Elsevier

Seminars in Perinatology

Volume 33, Issue 1, February 2009, Pages 29-34
Seminars in Perinatology

Current Controversies in the Management of the Anemia of Prematurity

https://doi.org/10.1053/j.semperi.2008.10.006Get rights and content

Preterm infants, especially those with extremely low birth weight (ELBW) are exposed to frequent blood draws as part of their care in the neonatal intensive care unit. ELBW infants develop the anemia of prematurity (AOP), a hypo-proliferative anemia marked by inadequate production of erythropoietin (Epo). Treatment of AOP includes red blood cell transfusions, which are given to preterm infants based on indications and guidelines (hematocrit/hemoglobin levels, ventilation and oxygen need, apneas and bradycardias, poor weight gain) that are relatively non-specific. In this article we review recent studies evaluating transfusion guidelines, discuss ways to decrease phlebotomy losses and examine the use of red cell growth factors such as Epo in preventing and treating anemia in preterm infants.

Section snippets

Transfusion Studies

Newer, more restrictive transfusion guidelines have been evaluated in randomized, controlled trials (RCTs) over the past two decades. The ability of critically ill adults and children to adapt to lower hemoglobin levels has recently been evaluated, and studies have sought to determine the safety and efficacy of more restrictive transfusion guidelines.5

Adult and Pediatric Transfusion Studies

Studies evaluating transfusion guidelines in critically ill adults have significantly changed transfusion practices over the last decade.6, 7, 8, 9 The largest of these was the Transfusion Requirements in Critical Care trial, a RCT involving 838 critically ill adults.10 The investigators determined whether a restrictive approach to transfusions was equivalent to a liberal strategy. In patients who were less acutely ill, the mortality rates were lower in the restrictive group (8.7% versus

Neonatal Transfusion Practices

Similar to transfusion practices in adult critically ill patients, neonatal transfusion practices have changed significantly in the last 30 years. In the 1970s and 1980s, a common approach to neonatal transfusion was to maintain the hematocrit at or above 40%. Blood losses due to laboratory draws were carefully monitored, and blood was replaced in the form of packed red cell transfusions when the total volume reached 10 mL/kg.5 Many neonatal intensive care units modified their transfusion

Neonatal Transfusion Studies

Bifano was the first to evaluate neonatal transfusion guidelines in prospective fashion. They randomized 50 infants with birth weights of 650 to 1000 g to two groups, a high hematocrit strategy (>32%) and a low hematocrit strategy (<30%).15 In the high group, the hematocrit was maintained with Epo and transfusions, while in the “low” group the hematocrit was maintained by transfusions only. Statistically significant differences in hematocrit were achieved by the second week of the study and

Phlebotomy Losses

ELBW infants are among the most highly transfused group of patients, in part due to the phlebotomy losses occurring in the first weeks of life. Strategies to decrease phlebotomy losses include microsampling, batching of blood labs, cord blood sampling for immediate postnatal labs such as type and cross-match, removing central lines as soon as possible, ordering labs judiciously, careful monitoring of phlebotomy losses, and the use of blood-testing devices operated at the bedside or point of

Red Cell Growth Factors

Red cell growth factors such as human recombinant Epo have been extensively studied as a treatment for a variety of anemias. In vitro and in vivo studies determined that the anemia of prematurity was primarily a result of low endogenous Epo production. Clinical trials have evaluated the administration of Epo to preterm infants to treat anemia of prematurity. Recent studies have focused on the administration of Epo in the first weeks of life to alleviate the anemia caused by excessive phlebotomy

Randomized Epo Trials

The results of initial studies evaluating Epo administration to preterm infants were highly variable due to numerous methodological problems, including a lack of randomization, small sample size, and use of different Epo protocols regarding dosage, route of administration, onset, and duration of treatment. Despite these limitations, these early studies provided helpful information, demonstrating that the response to Epo was dose related.32 Studies in the 1990s that employed adequate dosing

Darbepoetin

Darbepoetin alfa, a biologically modified, long-acting version of Epo, was approved in 2001 by the US Food and Drug Administration for the treatment of anemia of chronic renal failure. Darbepoetin contains 5 N-linked oligosaccharide chains along the 165 amino acid backbone, which do not alter its biologic activity or tertiary structure, but increase the half-life. Single-dose darbepoetin pharmacokinetics35, 36 showed that neonates had a shorter half-life, a larger volume of distribution, and

Epo and Retinopathy of Prematurity

In addition to its hematopoietic properties, Epo is also a vascular growth factor. Retrospective analyses and meta-analyses have raised concerns about an association between retinopathy of prematurity (ROP) and Epo administration. Epo plays a role in the developing human eye, where Epo concentrations have been measured that exceed serum concentrations.41 However, no RCTs published in peer-reviewed journals have reported an increased incidence of ROP in Epo-treated groups. A Cochrane Review of

Epo and Neuroprotection

The risks versus benefits of Epo administration to preterm infants continue to be evaluated in RCTs. One benefit currently being investigated involves the potential neuroprotective effect of Epo in the developing preterm infant. Numerous animal studies over the past 15 years suggest a neuroprotective effect of Epo43 and pilot studies suggest that high-dose Epo is safe in ELBW infants.44 Our group was the first to publish a relationship between elevated serum Epo concentrations and improved

Summary

It is likely that Epo administration in combination with restrictive transfusion guidelines and a multi-factorial approach to minimize red cell blood loss will have the greatest impact in reducing transfusion requirements in preterm and term neonates, regardless of the etiology of their anemia. Research continues on identifying a clear marker for transfusion need, on refining dosing strategies of red cell growth factors, and on evaluating potential neuroprotective benefits of Epo

References (45)

  • R. Maier et al.

    High-versus low-dose erythropoietin in extremely low birth weight infantsThe European Multicenter rhEPO Study Group

    J Pediatr

    (1998)
  • R. Ohls 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)
  • H. Donato et al.

    Effect of early versus late administration of human recombinant erythropoietin on transfusion requirements in premature infants: Results of a randomized, placebo-controlled, multicenter trial

    Pediatrics

    (2000)
  • C. Chant et al.

    Anemia, transfusion, and phlebotomy practices in critically ill patients with prolonged ICU length of stay: A cohort study

    Crit Care

    (2006)
  • M. Croce et al.

    Transfusions result in pulmonary morbidity and death after a moderate degree of injury

    J Trauma

    (2005)
  • D. Malone et al.

    Blood transfusion, independent of shock severity, is associated with worse outcome in trauma

    J Trauma

    (2003)
  • P. Hébert et al.

    A multicenter, randomized, controlled clinical trial of transfusion requirements in critical careTransfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group

    N Engl J Med

    (1999)
  • J. Lacroix et al.

    Transfusion strategies for patients in pediatric intensive care units

    N Engl J Med

    (2007)
  • K. Shannon et al.

    Recombinant human erythropoietin stimulates erythropoiesis and reduces erythrocyte transfusions in very low birth weight preterm infants

    Pediatrics

    (1995)
  • E. Bifano

    The effect of hematocrit (HCT) level on clinical outcomes in extremely low birthweight (ELBW) infants

    Pediatr Res

    (2001)
  • E. Bifano et al.

    Prospective randomized trial of high vs. low hematocrit in Extremely Low Birth Weight (ELBW) infants: One year growth and neurodevelopmental outcome

    Pediatr Res

    (2002)
  • E. Bell et al.

    Randomized trial of liberal versus restrictive guidelines for red blood cell transfusion in preterm infants

    Pediatrics

    (2005)
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