Stimulating erythropoiesis in neonates
Authors: Vijay G. Sankaran, Pankaj B. Agrawal
Journal: American Journal of Hematology (2013)

Preterm infants in neonatal intensive care units frequently receive transfusions of packed red blood cells (PRBCs) 1-3. This is largely attributable to the common occurrence of what is termed the anemia of prematurity in this vulnerable patient population. The anemia of prematurity has been attributed to substantial blood loss from phlebotomy, deficiencies of a variety of nutrients essential for red blood cell production (erythropoiesis), impairments in erythropoiesis due to critical illness, and a more pronounced nadir of hemoglobin in comparison with that observed physiologically in term infants 1, 3. The contributions of these various factors to different cases of anemia in neonates vary with the extent of illness in a neonate and a number of other factors, such as the gestational age at the time of birth. For simplicity in neonatal intensive care unit (NICU) management, these varied causes of anemia have been lumped together and are often treated similarly with the use of PRBC transfusions 1. While no universal guidelines exist for particular transfusion thresholds in neonates, various NICUs have established their own guidelines based on experience and limited evidence 3-5. While the use of red cell transfusions is highly prevalent in NICUs, there have been long standing and more recent emerging concerns over the use of this frequent intervention. Some of the older concerns over the use of transfusion stemmed from exposure to multiple donors and the potential short- and long-term consequences of this, such as alloimmunization and risk of infectious disease transmission 3. More recently, both increased risks of significant intracranial hemorrhage (ICH) with early red cell transfusions 6 and necrotizing enterocolitis (NEC; a condition where necrosis of the bowel occurs in neonates) with late transfusions 7 has prompted further concern over this intervention. Furthermore, recent studies suggest that lower hematocrit levels are associated with red cell transfusion-associated NEC 8, which has been suggested to occur since anemia could compromise mucosal integrity and lead to poor wound healing 9. This has prompted a revision of guidelines in many NICUs with an attempt to maintain higher hemoglobin levels in asymptomatic preterm infants, which in turn means more red cell transfusions are given to these neonates. Since the early 1990s, a number of studies have explored whether erythropoietin (Epo) administration could help to reduce the number of or need for packed red cell transfusions in neonates with the anemia of prematurity 10. Epo stimulates a crucial signaling pathway that promotes erythroid progenitor and precursor survival, proliferation, and differentiation (Fig. 1). The initial motivation for trialing Epo in neonates was to reduce the number of donors that these patients were exposed to. A number of studies examining Epo administration in neonates have shown that there is some benefit to the use of these medications with a reduction of one to two transfusions in these patients 11, 12. The clinical utility of this reduction in transfusions is not clear. Additionally, there has been concern over a potential increase in the risk of the retinopathy of prematurity (ROP) as a result of early Epo treatment 12, which has resulted in many clinicians being reluctant to use Epo in neonates. It should be noted that there is some controversy about the meta-analyses that have shown an increased risk of ROP and there may have been misclassification of certain studies involved 13. Given these controversies and the recently recognized additional risks of red cell transfusions in neonates 6, 7, there has been a resurgent interest in whether erythropoiesis stimulating agents like Epo may have clinical benefit in neonates. In a recent study from Ohls et al., a randomized, placebo-controlled trial was performed to test whether either Epo or the longer-acting Epo analog darbepoetin alfa (Darbe) can reduce the need for transfusions, while also measuring the incidence of morbidities of concern in these groups, such as the ROP 10. The authors provided preterm infants with birth weights between 500 and 1250 g who were less than 48 hr at the time of enrollment, with either weekly Darbe treatment at 10 µg/kg subcutaneously or Epo at 400 U/kg three times per week subcutaneously. There were 33 neonates in each of the treatment groups and the same numbers were in the placebo control group. A sham-dosing scheme was used as the placebo for blinding purposes. All patients in the study received supplementation with iron, folate, and vitamin E. In addition, all enrolled patients were transfused according to a strict protocol that depended upon the need for respiratory support and symptoms 10. This protocol is consistent with restrictive transfusion regimens that are used in a variety of major NICUs. As expected, both hematocrit levels and absolute reticulocyte counts were higher in the Darbe and Epo treatment groups, as compared with the controls. Importantly, the authors could demonstrate that treatment of infants with either Darbe or Epo reduced both the number of transfusions (from an average of 2.4 transfusions down to 1.2 transfusions) and the number of donors (from an average of 1.2 in the control compared with 0.7–0.8 in the treatment groups) by nearly twofold. Importantly, nearly half of the infants treated with Darbe or Epo could completely avoid transfusions. Ohls et al. have additionally measured the incidence of a variety of morbidities of concern in the treatment and placebo groups 10. There was no significant difference in the incidence of ROP, ICH, NEC, or other complications seen frequently in the NICU. This study may be underpowered to detect a subtle effect on any of these complications. Additionally, these treatments did not affect the length of hospital stay, the risk of mortality, or the growth of the children as assessed at 36 weeks gestational age. This study raises as many questions as it answers 10. More clinical studies are needed to further pursue whether Darbe or other erythropoiesis stimulating agents may be clinically beneficial for use in neonates. In particular, it will be interesting to examine whether the use of these agents can reduce the newly appreciated risks of PRBC transfusions in neonates, such as the risks of ICH with early transfusions or NEC with late transfusions. It is possible that more effective erythropoiesis stimulating agents (including newer agents that take advantage of other aspects of the Epo signaling or other pathways; Fig. 1) or better dosing regimens can completely prevent the administration of red cells in these patients. Indeed, almost half of the treated patients did not require PRBC transfusions, suggesting that such goals can readily be achieved. Longer term and larger studies are needed to ensure that no additional risks are seen with these agents (particularly ROP). Additionally, cost-benefit analyses are needed to see whether a cost savings could occur with the use of such agents, particularly those that are longer acting. Finally and perhaps most interestingly, future studies will need to examine whether longer-acting agents like Darbe could be more beneficial in comparison with Epo that requires frequent treatments. While many more studies are needed, the resurgence of interest in the use of erythropoiesis stimulating agents raises hopes for improving interventions performed to treat the anemia commonly seen in this vulnerable patient population.