eMedicine Specialties > Pediatrics: Cardiac Disease and Critical Care Medicine > Neonatology
Anemia of Prematurity
Updated: Jan 15, 2009
Introduction
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.
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.
Pathophysiology
The 3 basic mechanisms for the development of AOP include inadequate RBC production for a growing premature infant, shortened RBC life span or hemolysis, and 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 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 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 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. Although 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 RBC 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. Conversely, delayed cord clamping may lessen the degree of AOP. 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 during rapid growth, diminished RBC life span, and increased loss of RBCs.
Frequency
United States
Frequency of AOP is inversely related to the gestational age and/or birthweight of the population. As many as 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 various 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 is not typically a significant issue for infants born beyond 32 weeks' gestation. The nadir of the hemoglobin level is typically 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
History
Few symptoms are universally accepted as attributable to anemia of prematurity (AOP); however, the following are among the symptoms that clinicians attribute to 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 is often 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.
- Although 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 is frequently 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.
More on Anemia of Prematurity |
 Overview: Anemia of Prematurity |
| Differential Diagnoses & Workup: Anemia of Prematurity |
| Treatment & Medication: Anemia of Prematurity |
| Follow-up: Anemia of Prematurity |
| References |
| Next Page » |
References
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Further Reading
Keywords
anemia of prematurity, AOP, erythropoietin, EPO, hemoglobin, red blood cell, hemolysis, blood loss, tachycardia, metabolic acidosis, respiratory depression, apnea, lactic acid, necrotizing enterocolitis, NEC, brain hemorrhage, periventricular leukomalacia, cytomegalovirus, CMV, Epstein-Barr virus, retroviruses, Yersinia enterocolitica
