THE USE OF ERYTHROPOIETIN IN NEONATES
Section snippets
PHYSIOLOGIC ANEMIA IN TERM AND PRETERM NEONATES
In term infants, improved oxygenation after birth results in systemic oxygen delivery that far exceeds oxygen consumption. Without a hypoxic stimulus for Epo production, serum Epo concentrations fall and erythropoiesis rapidly declines. The hemoglobin concentration decreases over the first 2 to 3 months of life as the infant gains weight, remains stable over the next several weeks as erythropoiesis is reinitiated, then rises in the fourth to sixth month of life in response to a greater Epo
CLINICAL STUDIES
Multiple clinical trials evaluating the use of Epo to prevent and treat anemia in preterm infants have been published in recent years and have reported a variety of results. Early pilot studies used doses that were effective in adults but were inadequate for neonates. These studies reported little or no effect of Epo in preterm infants. Following these initial reports, pharmacokinetic studies in newborn monkeys and sheep indicated that neonates have a larger volume of distribution and a more
EPO TREATMENT FOR OTHER NEONATAL ANEMIAS
Older term and preterm infants with hyporegenerative anemias seem to respond to Epo administration. One such group are infants with the anemia of bronchopulmonary dysplasia. This anemia was initially described by Alverson et al3 and subsequently characterized by Christensen and colleagues17 as a normocytic, normochromic, hyporegenerative anemia with marrow normoblast iron stains that are distinct from those observed in the anemia of chronic disorders and the anemia of prematurity. Patients with
PHARMACOKINETICS AND SIDE EFFECTS
As mentioned previously, studies in newborn monkeys and sheep demonstrate that neonates have a larger volume of distribution and a more rapid elimination of Epo,23, 75 necessitating the use of higher doses than required for adults. In preterm infants, the volume of distribution is threefold to fourfold greater than that seen in adults, whereas the clearance is three to four times greater (Table 4).59
Little is known about the efficacy of daily versus less frequent dosing schedules. Brown and
TRANSFUSION PRACTICES IN NEONATES
The clinical impact of Epo in preterm infants has had implications beyond testing a new therapy. Stricter transfusion criteria have been implemented as a result of these studies, resulting in safe and effective decreases in transfusions without an increase in the length of hospital stay or neonatal morbidities.10 Moreover, phlebotomy practices and blood banking techniques have been modified to meet the needs of VLBW infants in many of the clinical studies. Implementing and completing these
IS EPO BENEFICIAL?
The clinical use of Epo in preterm infants has clearly been shown to stimulate erythropoiesis, as evidenced by increased reticulocytosis and increased hematocrit. The question remains whether this stimulus is significant enough to offset the significant loss of blood that occurs in the first weeks of life on critically ill preterm infants. Numerous studies have demonstrated that the volume of phlebotomy losses, generally a measure of the severity of illness or prematurity, correlates directly
SUMMARY
Although much information has been accumulated about the clinical use of Epo in preterm infants, many questions remain unanswered. The evolution of clinical practice in the care of extremely ill, preterm infants continues to affect the number of transfusions required during hospitalization. Decreasing phlebotomy losses and instituting standardized transfusion guidelines have both been shown significantly to decrease the transfusion requirements of preterm infants. The administration of Epo
References (80)
- et al.
Erythropoietin therapy in neonates at risk of having bronchopulmonary dysplasia and requiring multiple transfusions
J Pediatr
(1996) - et al.
Effect of booster blood transfusions on oxygen utilization in infants with bronchopulmonary dysplasia
J Pediatr
(1988) - et al.
Myocardial, erythropoietic, and metabolic adaptations to anemia of prematurity in infants with bronchopulmonary dysplasia
J Pediatr
(1998) - et al.
Minimizing donor blood exposure in the neonatal intensive care unit. Current trends and future prospects
Clin Perinatol
(1995) - et al.
Relationship between determinants of oxygen delivery and respiratory abnormalities in preterm infants with anemia
J Pediatr
(1992) - et al.
Decreased response of plasma immunoreactive erythropoietin to “available oxygen” in anemia of prematurity
J Pediatr
(1984) - et al.
Single-dose pharmacokinetics of recombinant human erythropoietin in preterm infants after intravenous and subcutaneous administration
J Pediatr
(1993) - et al.
Effect of high doses of human recombinant erythropoietin on the need for blood transfusions in preterm infants
J Pediatr
(1992) - et al.
Evaluation of the mechanism causing anemia in infants with bronchopulmonary dysplasia
J Pediatr
(1992) - et al.
Erythropoietin mRNA expression in human fetal and neonatal tissue
Blood
(1998)
The liver as a source of extrarenal erythropoietin production
Blood
Effects of recombinant human erythropoietin in infants with the anemia of prematurity: A pilot study
J Pediatr
Lactac acid as a predictor for erythrocyte transfusion in healthy preterm infants with the anemia of prematurity
J Pediatr
Serum erythropoietin levels during infancy: Associations with erythropoiesis
J Pediatr
Pharmacokinetics and pharmacodynamics of erythropoietin therapy in an infant with renal failure
J Pediatr
Late hyporegenerative anemia in Rh hemolytic disease
J Pediatr
Myocardial, erythropoietic, and metabolic adaptations to anemia of prematurity
J Pediatr
Ontogeny of erythropoietin gene expression in the sheep fetus: Effect of dexamethasone at 60 days gestation
Blood
High-versus low-dose erythropoietin in extremely low birth weight infants
J Pediatr
A comparison of oral and intravenous iron supplementation in preterm infants receiving recombinant erythropoietin
J Pediatr
Effects of intravascular, intrauterine transfusion on prenatal and postnatal hemolysis and erythropoiesis in severe fetal isoimmunization
J Pediatr
Recombinant erythropoietin compared with erythrocyte transfusion in the treatment of anemia of prematurity
J Pediatr
A randomized, placebo-controlled trial of recombinant erythropoietin as treatment for the anemia of bronchopulmonary dysplasia
J Pediatr
Erythroid “burst promoting activity” in the serum of patients with the anemia of prematurity
J Pediatr
Pharmacokinetics of recombinant erythropoietin administered to preterm infants by continuous infusion in parenteral nutrition solution
J Pediatr
Responsiveness to recombinant human erythropoietin of marrow erythroid progenitors from infants with the “anemia of prematurity.”
J Pediatr
Suppression of erythropoiesis by intrauterine transfusions in hemolytic disease of the newborn: Use of erythropoietin to treat the late anemia
J Pediatr
Recombinant human erythropoietin in neonatal anemia
Clin Perinatol
Erythropoietin in pediatric cardiac surgery: Clinical efficacy and effective dose
Chest
Follow-up of very low birth weight infants after erythropoietin treatment to prevent anemia of prematurity
J Pediatr
Anemia of prematurity: Determinants of the erythropoietin response
J Pediatr
Erythropoietin levels and erythropoiesis at birth in infants with Potter's syndrome
J Pediatr
Changing patterns of red blood cell transfusion in very low birth weight infants
J Pediatr
Packed red cell transfusions do not modify cardiac function of premature infants with “very low hematocrits.”
J Clin Invest
Optimizing the approach to anemia in the preterm infant: Is there a role for erythropoietin therapy?
J Perinatol
Effects of theophylline on erythropoietin production in normal subjects and in patients with erythrocytosis after renal transplantation
N Engl J Med
Effect of low and moderate doses of recombinant human erythropoietin on the haematological response inpremature infants on a high protein and iron intake
Eur J Pediatr
Weekly intravenous administration of recombinant human erythropoietin in infants with the anaemia of prematurity
Eur J Pediatr
Expression of the erythropoietin gene
Mol Cell Biol
Comparison between two and five doses a week of recombinant human erythropoietin for anemia of prematurity: A randomized trial
Pediatrics
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Address reprint requests to Robin K. Ohls, MD Department of Pediatrics, ACC-3W University of New Mexico Health Sciences Center Albuquerque, NM 87131–5311 e-mail: [email protected]
Supported by grants HD-00988 and RR-00997 from the National Institutes of Health.