Anemia of Prematurity

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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.

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.

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.

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.

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.

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.

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.

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.

Ultee CA, van der Deure J, Swart J, Lasham C, van Baar AL. Delayed cord clamping in preterm infants delivered at 34 36 weeks’ gestation: a randomised controlled trial. Arch Dis Child Fetal Neonatal Ed. 2008 Jan. 93(1):F20-3. [Medline].

Elimian A, Goodman J, Escobedo M, Nightingale L, Knudtson E, Williams M. Immediate compared with delayed cord clamping in the preterm neonate: a randomized controlled trial. Obstet Gynecol. 2014 Dec. 124 (6):1075-9. [Medline].

Mally P, Golombek SG, Mishra R, et al. Association of necrotizing enterocolitis with elective packed red blood cell transfusions in stable, growing, premature neonates. Am J Perinatol. 2006 Nov. 23(8):451-8. [Medline].

Singh R, Shah BL, Frantz ID 3rd. Necrotizing enterocolitis and the role of anemia of prematurity. Semin Perinatol. 2012 Aug. 36(4):277-82. [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. 2005 Jun. 115(6):1685-91. [Medline]. [Full Text].

Fredrickson LK, Bell EF, Cress GA, et al. Acute physiological effects of packed red blood cell transfusion in preterm infants with different degrees of anaemia. Arch Dis Child Fetal Neonatal Ed. 2011 Jul. 96(4):F249-53. [Medline]. [Full Text].

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. 2006 Sep. 149(3):301-307. [Medline].

Bell EF, Nahmias C, Sinclair JC, Zipursky A. Changes in circulating red cell volume during the first 6 weeks of life in very-low-birth-weight infants. Pediatr Res. 2014 Jan. 75 (1-1):81-4. [Medline].

Ohlsson A, Aher SM. Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD004863. DOI: 10.1002/14651858.CD004863.pub2.

Brown MS, Baron AE, France EK, Hamman RF. Association between higher cumulative doses of recombinant erythropoietin and risk for retinopathy of prematurity. J AAPOS. 2006 Apr. 10(2):143-9. [Medline].

Suk KK, Dunbar JA, Liu A, et al. Human recombinant erythropoietin and the incidence of retinopathy of prematurity: a multiple regression model. J AAPOS. 2008 Jun. 12(3):233-8. [Medline].

Yasmeen BH, Chowdhury MA, Hoque MM, Hossain MM, Jahan R, Akhtar S. Effect of short-term recombinant human erythropoietin therapy in the prevention of anemia of prematurity in very low birth weight neonates. Bangladesh Med Res Counc Bull. 2012 Dec. 38(3):119-23. [Medline].

George Cassady, MD 

George Cassady, MD is a member of the following medical societies: American Academy of Pediatrics, American Pediatric Society, Society for Pediatric Research, Southern Society for Pediatric Research

Disclosure: Partner received salary from Genentech/Roche for employment.

Charles F Potter, MD Consulting Neonatologist, Newborn Care Physicians of Southeastern Wisconsin

Charles F Potter, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association

Disclosure: Nothing to disclose.

W Michael Southgate, MD Professor of Pediatrics, Pediatrics Program Director, Medical University of South Carolina College of Medicine

W Michael Southgate, MD is a member of the following medical societies: American Academy of Pediatrics, National Perinatal Association

Disclosure: Nothing to disclose.

Ted Rosenkrantz, MD Professor, Departments of Pediatrics and Obstetrics/Gynecology, Division of Neonatal-Perinatal Medicine, University of Connecticut School of Medicine

Ted Rosenkrantz, MD is a member of the following medical societies: American Academy of Pediatrics, American Pediatric Society, Eastern Society for Pediatric Research, American Medical Association, Connecticut State Medical Society, Society for Pediatric Research

Disclosure: Nothing to disclose.

Brian S Carter, MD, FAAP Professor of Pediatrics (Neonatology), Vanderbilt University School of Medicine; Director, Neonatal Follow-up Program, Monroe Carell Jr Children’s Hospital at Vanderbilt

Brian S Carter, MD, FAAP is a member of the following medical societies: Alpha Omega Alpha, American Academy of Hospice and Palliative Medicine, American Academy of Pediatrics, American Society for Bioethics and Humanities, American Society of Law, Medicine & Ethics, National Hospice and Palliative Care Organization, Society for Pediatric Research, and Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Scott S MacGilvray, MD Clinical Professor, Department of Pediatrics, Division of Neonatology, The Brody School of Medicine at East Carolina University

Scott S MacGilvray, MD is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Anemia of Prematurity

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