Erythropoietin therapy in a case of neonatal anemia after exposure to natalizumab throughout pregnancy.

BACKGROUND: Natalizumab is a monoclonal antibody approved for the treatment of patients with relapsing-remitting multiple sclerosis. According to the current clinical recommendations, its use during pregnancy should be carefully evaluated only in women with highly active disease who plan a pregnancy or have an unplanned pregnancy, after accurate counseling about eventual maternal disease relapse due to therapy suspension. CASE PRESENTATION: This brief case report describes a case of documented anemia that we observed in a newborn whose mother with relapsing-remitting multiple sclerosis was treated with an extended dosing protocol of natalizumab throughout pregnancy. The newborn received the infusion of erythropoietin every seven days from the fortieth day of life; subsequently, the status of anemia underwent clinical resolution. CONCLUSIONS: This case report confirmed that natalizumab can cause disorders of hematopoiesis, including anemia, thrombocytopenia, or pancytopenia, in newborns of patients treated during pregnancy. A multidisciplinary team, including experienced pediatricians and pediatric hematologists, has a critical role in managing newborns delivered by women, being treated with natalizumab for treating relapsing-remitting multiple sclerosis during pregnancy.

Utilization of Erythropoietin within the United States Neonatal Intensive Care Units from 2008 to 2017.

OBJECTIVE: Little data are available regarding erythropoietin (Epo) utilization patterns within neonatal intensive care units (NICUs). We sought to describe the trends in Epo utilization across a large cohort of U.S. NICUs. STUDY DESIGN: This is a retrospective cohort study of infants discharged from 2008 to 2017 using the Pediatrix Clinical Data Warehouse. RESULTS: We identified 704,159 eligible infants from 358 sites, of whom 9,749 (1.4%) had Epo exposure. For extremely low gestational age newborns (ELGANs), Epo exposure ranged from 7.6 to 13.5%. We found significant site variability in Epo utilization in ELGANs. Among the 299 NICUs caring for ELGANs during the study period, 184 (61.5%) never used Epo for this population, whereas 21 (7%) utilized Epo in 50% or more of eligible infants. Epo was initiated at a median of 25 days in ELGANs. For infants with hypoxic-ischemic encephalopathy (HIE), Epo exposure remained ≤1% through 2014 then increased fourfold to 3.4% by 2017. The median day of Epo initiation was the day of birth for infants diagnosed with HIE. CONCLUSION: Epo is utilized in ELGANs more commonly than for other NICU populations. Utilization patterns appear to indicate the treatment of established anemia for ELGANs and more recently for neuroprotection in patients diagnosed with HIE.

Micronutrient supplementation adherence and influence on the prevalences of anemia and iron, zinc and vitamin A deficiencies in preemies with a corrected age of six months.

OBJECTIVE: To analyze adherence to the recommended iron, zinc and multivitamin supplementation guidelines for preemies, the factors associated with this adherence, and the influence of adherence on the occurrence of anemia and iron, zinc and vitamin A deficiencies. METHODS: This prospective cohort study followed 58 preemies born in 2014 until they reached six months corrected age. The preemies were followed at a referral secondary health service and represented 63.7% of the preterm infants born that year. Outcomes of interest included high or low adherence to iron, zinc and multivitamin supplementation guidelines; prevalence of anemia; and prevalences of iron, zinc, and vitamin A deficiencies. The prevalence ratios were calculated by Poisson regression. RESULTS: Thirty-eight (65.5%) preemies presented high adherence to micronutrient supplementation guidelines. At six months of corrected age, no preemie had vitamin A deficiency. The prevalences of anemia, iron deficiency and zinc deficiency were higher in the low-adherence group but also concerning in the high-adherence group. Preemies with low adherence to micronutrient supplementation guidelines were 2.5 times more likely to develop anemia and 3.1 times more likely to develop zinc deficiency. Low maternal education level increased the likelihood of nonadherence to all three supplements by 2.2 times. CONCLUSIONS: Low maternal education level was independently associated with low adherence to iron, zinc and vitamin A supplementation guidelines in preemies, which impacted the prevalences of anemia and iron and zinc deficiencies at six months of corrected age.

Micronutrient supplementation adherence and influence on the prevalences of anemia and iron, zinc and vitamin A deficiencies in preemies with a corrected age of six months

OBJECTIVE: To analyze adherence to the recommended iron, zinc and multivitamin supplementation guidelines for preemies, the factors associated with this adherence, and the influence of adherence on the occurrence of anemia and iron, zinc and vitamin A deficiencies. METHODS: This prospective cohort study followed 58 preemies born in 2014 until they reached six months corrected age. The preemies were followed at a referral secondary health service and represented 63.7% of the preterm infants born that year. Outcomes of interest included high or low adherence to iron, zinc and multivitamin supplementation guidelines; prevalence of anemia; and prevalences of iron, zinc, and vitamin A deficiencies. The prevalence ratios were calculated by Poisson regression. RESULTS: Thirty-eight (65.5%) preemies presented high adherence to micronutrient supplementation guidelines. At six months of corrected age, no preemie had vitamin A deficiency. The prevalences of anemia, iron deficiency and zinc deficiency were higher in the low-adherence group but also concerning in the high-adherence group. Preemies with low adherence to micronutrient supplementation guidelines were 2.5 times more likely to develop anemia and 3.1 times more likely to develop zinc deficiency. Low maternal education level increased the likelihood of nonadherence to all three supplements by 2.2 times. CONCLUSIONS: Low maternal education level was independently associated with low adherence to iron, zinc and vitamin A supplementation guidelines in preemies, which impacted the prevalences of anemia and iron and zinc deficiencies at six months of corrected age.

Diffuse neonatal hemangiomatosis in a very low-birthweight infant treated with erythropoietin.

Diffuse neonatal hemangiomatosis (DNH) is a rare condition characterized by the concomitant development of multiple cutaneous infantile hemangiomas (IH) and visceral hemangiomas. Recently, an association between erythropoietin treatment and an increased incidence of infantile hemangioma was noted. A Japanese male infant was born via cesarean section at 27 weeks of gestation. Following the commencement of erythropoietin treatment for anemia of prematurity, he developed multiple cutaneous hemangiomas, high cardiac output heart failure and hepatomegaly. Abdominal imaging indicated comorbidity of diffuse infantile hepatic hemannigomas, resulting in the final diagnosis of DNH. The discontinuation of erythropoietin treatment and long-term therapy with propranolol improved the hepatic lesions and cutaneous hemangiomas. The possibility of multiple organ involvement and the exacerbating effects of erythropoietin treatment should be considered in cases in which multiple cutaneous hemangiomas develop in preterm infants receiving erythropoietin treatment.

[Clinical study of iron protein succinylate oral solution for preventing and treating anemia of prematurity].

OBJECTIVE: To evaluate the efficacy and safety of iron protein succinylate (IPS) oral solution in preventing and treating anemia of prematurity (AOP). METHODS: Sixty premature infants less than 35 weeks of gestation were randomly divided into IPS (n=30) and polysaccharide iron complex (PIC) groups(n=30). Treatment began at two weeks after birth. The infants received IPS or PIC in addition to recombinant human erythropoietin. On days 14, 28, 42, and 60 after treatment, hemoglobin (Hb), red blood cell count(RBC), hematocrit (HCT), percentage of reticulocytes, serum iron, and serum ferritin were determined. Liver and renal functions were evaluated before and after treatment. RESULTS: There were significant differences in the changing trends of RBC and HCT between the two groups (P<0.05). In the IPS group, RBC and HCT gradually decreased after birth, but began to rise gradually on days 28 and 42 of treatment; in the PIC group, RBC and HCT kept decreasing from birth to day 60 of treatment. On day 60 of treatment, the IPS group had significantly higher levels of Hb, RBC, HCT, serum iron, and serum ferritin than the PIC group (P<0.05). No notable adverse events occurred in either group. CONCLUSIONS: IPS oral solution has good efficacy and tolerability in preventing and treating AOP.

A randomized, masked, placebo-controlled study of darbepoetin alfa in preterm infants.

BACKGROUND: A novel erythropoiesis stimulating agent (ESA), darbepoetin alfa (Darbe), increases hematocrit in anemic adults when administered every 1 to 3 weeks. Weekly Darbe dosing has not been evaluated in preterm infants. We hypothesized that infants would respond to Darbe by decreasing transfusion needs compared with placebo, with less-frequent dosing than erythropoietin (Epo). METHODS: Preterm infants 500 to 1250 g birth weight and ≤48 hours of age were randomized to Darbe (10 µg/kg, 1 time per week subcutaneously), Epo (400 U/kg, 3 times per week subcutaneously) or placebo (sham dosing) through 35 weeks' gestation. All received supplemental iron, folate, and vitamin E, and were transfused according to protocol. Transfusions (primary outcome), complete blood counts, absolute reticulocyte counts (ARCs), phlebotomy losses, and adverse events were recorded. RESULTS: A total of 102 infants (946 ± 196 g, 27.7 ± 1.8 weeks' gestation, 51 ± 25 hours of age at first dose) were enrolled. Infants in the Darbe and Epo groups received significantly fewer transfusions (P = .015) and were exposed to fewer donors (P = .044) than the placebo group (Darbe: 1.2 ± 2.4 transfusions and 0.7 ± 1.2 donors per infant; Epo: 1.2 ± 1.6 transfusions and 0.8 ± 1.0 donors per infant; placebo: 2.4 ± 2.9 transfusions and 1.2 ± 1.3 donors per infant). Hematocrit and ARC were higher in the Darbe and Epo groups compared with placebo (P = .001, Darbe and Epo versus placebo for both hematocrit and ARCs). Morbidities were similar among groups, including the incidence of retinopathy of prematurity. CONCLUSIONS: Infants receiving Darbe or Epo received fewer transfusions and fewer donor exposures, and fewer injections were given to Darbe recipients. Darbepoetin and Epo successfully serve as adjuncts to transfusions in maintaining red cell mass in preterm infants.

Eficacia y seguridad de la eritropoyetina en la anemia de la prematuridad / Efficacy and safety of erythropoietin for anemia of prematurity

Introducción: la eritropoyetina alfa recombinante forma parte del tratamiento de la anemia de la prematuridad. En Cuba su uso ha sido limitado y controvertido en cuanto a esquema y dosis empleada. Métodos: ensayo clínico prospectivo, multicéntrico, no aleatorizado, de eficacia y seguridad de eritropoyetina en la disminución de transfusiones en el recién nacido pretérmino de muy bajo peso. Se incluyeron 72 neonatos con edad gestacional menor de 34 semanas posmenstruales, y peso al nacer menor o igual a 1 500 g, con más de 7 días posnatales e ingesta de 50 mL/kg/día. Resultados: todos recibieron eritropoyetina 300 U/kg, subcutánea, 3 veces/semana, hasta las 40 semanas de edad gestacional y suplemento de hierro y vitaminas. La eritropoyetina fue muy segura, solo se notificó con relación posible una retinopatía de la prematuridad, ligera y recuperada. Conclusiones: se transfundieron 7 pacientes (9,7 por ciento) en el curso del estudio. El uso tardío de eritropoyetina en el pretérmino de muy bajo peso confirma su eficacia y seguridad(AU)

Introduction: recombinant alpha erythropoietin is part of the treatment for anemia of prematurity. The use of this one in Cuba has been restricted and controversial as to schedule and dose. Methods: prospective, non-randomized multicenter assay on the safety and efficacy of erythropoietin in the reduction of blood transfusion in very-low-weight preterm newborn. Seventy two neonates with gestational age under 34 post-menstruation weeks, weighing equal or less than 1 500 g, over 7 days of life after birth and fed on 50 mL/kg/day were included in the study. Results: all of them received 300 U/kg erythropoietin by subcutaneous administration three times a week up to reaching 40 weeks of gestational age and an iron and vitamin supplement. Erythropoietin is very safe; it was just possibly related to slight retinopathy of prematurity, but overcome. Conclusions: seven patients were transfused (9.7 percent ) in the course of study. The late use of erythropoietin in very-low-weight preterm child confirms its efficacy and safety(AU)

Eficacia y seguridad de la eritropoyetina en la anemia de la prematuridad / Efficacy and safety of erythropoietin for anemia of prematurity

Introducción: la eritropoyetina alfa recombinante forma parte del tratamiento de la anemia de la prematuridad. En Cuba su uso ha sido limitado y controvertido en cuanto a esquema y dosis empleada.Métodos: ensayo clínico prospectivo, multicéntrico, no aleatorizado, de eficacia y seguridad de eritropoyetina en la disminución de transfusiones en el recién nacido pretérmino de muy bajo peso. Se incluyeron 72 neonatos con edad gestacional menor de 34 semanas posmenstruales, y peso al nacer menor o igual a 1 500 g, con más de 7 días posnatales e ingesta de 50 mL/kg/día.Resultados: todos recibieron eritropoyetina 300 U/kg, subcutánea, 3 veces/semana, hasta las 40 semanas de edad gestacional y suplemento de hierro y vitaminas. La eritropoyetina fue muy segura, solo se notificó con relación posible una retinopatía de la prematuridad, ligera y recuperada.Conclusiones: se transfundieron 7 pacientes (9,7 por ciento) en el curso del estudio. El uso tardío de eritropoyetina en el pretérmino de muy bajo peso confirma su eficacia y seguridad(AU)

Introduction: recombinant alpha erythropoietin is part of the treatment for anemia of prematurity. The use of this one in Cuba has been restricted and controversial as to schedule and dose.Methods: prospective, non-randomized multicenter assay on the safety and efficacy of erythropoietin in the reduction of blood transfusion in very-low-weight preterm newborn. Seventy two neonates with gestational age under 34 post-menstruation weeks, weighing equal or less than 1 500 g, over 7 days of life after birth and fed on 50 mL/kg/day were included in the study.Results: all of them received 300 U/kg erythropoietin by subcutaneous administration three times a week up to reaching 40 weeks of gestational age and an iron and vitamin supplement. Erythropoietin is very safe; it was just possibly related to slight retinopathy of prematurity, but overcome.Conclusions: seven patients were transfused (9.7 percent) in the course of study. The late use of erythropoietin in very-low-weight preterm child confirms its efficacy and safety(AU)

Eficacia y seguridad de la eritropoyetina en la anemia de la prematuridad / Efficacy and safety of erythropoietin for anemia of prematurity

Introducción: la eritropoyetina alfa recombinante forma parte del tratamiento de la anemia de la prematuridad. En Cuba su uso ha sido limitado y controvertido en cuanto a esquema y dosis empleada. Métodos: ensayo clínico prospectivo, multicéntrico, no aleatorizado, de eficacia y seguridad de eritropoyetina en la disminución de transfusiones en el recién nacido pretérmino de muy bajo peso. Se incluyeron 72 neonatos con edad gestacional menor de 34 semanas posmenstruales, y peso al nacer menor o igual a 1 500 g, con más de 7 días posnatales e ingesta de 50 mL/kg/día. Resultados: todos recibieron eritropoyetina 300 U/kg, subcutánea, 3 veces/semana, hasta las 40 semanas de edad gestacional y suplemento de hierro y vitaminas. La eritropoyetina fue muy segura, solo se notificó con relación posible una retinopatía de la prematuridad, ligera y recuperada. Conclusiones: se transfundieron 7 pacientes (9,7 por ciento) en el curso del estudio. El uso tardío de eritropoyetina en el pretérmino de muy bajo peso confirma su eficacia y seguridad

Introduction: recombinant alpha erythropoietin is part of the treatment for anemia of prematurity. The use of this one in Cuba has been restricted and controversial as to schedule and dose. Methods: prospective, non-randomized multicenter assay on the safety and efficacy of erythropoietin in the reduction of blood transfusion in very-low-weight preterm newborn. Seventy two neonates with gestational age under 34 post-menstruation weeks, weighing equal or less than 1 500 g, over 7 days of life after birth and fed on 50 mL/kg/day were included in the study. Results: all of them received 300 U/kg erythropoietin by subcutaneous administration three times a week up to reaching 40 weeks of gestational age and an iron and vitamin supplement. Erythropoietin is very safe; it was just possibly related to slight retinopathy of prematurity, but overcome. Conclusions: seven patients were transfused (9.7 percent ) in the course of study. The late use of erythropoietin in very-low-weight preterm child confirms its efficacy and safety

A mathematical modeling approach to quantify the role of phlebotomy losses and need for transfusions in neonatal anemia.

BACKGROUND: Very preterm infants commonly develop anemia requiring multiple red blood cell transfusions (RBCTx). This is in part attributable to heavy laboratory phlebotomy loss. Quantification of the extent to which laboratory blood loss contributes to anemia sufficient to prompt RBCTx has not been examined. STUDY DESIGN AND METHODS: Twenty-six preterm infants weighing less than 1500 g at birth requiring ventilator support who received one or more RBCTx were intensively studied during the first month of life. Hemoglobin (Hb) loss via laboratory blood loss and RBC senescence and Hb gain from RBCTx were precisely accounted for in a Hb mass balance mathematical model developed to assess the impact of phlebotomy on RBCTx when restrictive RBCTx criteria were applied. RESULTS: Study subjects had a birth weight of 880 ± 240 g (mean ± SD) and a Hb level of 14.4 ± 2.4 g/dL at birth and received 3.81 ± 2.15 RBCTx during the study period. Modeling indicated that even with the total elimination of laboratory phlebotomy loss, a reduction of 41% to 48% in RBCTx was achievable. CONCLUSION: The present modeling results indicate that while phlebotomy reduction can significantly decrease the number of RBCTx administered to preterm infants, total elimination of all RBCTx will likely require other approaches, for example, stimulation of erythropoiesis with erythropoiesis-stimulating agents.

Comparison between two treatment protocols with recombinant human erythropoietin (rHuEpo) in the treatment of late anemia in neonates with Rh-isoimmunization.

OBJECTIVE: [corrected] The Rh-hemolytic disease can lead to a late anemia by hemolytic and hyporigenerative mechanism. We compared the effectiveness of rHuEPO in two care protocols that differ for doses of rHuEPO administrated and for timing of administration. METHODS: A cohort of 14 neonates was investigated. The neonates were treated with two different protocols. Protocol A: a dose of 200 U/kg/day of rHuEpo administered subcutaneously starting from the end of the second week of life; Protocol B: a dose of 400 U/kg/day of rHuEpo administered subcutaneously starting from the end of the first week of life. RESULTS: The hematocrit values in the protocol A group decreased during treatment (32,5% vs 25,2%), whereas the hematocrit value in protocol B group remained almost stable (38,7% vs 42,8%). The mean numbers of platelets remained stable in both groups while neutrophils increased in protocol A group and decreased in protocol B (p<0,05). Reticulocyte count increased during treatment in both groups, although only in protocol B group it was statistically significative (p<0,05). CONCLUSIONS: Our results suggest a similar efficacy between the two treatment protocols. Increasing doses of rHuEPO do not seem enhancing their effectiveness and the incidence of side effects.

A randomized, masked study of weekly erythropoietin dosing in preterm infants.

OBJECTIVE: To compare reticulocyte responses of once-per-week erythropoietin (EPO) dosing with 3-times-a-week dosing in preterm infants. STUDY DESIGN: Infants weighing ≤ 1500 g and ≥ 7 days of age were randomized to once-per-week EPO, 1200 U/kg/dose, or 3-times-a-week EPO, 400 U/kg/dose, subcutaneously for 4 weeks, along with iron and vitamin supplementation. Complete blood counts, absolute reticulocyte counts (ARCs), transfusions, phlebotomy losses, and adverse events were recorded. RESULTS: Twenty preterm infants (962 ± 55 g, 27.9 ± 0.4 weeks, 17 ± 3 days of age) were enrolled. Groups were similar at baseline. Infants in both groups had increased ARCs, which were similar between treatment groups at the start and end of 4 weeks. Hematocrit remained stable, and similar numbers of transfusions were administered. No adverse effects of either dosing schedule were noted. CONCLUSIONS: Preterm infants respond to weekly EPO by increasing ARCs and maintaining hematocrit. We speculate that once-per-week EPO dosing might be beneficial to preterm infants requiring increased erythropoiesis.

[Treatment of anaemia of prematurity with SS-R-Hu-erythropoietin and significance of hypoxia-inducible factor].

UNLABELLED: The main cause of anaemia of prematurity is low erythropoietin levels. A few years ago hypoxia-inducible factor/HIF/gene transcriptor was established, regulating not only the synthesis of erythropoietin /EPO/, but also other growth factors as well as enzymes of anaerobic glycolysis, activated by hypoxia. OBJECTIVES: The aim of the study is to establish in clinical practice the role of hypoxia, respectively, activated HIF during treatment with erythropoietin by analyzing variations in hematological values; to examine blood lactate levels as an indicator of activated HIF and anaerobic glycolysis with Hb values 110-120 g/l; to analyze the number and impact of red blood cells transfusions on different categories of babies. STUDY DESIGN; The study includes 112 premature infants born before 34 weeks of gestation and below 1400 g. 90 babies, treated with EPO (700-1000 E/kg weekly dose in 2-3 applications, for 2-4 weeks), values of Hb g/l, Ht%, Ret%, Platelets 109/l were followed and compared. Treated babies were divided in two groups: group I--treatment (starting at Hb below 106 g/l, Ht less than 31%); group II--late prophylaxis (starting at Hb > or = 106 g/l, Ht > or = 31%). Blood lactate was examined in 22 non oxygen dependent premature babies without EPO treatment, with Hb 110-120 g/l, Ht 29-32%. RESULTS: We found that in group II during the first 7-10 days Hb decreases to 105.6 (+/- 9.4) g/l, rising up afterwards to 113.5 (+/-11.0) g/l at day 25-30. Ret reach maximal values at day 15-20 when Hb drops below 110 g/l and Ht below 31%. In group I at day 25-30 of treatment is observed a rise in Hb up to 117.3 (+/-11.3) and of Ht up to 32.7% (+/- 2.6) and no decrease of Hb and Ht values during the first 7-10 days, while Ret rise up to maximal values 6.5% (+/- 3.6) at day 7-10. With Hb levels of 116.4 (+/- 4.6) g/l we found an increase in blood lactate levels up to 2.6 (+/- 0.7) mmol/l as an indicator of relative hypoxia and activated HIF. Mean number of blood transfusions in group I is 3.01(+/- 1.7), versus 2.15 (+/- 1.7) in group II (statistically non-significant). In 29 infants in group II treatment was started at Hb 110-120 g/l and the mean number of red blood cell transfusion is 1.8 (1.5)--statistically significant difference with group I. In 32% from the treated infants we found platelets count rising above 500 x 109/l. CONCLUSIONS: The presence of hypoxia at low levels of Hb and Ht leads to more rapid activation of erythropoiesis. Nevertheless, these babies need more red blood cell transfusions due to clinical symptoms of hypoxia. Normoxia after red blood cell transfusion leads to decrease of reticulocytes count by 30% and platelets by 35% in spite of treatment. The presence of relative hypoxia with Hb 110-120 g/l u Ht 31-32% is optimal for starting treatment with EPO--levels, low enough for activation of HIF and high enough to avoid blood transfusions.

[Does human recombinant erythropoetin /R-HU-EPO/ treatment for anemia of prematurity have any effect on reducing the number of blood transfusions?].

OBJECTIVES: The aim of the study is to establish the influence of r-hu-EPO treatment for anemia of prematurity on changes in blood count values and the number of inevitable blood transfusions in premature infants. STUDY DESIGN: The study includes 148 newborn babies--birth weight < or =1400 g, gestational age < or =34 g.w. They were divided in 2 groups: group I--treated with r-hu-EPO 1000 E/kg/week and Fe++ 3-6 mg/kg/day from week 3 after birth; group II--controls, treated only with transfusions of red blood cells. The changes in blood count values (Hb, Ht, Ery, Ret) from day 15-25 until day 60-70 were followed and analyzed, as well as the number of inevitable blood transfusions. RESULTS: A significant increase in Hb and Ht values was established with r-hu-EPO treated babies. At day 60-70 mean values of Hb are: in r-hu-EPO group 111.1 +/- 11.06 g/l; in control group 99.20 +/- 10.77 g/l (p < 0.001). At the end of the period Ht is 32.02 +/- 3.28% in babies treated with r-hu EPO versus 29.10 +/- 2.87% with controls (p < 0.005). Ret count is significantly higher from day 25-30 in r-hu-EPO group (5.16 +/- 3.23%) versus controls (2.75 +/- 1.33%). Mean number of inevitable blood transfusions in r-hu-EPO treated group is significantly lower (2.06 +/- 1.62) versus controls--3.75 +/- 1.95 (p < 0.001). CONCLUSION: r-hu EPO treatment has effect on changes in Hb, Ht, Ret and reduces the number of inevitable blood transfusions for anaemia of prematurity.

Erythropoietin pharmacokinetic/pharmacodynamic analysis suggests higher doses in treating neonatal anemia.

BACKGROUND: The establishment of effective treatment of neonatal anemia using recombinant human erythropoietin (r-HuEPO) requires a thorough understanding of the physiology and mechanism of EPO's pharmacologic effect. The purpose of the present preclinical study in sheep was to elucidate the stimulatory effect of EPO on erythroid progenitors and their differentiation into reticulocytes useful in predicting optimal r-HuEPO dosing. METHODS: Five young adult sheep each underwent two phlebotomies spaced 4-6 weeks apart in which their hemoglobin levels were reduced from 12 g/dL to 3-4 g/dL. Endogenous EPO levels and reticulocyte counts produced in response to anemia were sampled throughout the study and analyzed using a pharmacokinetic/pharmacodynamic (PK/PD) model. RESULTS: The phlebotomy-induced drop in hemoglobin resulted in a increase in EPO levels, which reached a maximum of 764 +/- 55 mU/mL (mean +/- %CV) in 0.5-2.6 days. The reticulocyte counts increased from baseline values of 76.9 x 10(3) +/- 67/microL to 619 x 10(3) +/- 30/microL in 8 days. The PK/PD analysis indicated an increased maturation time for the reticulocytes (4.88 +/- 35 days) and demonstrated that the E(max) model for EPO's activation of the progenitors did not show significant effect saturation at the endogenous EPO levels reached. CONCLUSIONS: In extrapolating from the animal pilot experiment, the present study provides a case for the use of higher r-HuEPO doses in human studies to determine if higher doses are more effective in treatment of neonatal anemia to reduce, and in some less severe cases, eliminate, the need for blood transfusions.

Current controversies in the management of the anemia of prematurity.

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.