The Role of High-Dose Oral Iron Supplementation During Erythropoietin Therapy for Anemia of Prematurity D. Bader, MD A. Kugelman, MD N. Maor-Rogin, MD M. Weinger-Abend, MD S. Hershkowitz, MD A. Tamir, MD A. Lanir, PhD D. Attias, MD M. Barak, MD INTRODUCTION Recent studies show reduced transfusion requirements when recombinant human erythropoietin (rHuEPO) is used in preterm infants. 1–3 There remain, however, some unanswered questions. One of these is how much supplemental iron is needed for optimal erythropoietic response to rHuEPO administration. Several recent trials have shown significantly decreased serum ferritin levels with rHuEPO therapy, despite 2 to 6 mg / kg per day of elemental oral iron supplementation. 1,2,4,5 While anemia of prematurity may result from erythropoietin deficiency and blood withdrawals, and iron deficiency may evolve earlier in premature infants, 6–8 treatment with rHuEPO may further contribute to functional iron deficiency. This may result in limited erythropoietic effectiveness of rHuEPO therapy without adequate iron supplementation. Bechensteen et al. 9,10 reported a good response to rHuEPO therapy when using very high doses of oral iron ( 18 to 36 mg / d in infants at 3 weeks of age and birth weight of 900 to 1400 g ) , with no apparent side effects, while most of the other studies were using much lower doses of iron supplementation (2 to 6 mg/kg per day). 1–3 Our hypothesis was that using a higher dose of oral iron supplementation would prevent iron functional depletion and enhance erythropoiesis in premature infants treated with rHuEPO. Our study was designed to compare the effectiveness of a high dose ( 16 mg / kg per day ) versus a lower dose ( 8 mg / kg per day ) of oral iron supplementation in preterm infants receiving rHuEPO for anemia of prematurity. MATERIALS AND METHODS Subjects Preterm infants were recruited for the study from all admissions to the neonatal intensive care units at the ‘‘Bnai-Zion’’ Medical OBJECTIVE: To assess whether a high intake of oral iron would increase the effect of recombinant human erythropoietin ( rHuEPO ) on hemoglobin synthesis. METHODS: We studied 30 preterm infants ( gestational age 29 ± 1.8 weeks, birth weight 1161±200 g, at age of 28±10 days) who were randomly assigned to receive either 8 mg / kg per day ( n = 15 ) or 16 mg / kg per day of oral iron during a course of rHuEPO therapy ( 900 g / kg per week ) for a duration of 4 weeks. Both groups were comparable in regard to clinical and laboratory data at the time of enrollment. RESULTS: rHuEPO caused a significant increase in reticulocyte count in the low - and high - dose iron groups, 17.1 ± 5.3 to 34.7 ± 9.2 and 16.3 ± 3.3 to 42.5 ± 5.6 (10 9 / l ) , respectively ( p < 0.05 ) . However, in both groups, hematocrit values remained stable at the end of the study as compared to baseline ( 0.35 ± 0.03% vs. 0.30 ± 0.03%, 0.35 ± 0.05% vs. 0.30 ± 0.03%, NS ) and in both groups there was a comparable and significant decrease in ferritin level (259±109 to 101±40 and 168±54 to 69±38 g / l, respectively; p < 0.01 ) . The rates of bloody stools without any evidence of necrotizing enterocolitis were not significantly different between the two treatment groups (1/15 vs. 4/15, NS). Department of Neonatology (D.B., A.K., N.M.-R., M. W.-A.), ‘‘Bnai - Zion’’ Medical Center; Department of Neonatology (S.H., M.B.), Western Galilee Medical Center; Department of Community Medicine and Epidemiology (A.T.), Lady Davis Carmel Hospital; Department of Clinical Biochemistry (A.L.), ‘‘Bnai - Zion’’ Medical Center; and Department of Hematology (D.A.), ‘‘Bnai - Zion’’ Medical Center, B. Rappaport School of Medicine, Technion - Israel Institute of Technology, Haifa, Israel. Address correspondence and reprint requests to D. Bader, MD, Department of Neonatology, ‘‘Bnai - Zion’’ Medical Center, 47 Golomb Street, Haifa 31048, Israel. CONCLUSION: We conclude that a higher dose (16 mg/kg per day) of oral iron is not more beneficial when compared to a lower dose ( 8 mg / kg per day ) during rHuEPO therapy for anemia of prematurity. Further studies will define the optimal dosage and route of administration of iron supplementation during rHuEPO therapy. Journal of Perinatology 2001; 21:215 – 220. Original Article & & & & & & & & & & & & & & 215 Journal of Perinatology 2001; 21:215 – 220 #2001 Nature Publishing Group All rights reserved. 0743-8346/01 $17 www.nature.com/jp