Anemia of prematurity

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 term infants, the hemoglobin level typically reaches an average nadir of 11 g/dL at approximately 8 to 12 weeks after birth.

In preterm infants who are already born with a lower hematocrit, this decline, referred to as anemia of prematurity (AOP), occurs earlier and is more pronounced in its severity than the anemia seen in term infants. The AOP will be reviewed here.

PATHOGENESIS

The primary cause of anemia of prematurity (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".)

                  

Subscribers log in here

To continue reading this article you must have access through your hospital or your group practice, log in to your personal subscription, or purchase a personal subscription. For more information, click below.
Literature review current through: May 2013. | This topic last updated: May 28, 2013.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2013 UpToDate, Inc.
References
Top
  1. Ohls RK. The use of erythropoietin in neonates. Clin Perinatol 2000; 27:681.
  2. Stockman JA 3rd, Graeber JE, Clark DA, et al. Anemia of prematurity: determinants of the erythropoietin response. J Pediatr 1984; 105:786.
  3. Brown MS, Phibbs RH, Garcia JF, Dallman PR. Postnatal changes in erythropoietin levels in untransfused premature infants. J Pediatr 1983; 103:612.
  4. Shannon KM, Naylor GS, Torkildson JC, et al. Circulating erythroid progenitors in the anemia of prematurity. N Engl J Med 1987; 317:728.
  5. Rhondeau SM, Christensen RD, Ross MP, et al. Responsiveness to recombinant human erythropoietin of marrow erythroid progenitors from infants with the "anemia of prematurity". J Pediatr 1988; 112:935.
  6. Ohls RK, Liechty KW, Turner MC, et al. Erythroid "burst promoting" activity in serum of patients with the anemia of prematurity. J Pediatr 1990; 116:786.
  7. Malek A, Sager R, Eckardt KU, et al. Lack of transport of erythropoietin across the human placenta as studied by an in vitro perfusion system. Pflugers Arch 1994; 427:157.
  8. Schneider H, Malek A. Lack of permeability of the human placenta for erythropoietin. J Perinat Med 1995; 23:71.
  9. Widness JA, Schmidt RL, Sawyer ST. Erythropoietin transplacental passage--review of animal studies. J Perinat Med 1995; 23:61.
  10. Palis J, Segel GB. Developmental biology of erythropoiesis. Blood Rev 1998; 12:106.
  11. Brown MS, Garcia JF, Phibbs RH, Dallman PR. Decreased response of plasma immunoreactive erythropoietin to "available oxygen" in anemia of prematurity. J Pediatr 1984; 105:793.
  12. Moritz KM, Lim GB, Wintour EM. Developmental regulation of erythropoietin and erythropoiesis. Am J Physiol 1997; 273:R1829.
  13. Dame C, Fahnenstich H, Freitag P, et al. Erythropoietin mRNA expression in human fetal and neonatal tissue. Blood 1998; 92:3218.
  14. Tan CC, Eckardt KU, Firth JD, Ratcliffe PJ. Feedback modulation of renal and hepatic erythropoietin mRNA in response to graded anemia and hypoxia. Am J Physiol 1992; 263:F474.
  15. Flake AW, Harrison MR, Adzick NS, Zanjani ED. Erythropoietin production by the fetal liver in an adult environment. Blood 1987; 70:542.
  16. Semenza GL. Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol 1999; 15:551.
  17. Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A 1995; 92:5510.
  18. Rajakumar A, Conrad KP. Expression, ontogeny, and regulation of hypoxia-inducible transcription factors in the human placenta. Biol Reprod 2000; 63:559.
  19. Lin JC, Strauss RG, Kulhavy JC, et al. Phlebotomy overdraw in the neonatal intensive care nursery. Pediatrics 2000; 106:E19.
  20. Ringer SA, Richardson DK, Sacher RA, et al. Variations in transfusion practice in neonatal intensive care. Pediatrics 1998; 101:194.
  21. KAPLAN E, HSU KS. Determination of erythrocyte survival in newborn infants by means of Cr51-labelled erythrocytes. Pediatrics 1961; 27:354.
  22. Shahal Y, Bauminger ER, Zmora E, et al. Oxidative stress in newborn erythrocytes. Pediatr Res 1991; 29:119.
  23. Robles R, Palomino N, Robles A. Oxidative stress in the neonate. Early Hum Dev 2001; 65 Suppl:S75.
  24. Haiden N, Schwindt J, Cardona F, et al. Effects of a combined therapy of erythropoietin, iron, folate, and vitamin B12 on the transfusion requirements of extremely low birth weight infants. Pediatrics 2006; 118:2004.
  25. Bard H, Fouron JC, Chessex P, Widness JA. Myocardial, erythropoietic, and metabolic adaptations to anemia of prematurity in infants with bronchopulmonary dysplasia. J Pediatr 1998; 132:630.
  26. Bard H. The postnatal decline of hemoglobin F synthesis in normal full-term infants. J Clin Invest 1975; 55:395.
  27. Bard H, Prosmanne J. Postnatal fetal and adult hemoglobin synthesis is preterm infants whose birth weight was less than 1,000 grams. J Clin Invest 1982; 70:50.
  28. Beuzard Y, Vainchenker W, Testa U, et al. Fetal to adult hemoglobin switch in cultures of early erythroid precursors from human fetuses and neonates. Am J Hematol 1979; 7:207.
  29. Stockman JA 3rd. Anemia of prematurity. Clin Perinatol 1977; 4:239.
  30. Stockman JA 3rd, Garcia JF, Oski FA. The anemia of prematurity. Factors governing the erythropoietin response. N Engl J Med 1977; 296:647.
  31. Stockman JA 3rd, Oski FA. RBC values in low-birth-weight infants during the first seven weeks of life. Am J Dis Child 1980; 134:945.
  32. Lachance C, Chessex P, Fouron JC, et al. Myocardial, erythropoietic, and metabolic adaptations to anemia of prematurity. J Pediatr 1994; 125:278.
  33. Böhler T, Janecke A, Linderkamp O. Blood transfusion in late anemia of prematurity: effect on oxygen consumption, heart rate, and weight gain in otherwise healthy infants. Infusionsther Transfusionsmed 1994; 21:376.
  34. Zagol K, Lake DE, Vergales B, et al. Anemia, apnea of prematurity, and blood transfusions. J Pediatr 2012; 161:417.
  35. Madsen LP, Rasmussen MK, Bjerregaard LL, et al. Impact of blood sampling in very preterm infants. Scand J Clin Lab Invest 2000; 60:125.
  36. Committee on Nutrition, American Academy of Pediatrics. Nutritional needs of the preterm infant. In: Pediatric Nutrition Handbook, 6th ed, Kleinman RE (Ed), American Academy of Pediatrics, Elk Grove Village 2009. p.79.
  37. Berseth CL, Van Aerde JE, Gross S, et al. Growth, efficacy, and safety of feeding an iron-fortified human milk fortifier. Pediatrics 2004; 114:e699.
  38. Ohls RK. Why study erythropoietin in preterm infants? Acta Paediatr 2013; 102:567.
  39. Birenbaum HJ, Pane MA, Helou SM, Starr KP. Comparison of a restricted transfusion schedule with erythropoietin therapy versus a restricted transfusion schedule alone in very low birth weight premature infants. South Med J 2006; 99:1059.
  40. Ohlsson A, Aher SM. Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database Syst Rev 2006; :CD004863.
  41. 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 2004; 114:1287.
  42. Aher S, Ohlsson A. Late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database Syst Rev 2006; :CD004868.
  43. Aher SM, Ohlsson A. Early versus late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database Syst Rev 2012; 10:CD004865.
  44. Aher SM, Ohlsson A. Early versus late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database Syst Rev 2006; :CD004865.
  45. Ohls RK, Christensen RD. Recombinant erythropoietin compared with erythrocyte transfusion in the treatment of anemia of prematurity. J Pediatr 1991; 119:781.
  46. Halpérin DS. Use of recombinant erythropoietin in treatment of the anemia of prematurity. Am J Pediatr Hematol Oncol 1991; 13:351.
  47. Carnielli VP, Da Riol R, Montini G. Iron supplementation enhances response to high doses of recombinant human erythropoietin in preterm infants. Arch Dis Child Fetal Neonatal Ed 1998; 79:F44.
  48. Bechensteen AG, Hågå P, Halvorsen S, et al. Effect of low and moderate doses of recombinant human erythropoietin on the haematological response in premature infants on a high protein and iron intake. Eur J Pediatr 1997; 156:56.
  49. Calhoun DA, Christensen RD, Edstrom CS, et al. Consistent approaches to procedures and practices in neonatal hematology. Clin Perinatol 2000; 27:733.
  50. Costa S, Romagnoli C, Zuppa AA, et al. How to administrate erythropoietin, intravenous or subcutaneous? Acta Paediatr 2013; 102:579.
  51. Ohls RK, Veerman MW, Christensen RD. Pharmacokinetics and effectiveness of recombinant erythropoietin administered to preterm infants by continuous infusion in total parenteral nutrition solution. J Pediatr 1996; 128:518.
  52. Ohls RK, Roohi M, Peceny HM, et al. A randomized, masked study of weekly erythropoietin dosing in preterm infants. J Pediatr 2012; 160:790.