respond to exogenously administered recombinant human EPO and supplemental iron with a brisk reticulocytosis. While EPO cannot prevent early transfusions, modest decreases in the frequency of late PRBC transfusions have been documented.
• Trials have evaluated the impact of EPO treatment in populations of the most immature neonates. These studies likewise have demonstrated that infants with VLBW are capable of responding to EPO with a reticulocytosis and that the drug appears to be safe. 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.
• No agreement regarding timing, dosing, route, or duration of therapy exists. Meta-analysis of controlled clinical trials show some benefit to EPO, but they cannot give firm guidelines on its use or recommend its routine use to prevent AOP. In short, the cost-benefit ratio for EPO has yet to be clearly established, and this medication is not accepted universally as a standard therapy for the individual with AOP. When the family has religious objections to transfusions, the use of EPO is advisable.

Consultations

• Neonatology
• Pediatric hematology

Diet

Provision of adequate amounts of vitamin E, vitamin B-12, folate, and iron are important to avoid exacerbating the expected decline in hemoglobin levels in the premature infant.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Drug Category: Growth factors

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

Drug Category: Vitamins and minerals

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.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• After discharge from the hospital, ensure regular determination of hematocrit levels in infants with APO. Once a steady increase in the hematocrit level has been established, only routine checks are required.

In/Out Patient Meds

• Administer and/or prescribe iron supplementation according to standard guidelines.

Transfer

• Transfer generally is not required unless transfusions cannot be carried out in the hospital's nursery.

Deterrence/Prevention

• Limit diagnostic blood draws to a minimum.

Complications

• Transfusion-acquired infections (eg, hepatitis, CMV, HIV, syphilis)
• Transfusion-associated fluid overload and electrolyte imbalances
• Transfusion-associated exposure to plasticizers
• Transfusion-associated hemolysis
• Posttransfusion graft versus host disease

Prognosis

• Spontaneous recovery in the individual with anemia of prematurity (AOP) occurs by age 3-6 months.

Patient Education

• Explain the normal course of anemia.
• Explain criteria for and risks of transfusions.
• Explain advantages and disadvantages of EPO administration.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to consider anemia as a possible cause of signs and symptoms
• Failure to notify the family about the patient's need for transfusion and obtain a consent before the transfusion
• Failure to consider the family's religious beliefs regarding transfusions
• Failure to anticipate transfusion-acquired infections and complications

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Al-Kharfy T, Smyth JA, Wadsworth L, et al. Erythropoietin therapy in neonates at risk of having bronchopulmonary dysplasia and requiring multiple transfusions. J Pediatr. Jul 1996;129(1):89-96. [Medline].
• Bell EF, Strauss RG, Widness JA, et al. Randomized trial of liberal versus restrictive guidelines for red blood cell transfusion in preterm infants. Pediatrics. Jun 2005;115(6):1685-91. [Medline]. [Full Text].
• Bowden RA, Slichter SJ, Sayers M, et al. A comparison of filtered leukocyte-reduced and cytomegalovirus (CMV) seronegative blood products for the prevention of transfusion-associated CMV infection after marrow transplant. Blood. Nov 1 1995;86(9):3598-603. [Medline].
• Carbonell-Estrany X, Figueras-Aloy J, Alvarez E. Erythropoietin and prematurity--where do we stand?. J Perinat Med. 2005;33(4):277-86. [Medline].
• DeMaio JG, Harris MC, Deuber C, Spitzer AR. Effect of blood transfusion on apnea frequency in growing premature infants. J Pediatr. Jun 1989;114(6):1039-41. [Medline].
• Kirpalani H, Whyte RK, Andersen C, et al. The Premature Infants in Need of Transfusion (PINT) study: a randomized, controlled trial of a restrictive (low) versus liberal (high) transfusion threshold for extremely low birth weight infants. J Pediatr. Sep 2006;149(3):301-307. [Medline].
• Lachance C, Chessex P, Fouron JC, et al. Myocardial, erythropoietic, and metabolic adaptations to anemia of prematurity. J Pediatr. Aug 1994;125(2):278-82. [Medline].
• Ohls RK. A multicenter randomized double-masked placebo-controlled trial of early erythropoietin and iron administration to preterm infants. Ped Res. 1999;45:1268.
• Ohls RK. Developmental erythropoiesis. In: Polin RA, Fox WW, eds. Fetal and Neonatal Physiology. Vol 2. 2nd ed. Philadelphia, Pa: WB Saunders Co:1762-1786.
• Ohls RK, Ehrenkranz RA, Das A, et al. Neurodevelopmental outcome and growth at 18 to 22 months' corrected age in extremely low birth weight infants treated with early erythropoietin and iron. Pediatrics. Nov 2004;114(5):1287-91. [Medline]. [Full Text].
• Ohls RK, Ehrenkranz RA, Wright LL, et al. Effects of early erythropoietin therapy on the transfusion requirements of preterm infants below 1250 grams birth weight: a multicenter, randomized, controlled trial. Pediatrics. Oct 2001;108(4):934-42. [Medline]. [Full Text].
• Ringer SA, Richardson DK, Sacher RA, et al. Variations in transfusion practice in neonatal intensive care. Pediatrics. Feb 1998;101(2):194-200. [Medline].
• Salsbury DC. Anemia of prematurity. Neonatal Netw. Aug 2001;20(5):13-20. [Medline].
• Schwarz KB, Dear PR, Gill AB, et al. Effects of transfusion in anemia of prematurity. Pediatr Hematol Oncol. Oct-Nov 2005;22(7):551-9. [Medline].
• Strauss RG. Erythropoietin in the pathogenesis and treatment of neonatal anemia. Transfusion. Jan 1995;35(1):68-73. [Medline].
• Strauss RG. Practical issues in neonatal transfusion practice. Am J Clin Pathol. Apr 1997;107(4 Suppl 1):S57-63. [Medline].
• Strauss RG. Controversies in the management of the anemia of prematurity using single-donor red blood cell transfusions and/or recombinant human erythropoietin. Transfus Med Rev. Jan 2006;20(1):34-44. [Medline].
• Vamvakas EC, Strauss RG. Meta-analysis of controlled clinical trials studying the efficacy of rHuEPO in reducing blood transfusions in the anemia of prematurity. Transfusion. Mar 2001;41(3):406-15. [Medline].
• Widness JA, Seward VJ, Kromer IJ, et al. Changing patterns of red blood cell transfusion in very low birth weight infants. J Pediatr. Nov 1996;129(5):680-7. [Medline].
• Young T, Mangum B. Neofax. Neofax. 2005.

Article Last Updated: Dec 12, 2006