losartan-potassium and Anemia--Neonatal

All neonates experience a downtrend in their hematocrit values immediately following the birth through normal falls in erythropoietin (Epo) production, transition to adult hemoglobin, and hemodilution with somatic growth. However, this drop is more pronounced in critically ill and preterm neonates and can lead to potentially pathologic anemia that impairs tissue oxygen delivery. In this review, we highlight the mechanisms underlying physiologic anemia and anemia of prematurity and briefly review the evidence for the treatment of anemia in the neonatal population, including the use of red blood cell transfusions, erythropoietic stimulating agents, and iron supplementation.

Topics: Age Factors; Anemia, Neonatal; Erythropoietin; Hematinics; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature

Anemia of prematurity affects the majority of preterm infants, particularly extremely low birthweight infants. Anemia of prematurity arises from both innate and iatrogenic causes and results in more than 80% of extremely preterm infants receiving red blood cell transfusions during the first month after birth. Multiple randomized controlled trials were conducted to evaluate the effect of using lower versus higher transfusion thresholds based on hemoglobin levels. These trials showed no difference in the primary outcome of neurodevelopmental impairment at 2 years of age between lower and higher thresholds. However, some uncertainties about transfusion thresholds remain. This review elaborates the following: 1) the etiology, prevention, and treatment of anemia of prematurity with a focus on red blood cell transfusions, 2) the history of randomized controlled trials on the treatment of anemia of prematurity, and 3) limitations of the evidence and remaining questions about thresholds for red blood cell transfusions in preterm infants.

Topics: Anemia; Anemia, Neonatal; Erythrocyte Transfusion; Erythropoietin; Humans; Infant, Extremely Low Birth Weight; Infant, Extremely Premature; Infant, Newborn; Retinopathy of Prematurity

Recombinant human erythropoietin (rhEPO) lost its role in minimizing red blood cell transfusion in very preterm infants after it had been associated with severe retinopathy of prematurity (ROP). Previous systematic reviews did not stratify ROP by gestation and birth weight (BW).. The aim of this study was to investigate the effect of early prophylactic rhEPO on ROP in a stratified meta-analysis of randomized controlled trials (RCTs).. The databases EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Trials were searched in January 2022 and complemented by citation searching. RCTs comparing early rhEPO treatment with no treatment or placebo were selected if they were published in a peer-reviewed journal and reported ROP outcomes. Previously unpublished data were requested from the study authors to allow stratified analyses by gestational age (GA) and BW. Data were extracted and analyzed using the standard methods of the Cochrane Neonatal Review Group. Pre-specified outcomes were "ROP stage ≥3" (primary outcome) and "any ROP.". Fourteen RCTs, comprising 2,040 infants of <29 weeks of GA, were included for meta-analysis. Data syntheses showed no effects of rhEPO on ROP stage ≥3 or on any ROP, neither in infants of <29 weeks GA, nor in infants of <1,000 g BW, nor in any GA strata. The risk ratio (95% confidence interval) for ROP stage ≥3 in infants of <29 weeks of GA was 1.13 (0.84, 1.53), p = 0.41 (quality of evidence: moderate).. The present meta-analysis detected no effects of early rhEPO on ROP in any comparison, but most stratified analyses were limited by low statistical power.

Topics: Anemia, Neonatal; Birth Weight; Erythropoietin; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Retinopathy of Prematurity; Risk Factors

Red blood cell transfusion is common in neonatal intensive care. Multiple trials have evaluated different thresholds for when to administer red blood cell transfusion. In contrast, there has been less focus on studies of the characteristics of red blood cells transfused into neonates. In this review, the authors summarize the emerging literature on the potential impact of the sex of blood donors on outcomes in transfused neonates using a systematic search strategy. The authors review the uncertainty generated from studies with conflicting findings and discuss considerations regarding the impact of blood donor sex and other characteristics on neonatal outcomes.

Topics: Age Factors; Anemia, Neonatal; Blood Donors; Erythropoietin; Humans; Infant; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature

The developing brain is particularly vulnerable to extrinsic environmental events such as anemia and iron deficiency during periods of rapid development. Studies of infants with postnatal iron deficiency and iron deficiency anemia clearly demonstrated negative effects on short-term and long-term brain development and function. Randomized interventional trials studied erythropoiesis-stimulating agents and hemoglobin-based red blood cell transfusion thresholds to determine how they affect preterm infant neurodevelopment. Studies of red blood cell transfusion components are limited in preterm neonates. A biomarker strategy measuring brain iron status and health in the preanemic period is desirable to evaluate treatment options and brain response.

Topics: Anemia, Neonatal; Brain; Dietary Supplements; Erythropoietin; Humans; Infant; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Iron; Iron Deficiencies

Previous systematic reviews suggest reduction in necrotizing enterocolitis (NEC) among preterm infants supplemented with erythropoietin (EPO). We aimed to update our 2018 systematic review in this field considering the evidence accumulated over the last 3 years. Randomized controlled trials (RCTs) reporting the effect of early EPO supplementation vs placebo/no EPO supplementation on any stage NEC in preterm infants were included. Fixed effect model was used for meta-analysis. Trial sequential analysis (TSA) was conducted to verify the effects of EPO on NEC after accounting for repeated significance testing. A total of 22 RCTs (n = 5359) were included, of which six were new (n = 2541 additional preterm infants) in comparison to our previous systematic review. EPO significantly decreased the risk of any stage NEC (232/2669 (8.7%) vs 313/2690 (11.6%); RR: 0·76; TSA adjusted 95% CI (0·64, 0·90); p = 0·0008, number needed to treat (NNT) = 34). The risk of definite NEC (≥ Stage II) was also significantly reduced by EPO administration (105/2219 (4.7%) vs 141/2246 (6.3%); RR: 0.77; 95% CI (0.61, 0.98); p = 0.03, NNT: 62). However, the results for definite NEC were no longer significant on sensitivity analyses that included (a) only double-blind RCTs and (b) only prospectively registered trials. The quality of evidence was deemed moderate-to-low for the reported outcomes.. There is moderate to low-quality evidence that early prophylactic EPO reduces any stage and ≥ Stage II NEC in preterm neonates. Prospectively registered, adequately powered, double-blind RCTs are required to confirm these findings.. • Experimental studies have shown that erythropoietin (EPO) has gastrointestinal trophic effects. • Systematic reviews have shown that early treatment with EPO may decrease the risk of gut injury in preterm or low birth weight infants.. • Early EPO supplementation significantly reduced the incidence of any stage NEC and definite NEC in preterm infants < 34 weeks of gestation. • EPO had no significant effect on definite NEC in the analyses that included only double-blinded and prospectively registered RCTs. How might it impact clinical practice in the foreseeable future? • Early prophylactic EPO can be recommended for NEC prevention if its benefits are consistently demonstrated in adequately powered randomized trials with a low risk of bias.

Topics: Anemia, Neonatal; Enterocolitis, Necrotizing; Erythropoietin; Female; Fetal Diseases; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Newborn, Diseases; Infant, Premature; Randomized Controlled Trials as Topic

Premature neonates are frequently transfused red blood cells (RBCs) or platelets to raise hemoglobin or platelet counts. However, these transfusions may have unintended effects on the immune system. This review will summarize the newest discoveries on the immunologic effects of RBC and platelet transfusions in neonates, and their potential impact on neonatal outcomes.. Neonatal RBC transfusions are associated with increases in plasma pro-inflammatory cytokines, but recent findings suggest sex-specific differential responses. At least one cytokine (monocyte chemoattractant protein-1) rises in females receiving RBC transfusions, but not in males. These inflammatory responses correlate with poorer neurodevelopmental outcomes in heavily transfused female infants, while preterm male infants seem to be more sensitive to severe anemia. Platelet transfusions in preterm neonates are associated with increased neonatal mortality and morbidity. The underlying mechanisms are unknown, but likely related to the immune/inflammatory effects of transfused platelets. Adult platelets are different from neonatal platelets, with the potential to be more pro-inflammatory. Early preclinical data suggest that platelet transfusions alter the neonatal systemic inflammatory response and enhance immune cell migration.. RBC and platelet transfusions alter neonatal immune and inflammatory responses. Their pro-inflammatory effects might worsen neonatal disease or affect neurodevelopmental outcomes.

Topics: Anemia, Neonatal; Chemokine CCL2; Erythrocyte Transfusion; Erythrocytes; Erythropoietin; Female; Humans; Infant, Low Birth Weight; Infant, Newborn; Male; Platelet Transfusion

Prematurity, maternal diabetes, maternal smoking, being medically underserved, and small size for gestational age are common characteristics of neonates in the NICU and can predispose them to develop congenital iron deficiency. Iron is critical for organ development. In the fetus and newborn, iron is prioritized for red blood cell production, sometimes at the expense of other tissues, including the brain. It is critical to optimize iron levels in newborns to support erythropoiesis, growth, and brain development. Available studies support improved neurodevelopmental outcomes with either iron supplementation or delayed umbilical cord clamping at birth. Erythropoietic doses of erythropoietin/erythrocyte-stimulating agents may also improve neurocognitive outcomes. However, the literature on the effect of liberal red blood cell transfusions on long-term neurodevelopment is mixed. Understanding age-specific normal values and monitoring of iron indices can help individualize and optimize the iron status of patients in the NICU.

Topics: Anemia, Neonatal; Child Development; Deficiency Diseases; Erythrocyte Transfusion; Erythrocytes; Erythropoiesis; Erythropoietin; Hematinics; Humans; Infant, Newborn; Intensive Care Units, Neonatal; Iron; Iron Deficiencies

Low plasma levels of erythropoietin (EPO) in preterm infants provide a rationale for the use of EPO to prevent or treat anaemia.. To assess the effectiveness and safety of early versus late initiation of EPO in reducing red blood cell (RBC) transfusions in preterm and/or low birth weight (LBW) infants.. Randomised or quasi-randomised controlled trials enrolling preterm or LBW infants less than eight days of age.. Early initiation of EPO (initiated at less than eight days of age) versus late initiation of EPO (initiated at eight to 28 days of age).. The standard methods of the CNRG were followed. Weighted treatment effects included typical risk ratio (RR), typical risk difference (RD), number needed to treat to benefit (NNTB), number needed to treat to harm (NNTH) and mean difference (MD), all with 95% confidence intervals (CI). A fixed-effect model was used for meta-analyses and heterogeneity was evaluated using the I-squared (I. No new trials were identified in March of 2012. Two high quality randomised double-blind controlled studies enrolling 262 infants were identified. A non-significant reduction in the 'Use of one or more RBC transfusions' [two studies 262 infants; typical RR 0.91 (95% CI 0.78 to 1.06); typical RD -0.07 (95% CI -0.18 to 0.04; I. The use of early EPO did not significantly reduce the 'Use of one or more RBC transfusions' or the 'Number of transfusions per infant" compared with late EPO administration. The finding of a statistically significant increased risk of ROP (any grade) and a similar trend for ROP stage > 3 with early EPO treatment is of great concern.

Topics: Anemia, Neonatal; Epoetin Alfa; Erythrocyte Transfusion; Erythropoietin; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Randomized Controlled Trials as Topic; Retinopathy of Prematurity

Preterm infants have low plasma levels of erythropoietin (EPO), providing a rationale for the use of erythropoiesis-stimulating agents (ESAs) to prevent or treat anaemia. Darbepoetin (Darbe) and EPO are currently available ESAs.. To assess the effectiveness and safety of late initiation of ESAs, between eight and 28 days after birth, in reducing the use of red blood cell (RBC) transfusions in preterm or low birth weight infants.. We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2018, Issue 5), MEDLINE via PubMed (1966 to 5 June 2018), Embase (1980 to 5 June 2018), and CINAHL (1982 to 5 June 2018). We searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials.. Randomised or quasi-randomised controlled trials of late initiation of EPO treatment (started at ≥ eight days of age) versus placebo or no intervention in preterm (< 37 weeks) or low birth weight (< 2500 grams) neonates.. We performed data collection and analyses in accordance with the methods of the Cochrane Neonatal Review Group. We used the GRADE approach to assess the quality of the evidence.. We include 31 studies (32 comparisons) randomising 1651 preterm infants. Literature searches in 2018 identified one new study for inclusion. No new on-going trials were identified and no studies used darbepoetin.Most included trials were of small sample size. The meta-analysis showed a significant effect on the use of one or more RBC transfusions (21 studies (n = 1202); typical risk ratio (RR) 0.72, 95% confidence interval (CI) 0.65 to 0.79; typical risk difference (RD) -0.17, 95% CI -0.22 to -0.12; typical number needed to treat for an additional beneficial outcome (NNTB) 6, 95% CI 5 to 8). There was moderate heterogeneity for this outcome (RR I² = 66%; RD I² = 58%). The quality of the evidence was very low. We obtained similar results in secondary analyses based on different combinations of high/low doses of EPO and iron supplementation. There was no significant reduction in the total volume (mL/kg) of blood transfused per infant (typical mean difference (MD) -1.6 mL/kg, 95% CI -5.8 to 2.6); 5 studies, 197 infants). There was high heterogeneity for this outcome (I² = 92%). There was a significant reduction in the number of transfusions per infant (11 studies enrolling 817 infants; typical MD -0.22, 95% CI -0.38 to -0.06). There was high heterogeneity for this outcome (I² = 94%).Three studies including 404 infants reported on retinopathy of prematurity (ROP) (all stages or stage not reported), with a typical RR 1.27 (95% CI 0.99 to 1.64) and a typical RD of 0.09 (95% CI -0.00 to 0.18). There was high heterogeneity for this outcome for both RR (I² = 83%) and RD (I² = 82%). The quality of the evidence was very low.Three trials enrolling 442 infants reported on ROP (stage ≥ 3). The typical RR was 1.73 (95% CI 0.92 to 3.24) and the typical RD was 0.05 (95% CI -0.01 to 0.10). There was no heterogeneity for this outcome for RR (I² = 18%) but high heterogeneity for RD (I² = 79%). The quality of the evidence was very low.There were no significant differences in other clinical outcomes including mortality and necrotising enterocolitis. For the outcomes of mortality and necrotising enterocolitis, the quality of the evidence was moderate. Long-term neurodevelopmental outcomes were not reported.. Late administration of EPO reduces the use of one or more RBC transfusions, the number of RBC transfusions per infant (< 1 transfusion per infant) but not the total volume (mL/kg) of RBCs transfused per infant. Any donor exposure is likely not avoided as most studies included infants who had received RBC transfusions prior to trial entry. Late EPO does not significantly reduce or increase any clinically important adverse outcomes except for a trend in increased risk for ROP. Further research of the use of late EPO treatment, to prevent donor exposure, is not indicated. Research efforts should focus on limiting donor exposure during the first few days of life in sick neonates, when RBC requirements are most likely to be required and cannot be prevented by late EPO treatment. The use of satellite packs (dividing one unit of donor blood into many smaller aliquots) may reduce donor exposure.

Topics: Age Factors; Anemia, Neonatal; Bronchopulmonary Dysplasia; Cause of Death; Drug Administration Schedule; Erythrocyte Transfusion; Erythropoietin; Hematinics; Hospital Mortality; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Randomized Controlled Trials as Topic; Retinopathy of Prematurity; Time Factors

Currently the question of whether to maintain a higher hemoglobin level by transfusing more liberally, as opposed to a more restrictive strategy with lower hemoglobin maintenance levels, has not been answered. We review summarized conclusions of a Cochrane systematic review and meta-analysis of 614 infants in 4 randomized controlled trials (RCT) pooling data. This suggests potential benefits of higher hemoglobin levels, i.e., a possible improved cognition of infants at 18-21 months' corrected age and a reduction of apnea. However, the data on cognition is hypothesis generating as it derives from a post hoc analysis from a single trial in 451 infants. Moreover, the data on apnea need confirmation in larger trials. The effect of adding data of cognitive 2-year outcomes of 1,744 infants from 2 RCT, which will be reported soon, should expand our understanding. This new data will need to be integrated with the older generation of RCTs but also with emerging suggestions from observational data on potential risks of blood transfusions. We discuss some of these warnings from observational studies. Finally, we ask whether we are ready to individualize blood transfusion to physiological measures made in individual infants, and we point to some current difficulties hindering this step.

Topics: Anemia, Neonatal; Apnea; Erythrocyte Transfusion; Erythropoietin; Evidence-Based Practice; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Randomized Controlled Trials as Topic; Retinopathy of Prematurity

The current evidence regarding the indication, advantages and risks of red blood cell transfusion (RBCT) for preterm infants is discussed. This is an important area in Neonatology to be examined given that 90% of extremely low birth weight infants receive RBCT and many controversies remain regarding when to transfuse and the risks of RBCT. The various treatment thresholds and guidelines used are presented and we compare the short-term clinical benefits of liberal and restrictive RBCT in preterm infants; the majority of these are equivocal and sadly long-term outcome data is limited. The latest evidence on how anaemia and blood transfusion affect organ perfusion in preterm infants is presented. This is important when trying to establish the optimal trigger threshold for RBCT in preterm infants, especially because the knowledge about the adaptive physiological responses to anaemia in very low birth weight infants and the effects of RBCT at various levels of anaemia is also inadequate. Further research into the physiological adaptive response to anaemia of varying degrees and to RBCT at different levels of anaemia in preterm infants of different gestational and post-natal ages is needed before we can conclusively guide the optimal timing and trigger thresholds for RBCT in preterm infants.

Topics: Anemia, Neonatal; Erythrocyte Transfusion; Erythropoietin; Humans; Infant, Extremely Low Birth Weight; Infant, Newborn; Infant, Premature; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Treatment Outcome

1/To assess the effectiveness and safety of EPO in reducing red blood cell (RBC) transfusions in preterm infants. 2/To provide guidelines for clinical practice in France.. 1/This systematic evidence review is based on PubMed search, Cochrane library. 2/Using French National Authority for Health methods concerning guidelines for clinical practice.. Early EPO reduced the risk of RBC transfusions, donor exposure, and the number of transfusions in very preterm infants (LE2). Late EPO reduced the risk of RBC transfusions and the number of transfusions in very preterm infants (LE2). There is no difference between the effectiveness of early and late EPO (LE2). There is no difference between high-dose and low-dose EPO (LE2). The level of evidence is too low to recommend the intravenous route. EPO has no impact on the rate of bronchopulmonary dysplasia, necrotizing enterocolitis (LE3), and retinopathy of prematurity (LE2). The level of evidence is too low to recommend EPO for neuroprotection in very preterm or term infants.. EPO to reduce RBC transfusion in very preterm infants is recommended (Level A). The optimal time to start therapy is unknown (Level B). The recommended dose is 750IU/kg/week via three subcutaneous injections for 6weeks (Level B).

Topics: Anemia, Neonatal; Erythrocyte Transfusion; Erythropoietin; Humans; Infant, Newborn; Infant, Premature; Recombinant Proteins

Neonatal anemia is a common disorder, particularly in (very) preterm neonates. Management of neonatal anemia is based principally on red blood cell (RBC) transfusion. Although the use of blood products is nowadays widespread in neonatal medicine, evidence on the potential benefit is extremely limited. Recent studies suggest that RBC transfusions in newborns may be associated with an increased risk for necrotizing enterocolitis, transfer of infectious agents and negative effects on neurodevelopmental outcome. Whether the benefits of RBC transfusions outweigh the risks is controversial and requires further studies. In this review, we summarize the current evidence on the management of neonatal anemia and compare the various international guidelines. In addition, we discuss the various strategies to prevent neonatal anemia and reduce the need for RBC transfusions and discuss important trials currently enrolling patients to improve the management in neonatal anemia.

Topics: Anemia, Neonatal; Cord Blood Stem Cell Transplantation; Databases, Factual; Enterocolitis, Necrotizing; Erythrocyte Transfusion; Erythropoietin; Guidelines as Topic; Humans; Infant, Newborn; Risk Factors

Low plasma levels of erythropoietin (EPO) in preterm infants provide a rationale for the use of EPO to prevent or treat anaemia.. To assess the effectiveness and safety of late initiation of erythropoietin (EPO) between eight and 28 days after birth, in reducing the use of red blood cell (RBC) transfusions in preterm and/or low birth weight infants.. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and CINAHL in July 2013. Additional searches included the Pediatric Academic Societies Annual Meetings from 2000 to 2013 (Abstracts2View™) and clinical trials registries (www.clinicaltrials.gov; www.controlled-trials.com; and who.int/ictrp/en). For this update we moved one study from the early EPO review to this late EPO review.. Randomised or quasi-randomised controlled trials of late initiation of EPO treatment (started at ≥ eight days of age) versus placebo or no intervention in preterm (< 37 weeks) and/or low birth weight (< 2500 g) neonates.. We performed data collection and analyses in accordance with the methods of the Cochrane Neonatal Review Group.. We include 30 studies (31 comparisons) randomising 1591 preterm infants. Literature searches in 2013 did not identify any new study for inclusion. For this update we moved one study enrolling 230 infants from the early EPO review to this late EPO review.Most included trials were of small sample size. The meta-analysis showed a significant effect of the use of one or more RBC transfusions (20 studies (n = 1142); typical risk ratio (RR) 0.71, 95% confidence interval (CI) 0.64 to 0.79; typical risk difference (RD) -0.17, 95% CI -0.22 to -0.12; typical number needed to treat for an additional beneficial outcome (NNTB) 6, 95% CI 5 to 8). There was moderate heterogeneity for this outcome (RR I² = 68%; RD I² = 60%). We obtained similar results in secondary analyses based on different combinations of high/low doses of EPO and iron supplementation. There was no significant reduction in the total volume (mL/kg) of blood transfused per infant [typical mean difference (MD) -1.6 mL/kg, 95% CI -5.8 to 2.6); 5 studies, 197 infants]. There was high heterogeneity for this outcome (I² = 92%). There was a significant reduction in the number of transfusions per infant (11 studies enrolling 817 infants; typical MD -0.22, 95% CI -0.38 to -0.06). There was high heterogeneity for this outcome (I² = 94%).Three studies including 404 infants reported on retinopathy of prematurity (ROP) (all stages or stage not reported), with a typical RR 1.27 (95% CI 0.99 to 1.64) and a typical RD of 0.09 (95% CI -0.00 to 0.18). There was high heterogeneity for this outcome for both RR (I² = 83%) and RD (I² = 82%). Three trials enrolling 442 infants reported on ROP (stage ≥ 3). The typical RR was 1.73 (95% CI 0.92 to 3.24) and the typical RD was 0.05 (95% CI -0.01 to 0.10). There was minimal heterogeneity for this outcome for RR (I² = 18%) but high heterogeneity for RD (I² = 79%). There were no significant differences in other clinical outcomes. There was no reduction in necrotizing enterocolitis in spite of a reduction in the use of RBC transfusions. Long-term neurodevelopmental outcomes were not reported.. Late administration of EPO reduces the use of one or more RBC transfusions, the number of RBC transfusions per infant (< 1 transfusion per infant) but not the total volume (ml/kg) of RBCs transfused per infant. Any donor exposure is likely not avoided as most studies included infants who had received RBC transfusions prior to trial entry. Late EPO does not significantly reduce or increase any clinically important adverse outcomes except for a trend in increased risk for ROP. Further research of the use of late EPO treatment to prevent donor exposure is not indicated. Research efforts should focus on limiting donor exposure during the first few days of life in sick neonates, when RBC requirements are most likely to be required and cannot be prevented by late EPO treatment. The use of satellite packs (dividing one unit of donor blood into many smaller aliquots) may reduce donor exposure.

Topics: Age Factors; Anemia, Neonatal; Cause of Death; Drug Administration Schedule; Erythrocyte Transfusion; Erythropoietin; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Randomized Controlled Trials as Topic; Time Factors

Low plasma levels of erythropoietin (EPO) in preterm infants provide a rationale for the use of EPO to prevent or treat anaemia.. To assess the effectiveness and safety of early initiation of EPO or darepoetin (initiated before eight days after birth) in reducing red blood cell (RBC) transfusions in preterm and/orlow birth weight infants.. The Cochrane Library, MEDLINE, EMBASE, CINAHL, reference lists of identified trials and reviews, Pediatric Academic Societies Annual meetings 2000 to 2013 (Abstracts2View(TM)) and clinical trials registries (clinicaltrials.gov; controlled-trials.com; and who.int/ictrp) were searched in July 2013.. Randomised or quasi-randomised controlled trials of early (< eight days of age) initiation of EPO treatment versus placebo or no intervention in preterm and/or low birth weightinfants.. The methods of the Neonatal Cochrane Review Group were used.. The updated review includes 27 studies enrolling 2209 infants. One study enrolling infants at a mean age of > eight days and one duplicate publication were excluded. One new study using darepoetin was identified.Early EPO reduced the risk of the 'use of one or more RBC transfusions' (typical risk ratio (RR) 0.79, 95% confidence interval (CI) 0.73 to 0.85; typical risk difference (RD) -0.14, 95% CI -0.18 to -0.10; I(2) = 54% for both; number needed to treat to benefit (NNTB) 7, 95% CI 6 to 10; 16 studies, 1661 infants).The total volume of RBCs transfused per infant was reduced (typical mean difference (MD) 7 mL/kg, 95% CI -12 to - 2; I(2) = 63%; 7 studies, 581 infants). The number of RBC transfusions per infant was minimally reduced (typical MD -0.27, 95% CI -0.42 to -0.12; I(2) = 64%; 13 studies, 951 infants). The number of donors to whom the infants were exposed was significantly reduced (MD-0.54, 95% CI -0.89 to -0.20; I(2) = 0%; 3 studies, 254 infants).There was a non-significant increase in the risk of stage ≥ 3 retinopathy of prematurity (ROP) with early EPO (typical RR 1.37, 95% CI 0.87 to 2.17; I(2) = 0%; typical RD 0.03, 95% CI -0.01 to 0.06; I(2) = 29%; 7 studies, 801 infants). A post hoc analysis including all studies that reported on ROP stage ≥ 3, regardless of the age of the infant when EPO treatment was started, showed a significantly increased typical RR of 1.48 (95% CI 1.02 to 2.13; P = 0.04; I(2) = 0%) and typical RD of 0.03 (95% CI 0.00 to 0.06; P = 0.03; I(2) = 50%; 10 studies, 1303 infants) with a number needed to treat to harm (NNTH) of 33 (95% CI 17 to infinity). In an Italian study in which the authors compared the use of early intravenous EPO with subcutaneous EPO the overall incidence of stage ≥ 3 was 15%, similar to the incidence of 17% in the study by Romagnoli and co-workers.The rates for mortality and morbidities including intraventricular haemorrhage and necrotizing enterocolitis were not significantly changed by early EPO treatment. Neurodevelopmental outcomes at 18 to 22 months varied.. Early administration of EPO reduces the use of RBC transfusions, the volume of RBCs transfused, and donor exposure after study entry. The small reductions are likely to be of limited clinical importance. Donor exposure is probably not avoided since all but one study included infants who had received RBC transfusions prior to trial entry. In this update there was no significant increase in the rate of ROP (stage ≥ 3) for studies that initiated EPO treatment at less than eight days of age. In a post hoc analysis including all studies that reported on ROP stage ≥ 3 regardless of age at initiation of treatment there was an increased risk of ROP. The rates for mortality and morbidities including intraventricular haemorrhage and necrotizing enterocolitis were not significantly changed by early EPO treatment. Neurodevelopmental outcomes at 18 to 22 months vary in the studies published to date. Ongoing research should deal with the issue of ROP and evaluate current clinical practice that will limit donor exposure. Due to the limited benefits and the possibly increased risk of ROP, administration of EPO is not recommended. Darbepoetin requires further study. The possible neuroprotective role of EPO in neonates will be reviewed in separate Cochrane reviews.

Topics: Anemia, Neonatal; Erythrocyte Transfusion; Erythropoietin; Humans; Infant, Low Birth Weight; Infant, Premature

The decision to transfuse a neonate can be approached by addressing a series of questions that cover the cause of anaemia, alternatives to transfusion, the need for transfusion and the risks. Recent clinical trials of red cell transfusions have started to inform evidence-based transfusion practice, but have raised uncertainties about neurological outcomes when policies advocating use of fewer red cell transfusions at lower haemoglobin concentration (Hb) thresholds were tested. Red cell transfusions should be considered when the Hb <120 g/l for premature neonates requiring mechanical ventilation support, with lower thresholds applying for oxygen-dependent neonates not requiring ventilation or for late anaemia (Hb <70-100 g/l, depending on gestational and post-natal age). There is no recent high quality evidence to inform thresholds for prophylactic platelet transfusions in stable non-bleeding premature neonates with platelet count levels of 50 × 10(9) /l, although common practice has become more restrictive, using lower safe thresholds for platelet transfusion between 20 and 30 × 10(9) /l. A more appropriate transfusion strategy for fresh frozen plasma (FFP) in neonates is one that emphasizes the therapeutic use of FFP in the face of bleeding, rather than prophylactic use in stable non-bleeding neonates who often have mild to moderate apparent abnormalities of standard coagulation tests, after allowing for appropriate reference ranges.

Topics: Anemia, Neonatal; Blood Grouping and Crossmatching; Constriction; Decision Making; Diagnosis, Differential; Erythrocyte Transfusion; Erythropoietin; Evidence-Based Medicine; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Platelet Transfusion; Practice Guidelines as Topic; Professional Practice; Umbilical Cord

Our objective was to survey neonatologists regarding international practice of red cell transfusion thresholds for premature infants with <1000-g birth weight and/or <28-week gestation. An invitation to fill out an 11-question web-based survey was distributed to neonatologists through their professional societies in 22 countries. Physicians were asked about which specific factors, in addition to hemoglobin levels, influenced their decisions about transfusing premature infants. These factors included gestational age, postnatal age, oxygen need, respiratory support, reticulocyte count, and inotropic support. Physicians were presented with 5 scenarios and asked to identify hemoglobin cutoff values for transfusing infants with <1000-g birth weight and/or <28-week gestation. One thousand eighteen neonatologists responded: the majority were from the United States (67.5%), followed by Germany (10.7%), Japan (8.0%), the United Kingdom (4.9%), Spain (3.9%), Italy (2.6%), Colombia (0.6%), Argentina (0.4%), Canada (0.4%), Belgium (0.1%), and the Netherlands (0.1%). Half of the respondents (51.1%) reported having a written policy with specific red cell transfusion guidelines in their unit. Factors considered "very important" regarding the need to administer blood transfusions included degree of oxygen requirement (44.7%) and need for respiratory support (44.1%). Erythropoietin was routinely used to treat anemia by 26.0% of respondents. Delayed cord clamping or cord milking was practiced by 29.1% of respondents. The main finding was of a wide variation in the hemoglobin values used to transfuse infants, regardless of postnatal age. Step-wise increments in the median hemoglobin cutoffs directly paralleled an increase in the need for levels of respiratory support. In the first week of life, there was a wider range in the distribution of hemoglobin transfusion thresholds for infants requiring no respiratory support and full mechanical ventilation compared with the thresholds used in the second, third, and fourth weeks of life. An international survey using hypothetical scenarios shows that red blood cell transfusion practices vary widely among practicing neonatologists in participating countries.

Topics: Anemia, Neonatal; Argentina; Belgium; Canada; Colombia; Erythrocyte Indices; Erythrocyte Transfusion; Erythropoietin; Germany; Gestational Age; Hematinics; Hemoglobins; Humans; Infant, Extremely Low Birth Weight; Infant, Extremely Premature; Infant, Newborn; Italy; Japan; Neonatology; Netherlands; Practice Patterns, Physicians'; Spain; Surveys and Questionnaires; United Kingdom; United States

Low plasma levels of erythropoietin (EPO) in preterm infants provide a rationale for the use of EPO to prevent or treat anaemia.. To assess the effectiveness and safety of early initiation of EPO in reducing red blood cell (RBC) transfusions in preterm and/or low birth weight infants.. The Cochrane Central Register of Controlled Trials (The Cochrane Library), MEDLINE, EMBASE, CINAHL, abstracts from scientific meetings published in Pediatric Research and reference lists of identified trials and reviews were searched through July 2009. Searches were repeated in March 2012 including searches of Pediatric Academic Societies Annual meetings 2000 to 2012 (Abstracts2View(TM)) and clinical trials registries (clinicaltrials.gov; controlled-trials.com; and who.int/ictrp).. Randomised or quasi-randomised controlled trials of early (< eight days of age) initiation of EPO treatment versus placebo or no intervention in preterm and/or low birth weight neonates.. Data collection and analysis were accomplished using the methods of the Neonatal Cochrane Review Group.. The May 2012 update did not identify any new studies for inclusion. A number of randomised controlled trials were excluded as they compared one EPO dosing regimen with another, did not provide the numbers of infants randomised to the EPO and the placebo group, or the dose of EPO was not stated. The update includes 27 studies that enrolled 2293 preterm infants. Early EPO reduced the risk of the "use of one or more RBC transfusions" [typical risk ratio (RR); 0.80 (95% confidence interval (CI) 0.75 to 0.86); typical risk difference (RD) -0.13, (95% CI -0.17 to -0.09); number needed to benefit (NNTB) = eight, (95% CI 6 to 11); 16 studies, 1,825 infants].There was moderate heterogeneity for this outcome [RR (P = 0.004; I(2) = 56.7%); RD (P = 0.003; I(2) = 56.0%)].A total of six studies enrolling 515 infants reported on the total volume of red blood cells transfused per infant. The significant typical mean difference (MD) was a reduction of 6 mL/kg of blood transfused (mL/kg) per infant (95% CI -11 to - 1). There was moderate heterogeneity for this outcome (P = 0.02; I(2) = 63.0%). The results from 14 studies enrolling 1131 infants reported on the number of red blood cell transfusions per infant. The significant typical MD for number of red blood cell transfusions per infant was -0.33, (95% CI -0.48 to -0.18). There was high heterogeneity for this outcome (P = 0.00001, I(2) = 78%). Two studies enrolling 188 infants reported on the number of donors to whom the infant was exposed; the MD was significantly reduced -0.63, (-1.07 to -0.19). There was no heterogeneity for this outcome (P = 0.59; I(2) = 0%).There was a significant increase in the risk of stage ≥ 3 retinopathy of prematurity (ROP) in the early EPO group [typical RR; 1.65, (95% CI 1.12 to 2.43); typical RD; 0.05 (95% CI 0.01 to 0.08); number needed to harm (NNTH); 20, (95% CI 13 to 100); eight studies, 984 infants]. There was no heterogeneity for this outcome for RR (P = 0.87; I(2) = 0%), but there was moderate heterogeneity for RD (P = 0.006; I(2) = 65%). The rates for mortality and other neonatal morbidities were not significantly changed by early EPO treatment nor were neurodevelopmental outcomes at 18 to 22 months in the small number of infants tested to-date.. Early administration of EPO reduces the use of RBC transfusions and the volume of RBCs transfused. These small reductions are of limited clinical importance. Donor exposure is probably not avoided since most studies included infants who had received RBC transfusions prior to trial entry. There was a significant increase in the rate of ROP (stage ≥ 3). Early EPO does not significantly decrease or increase any of the other important adverse outcomes. Ongoing research should deal with the issue of ROP and evaluate the current clinical practice that will limit donor exposure. Due to the limited benefits and the increased risk of ROP, early administration of EPO is not recommended. Evidence is lacking for the possible neuro protective role of EPO in preterm infants. This topic will be reviewed in separate Cochrane reviews for preterm and term and late preterm infants.

Topics: Age Factors; Anemia, Neonatal; Erythrocyte Transfusion; Erythropoietin; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Randomized Controlled Trials as Topic; Retinopathy of Prematurity; Time Factors

Low plasma levels of erythropoietin (EPO) in preterm infants provide a rationale for the use of EPO to prevent or treat anaemia.. To assess the effectiveness and safety of late initiation of EPO (initiated at eight days after birth or later) in reducing the use of red blood cell (RBC) transfusions in preterm and/or low birth weight infants.. For this update MEDLINE, EMBASE, CINAHL, and The Cochrane Library were searched in March 2012. Additional searches included the Pediatric Academic Societies Annual Meetings from 2000 to 2012 (Abstracts2 View(TM)) and clinical trials registries (clinicaltrials.gov; controlled-trials.com; and who.int/ictrp).. Randomised or quasi-randomised controlled trials of late initiation of EPO treatment (started at ≥ eight days of age) versus placebo or no intervention in preterm (< 37 weeks) and/or low birth weight (< 2500 g) neonates.. Data collection and analyses were performed in accordance with the methods of the Cochrane Neonatal Review Group.. In this 2012 update one new study for inclusion was identified. Twenty-eight studies enrolling 1361 preterm infants in 21 countries were included. Most trials were of small sample size. The meta-analysis showed a significant effect on the use of one or more RBC transfusions [typical risk ratio (RR); 0.66 (95% confidence interval (CI); 0.59 to 0.74); typical risk difference (RD) -0.21 (95% CI; -0.26 to -0.16); typical number needed to benefit (NNTB) of 5 (95% CI 4 to 6) 19 studies, 912 infants]. There was moderate heterogeneity for this outcome [for RR (P < 0.00001; I(2) = 74.0%); for RD (P = 0.0006; I(2) = 58.9%)]. Similar results were obtained in secondary analyses based on different combinations of high/low doses of EPO and iron supplementation. In this update there was no significant reduction in the total volume (mL/kg) of blood transfused per infant [typical MD -1.61mL/kg (95% CI -5.78 to 2.57); 5 studies, 197 infants] There was high heterogeneity for this outcome (P = 0.00001, I(2) = 92%). There was a significant reduction in the number of transfusions per infant (nine studies enrolling 567 infants); [typical MD -0.78 (-0.97 to -0.59)]. Three studies including 331 patients reported on retinopathy of prematurity (ROP) (all stages), with a typical RR 0.79 (95% CI 0.57 to 1.10) and a typical RD of -0.05 (95% CI -0.13 to 0.02). This outcome was not statistically significantly different between the groups. There was no heterogeneity for this outcome for either RR (P = 0.41; I(2) = 0%) or RD (P = 0.43; I(2) = 0%). Two trials enrolling 212 patients reported on severe ROP (stage 3 or greater). The typical RR was 0.83 (95% CI 0.23 to 2.98) and the typical RD was -0.01 (95% CI -0.06 to 0.05); neither were statistically significant. There was no heterogeneity for this outcome for either RR (P = 0.29; I(2) = 9.3%) or RD (P = 0.36; I(2) = 0%).There were no significant differences in other clinical outcomes. Long-term neurodevelopmental outcomes were not reported.. Late administration of EPO reduces the use of one or more RBC transfusions, the number of RBC transfusions per infant but not the total volume of RBCs transfused per infant. Any donor exposure is likely not avoided as most studies included infants who had received RBC transfusions prior to trial entry. Late EPO does not significantly reduce or increase any clinically important adverse outcomes. Further research of the use of late EPO treatment to prevent donor exposure is not indicated. Research efforts should focus on limiting donor exposure during the first few days of life in sick neonates, when RBC requirements are most likely to be required and cannot be prevented by late EPO treatment.

Topics: Age Factors; Anemia, Neonatal; Cause of Death; Erythrocyte Transfusion; Erythropoietin; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Randomized Controlled Trials as Topic; Time Factors

Low plasma levels of erythropoietin (EPO) in preterm infants provide a rationale for the use of EPO to prevent or treat anaemia.. To assess the effectiveness and safety of early versus late initiation of EPO in reducing red blood cell (RBC) transfusions in preterm and/or low birth weight (LBW) infants.. The standard search of the Cochrane Neonatal Review Group (CNRG) was performed in 2006 and updated in 2009. Updated search in September 2009 as follows: The Cochrane Library, MEDLINE (search via PubMed), CINAHL and EMBASE were searched from 2005 to September 2009. The searches were repeated in March 2012. The Pediatric Academic Societies' Annual meetings were searched electronically from 2000 to 2012 at Abstracts2View(TM) as were clinical trials registries (clinicaltrials.gov; controlled-trials.com; and who.int/ictrp).. Randomised or quasi-randomised controlled trials enrolling preterm or LBW infants less than eight days of age.. Early initiation of EPO (initiated at less than eight days of age) versus late initiation of EPO (initiated at eight to 28 days of age).. The standard methods of the CNRG were followed. Weighted treatment effects included typical risk ratio (RR), typical risk difference (RD), number needed to treat to benefit (NNTB), number needed to treat to harm (NNTH) and mean difference (MD), all with 95% confidence intervals (CI). A fixed-effect model was used for meta-analyses and heterogeneity was evaluated using the I-squared (I(2)) test.. No new trials were identified in March of 2012. Two high quality randomised double-blind controlled studies enrolling 262 infants were identified. A non-significant reduction in the 'Use of one or more RBC transfusions' [two studies 262 infants; typical RR 0.91 (95% CI 0.78 to 1.06); typical RD -0.07 (95% CI -0.18 to 0.04; I(2) = 0% for both RR and RD] favouring early EPO was noted. Early EPO administration resulted in a non-significant reduction in the "number of transfusions per infant" compared with late EPO [typical MD - 0.32 (95% CI -0.92 to 0.29)]. There was no significant reduction in total volume of blood transfused per infant or in the number of donors to whom the infant was exposed. Early EPO led to a significant increase in the risk of retinopathy of prematurity (ROP) (all stages) [two studies, 191 infants; typical RR 1.40 (95% CI 1.05 to 1.86); typical RD 0.16 (95% CI 0.03 to 0.29); NNTH 6 (95% CI 3 to 33)]. There was high heterogeneity for this outcome (I(2) = 86% for RR and 81% for RD). Both studies (191 infants) reported on ROP stage ≥ 3. No statistically significant increase in risk was noted [typical RR 1.56 (95% CI 0.71 to 3.41); typical RD 0.05 (-0.04 to 0.14)] There was no heterogeneity for this outcome (0% for both RR and RD). No other important favourable or adverse neonatal outcomes or side effects were reported.. The use of early EPO did not significantly reduce the 'Use of one or more RBC transfusions' or the 'Number of transfusions per infant" compared with late EPO administration. The finding of a statistically significant increased risk of ROP (any grade) and a similar trend for ROP stage ≥ 3 with early EPO treatment is of great concern.

Topics: Age Factors; Anemia, Neonatal; Erythrocyte Transfusion; Erythropoietin; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Randomized Controlled Trials as Topic; Retinopathy 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.

Topics: Anemia, Neonatal; Blood Transfusion; Erythropoietin; Hematocrit; Humans; Infant, Extremely Low Birth Weight; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases

Since it was first cloned in 1985, the therapeutic potential of recombinant human erythropoietin in the neonatal hyporegenerative anaemias has been studied-the anaemia of prematurity and haemolytic disease of the newborn. Between 60% and 100% of preterm infants are transfused before three weeks of age, a large proportion receiving more than one transfusion. Blood transfusions are currently also the mainstay of treatment for the hyporegenerative anaemia encountered in neonates with Rhesus disease. Sometimes the situation is complicated by the religious beliefs of the parents. Blood transfusions are associated with numerous risks, from transmission of infection to local injury, and in an effort to minimize these risks Neonatologists have looked to recombinant erythropoietin. Despite an extensive number of studies, there is as yet no clear consensus as to whether the use of recombinant erythropoietin in Neonatal medicine minimizes the need for blood transfusions without risk to the neonate. In this article we review the evidence for and against the use of recombinant erythropoietin in Neonatal medicine.

Topics: Anemia, Neonatal; Erythropoietin; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Neonatology; Recombinant Proteins

Neonatal anemia and the need for red blood cell (RBC) transfusions are very common in neonatal intensive care units. Neonatal anemia can be due to blood loss, decreased RBC production, or increased destruction of erythrocytes. Physiologic anemia of the newborn and anemia of prematurity are the two most common causes of anemia in neonates. Phlebotomy losses result in much of the anemia seen in extremely low birthweight infants (ELBW). Accepting a lower threshold level for transfusion in ELBW infants can prevent these infants being exposed to multiple donors.

Topics: Anemia, Neonatal; Blood Transfusion; Erythropoietin; Humans; Infant, Newborn; Infant, Premature

Recombinant human erythropoietin (rHuEpo) has become the most widely used cytokine in the world. Following the success of its use in patients with end-stage renal disease, the usefulness of rHuEpo to ameliorate other anemias was assessed, including pediatric patients and newborn infants. The treatment or prevention of anemia of prematurity with rHuEpo resulted in a significant reduction in the number of transfusions and donor exposure. A clear definition of which premature babies must receive therapy needs yet to be established. Other indications in neonatal period include hyporegenerative and hemolytic anemias. With the exception of chronic renal failure, in older children the efficacy of rHuEpo has not been evaluated as in adults. While an impressive amount of studies were carried out during the last years in adult patients with cancer-related or HIV-infection-related anemias, allowing to establish clear conclusions on its efficacy, only a few trials with small number of patients have been reported in children. Up to date, results in pediatric patients suggest that rHuEpo therapy is as useful as in adult patients, but prospective, randomized trials including large number of patients are essential to achieve definitive conclusions. Results of studies designed to evaluate the efficacy of rHuEpo for sustaining an adequate dose of ribavirin in patients receiving treatment for hepatitis C are encouraging. The potential for use of the non-hematopoietic effects of rHuEpo in newborn infants is a novel and exciting issue. The role of rHuEpo as a tissue protective factor for central nervous system and intestinal mucosa is under exhaustive investigation.

Topics: Adult; Anemia; Anemia, Neonatal; Child; Child, Preschool; Erythropoietin; Hepatitis C; HIV Infections; Humans; Infant; Infant, Newborn; Infant, Postmature; Neoplasms; Recombinant Proteins; Renal Dialysis; Renal Insufficiency

Hematocrit falls after birth in preterm infants due to physiological factors and blood letting. Low plasma levels of erythropoietin (EPO) in preterm infants provide a rationale for the use of EPO to prevent or treat anemia.. To assess the effectiveness and safety of early initiation of EPO (initiated before eight days after birth) in reducing red blood cell transfusions in preterm and/or low birth weight infants.. Subgroup analyses of low (< 500 IU/kg/week) and high (> 500 IU/kg/week) doses of EPO and, within these subgroups, analyses of the use of low (< 5 mg/kg/day) and high (> 5 mg/kg/day) doses of supplemental iron, in reducing red blood cell transfusions in these infants.. The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE, EMBASE, CINAHL, abstracts from scientific meetings published in Pediatric Research and reference lists of identified trials and reviews were searched in November 2005. No language restrictions were applied.. Randomised or quasi-randomized controlled trials of early initiation of EPO treatment (started before 8 days of age) vs. placebo or no intervention in preterm (< 37 weeks) and/or low birth weight (< 2500 g) neonates. For inclusion, the studies needed to provide information on at least one outcome of interest.. Data were abstracted by the two authors on pre-tested data collection forms. Data were entered by one review author (AO) and checked for accuracy by the other (SA). Data were analysed using RevMan 4.2.8. The statistical methods included 'typical' relative risk (RR), risk difference (RD), number needed to treat to benefit (NNTB) and needed to treat to harm (NNTH) for dichotomous outcomes and weighted mean difference (WMD) for continuous outcomes reported with their 95% confidence intervals (CI). A fixed effects model was used for meta-analyses. Heterogeneity tests, including the I(-)squared (I(2)) statistic, were performed to assess the appropriateness of pooling the data.. Twenty-three studies enrolling 2074 preterm infants in 18 countries were included in the review. All studies except one applied transfusion guidelines. The quality of the trials varied. Most trials were of small sample size. Only one study clearly stated that infants were excluded if they had received red blood cell transfusion prior to study entry (Arif 2005). A total of 16 studies, including 1825 infants reported on the primary outcome of "use of one or more red cell transfusions". The summary estimates were significant [typical RR; 0.80 (95% CI 0.75, 0.86); typical RD; -0.13 (95% CI -0.17, -0.09); typical NNTB; 8 (95% CI 6, 11)]. There was statistically significant heterogeneity [for RR (p< 0.004), I(2) = 56.7%; for RD (p = 0.003), I(2 ) = 56.0%]. Similar results were obtained in secondary analyses based on different combinations of high doses of EPO and high and low iron supplementation. There were insufficient data to draw conclusions for low doses EPO in combination with high or low dose of iron. Two studies (n = 188) reported a significant reduction in the number of donors to whom the infant was exposed [typical WMD; -0.63 (95% CI -1.07, -0.19)]. A significant reduction in the total volume (ml/kg) of blood transfused per infant [typical WMD; -6 ml (95% CI -1, -11)] and in the number of transfusions per infant [typical WMD -0.27 (95% CI -0.12, -0.42 )] was noted. There was a significant increase in the risk of stage > 3 retinopathy of prematurity (ROP) in the EPO group [typical RR; 1.71 (95% CI 1.15, 2.54); typical RD; 0.05 (95% CI 0.01, 0.09); NNTH; 20 (95% CI 11, 100)]. The non-significant results for ROP (any stage reported) showed a similar trend. The increased risk for ROP may be associated with use of higher doses of supplemental of iron in the EPO group than in the control group. The rates for mortality, sepsis, intraventricular haemorrhage, periventricular leukomalacia, necrotizing enterocolitis, bronchopulmonary dysplasia, neutropenia, hypertension, length of hospital stay or long-term neurodevelopmental outcomes were not significantly change by the administration of EPO.. Early administration of EPO reduces the use one or more red blood cell transfusions, the volume of red blood cells transfused, and the number of donors and transfusions the infant is exposed to following study entry. The small reductions are of limited clinical importance. Any donor exposure is likely not avoided as most studies included infants, who had received red cell transfusions prior to trial entry. There was a significant increase in the rate of ROP (stage >3). Animal data and observational studies in humans support a possible association between treatment with EPO and the development of ROP. EPO does not significantly decrease or increase any of the other important neonatal adverse outcomes including mortality. The incidence of ROP should be ascertained in the studies that have already been conducted but did not report on this outcome. Any ongoing research should deal with the issue of ROP and evaluate the current clinical practice that will limit donor exposure through satellite units. Research efforts should focus on limiting donor exposure (to as few donors as possible) during the first few days of life in sick neonates, when red blood cell transfusions are most likely to be required and cannot be prevented by early (or late) EPO treatment. Due to the limited benefits and the increased risk of ROP, early administration of EPO is not recommended.

Topics: Age Factors; Anemia, Neonatal; Erythrocyte Transfusion; Erythropoietin; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Randomized Controlled Trials as Topic; Retinopathy of Prematurity

Hematocrit falls after birth in preterm infants due to physiological factors and frequent blood letting. Low plasma levels of erythropoietin (EPO) in preterm infants provide a rationale for the use of EPO to prevent or treat anaemia.. To assess the effectiveness and safety of early (before 8 days after birth) versus late (between 8 - 28 days after birth) initiation of EPO in reducing red blood cell transfusions in preterm and/or low birth weight infants.. The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2006) was searched. Electronic and manual searches were conducted in November 2005 of MEDLINE, EMBASE and CINAHL, personal files, bibliographies of identified trials and abstracts by the Pediatric Academic Societies' and the European Society of Pediatric Research Meetings published in Pediatric Research.. Randomized or quasi-randomized controlled trials.. Preterm (< 37 weeks gestational age) or low birth weight infants (< 2500 g) less than eight days of age.. Early initiation of EPO (initiated at < 8 days of age) vs. late initiation of EPO (initiated at 8 - 28 days of age). Outcomes; At least one of the following outcomes were reported: Use of one or more red blood cell transfusions; Total volume (ml/kg) of blood transfused per infant; Number of transfusions per infant; Number of donors to whom the infant was exposed; Mortality during initial hospital stay (all causes); and common outcomes associated with preterm birth.. The standard methods of the Cochrane Neonatal Review Group were followed independently by the authors to assess study quality and report outcomes. Weighted treatment effects, calculated using RevMan 4.2.8 included typical relative risk (RR), typical risk difference (RD), number needed to treat to benefit (NNTB), number needed to treat to harm (NNTH) and mean difference (MD), all with 95% confidence intervals (CI). A fixed effect model was used for meta-analyses. Heterogeneity tests including the I-squared (I(2)) test were performed to assess the appropriateness of pooling the data.. Two high quality randomized double-blind controlled studies enrolling 262 infants were identified (Donato 2000; Maier 2002). Both studies used well defined, but not identical, criteria for blood transfusions. Between 14 and 32% of the enrolled infants had received blood transfusions prior to study entry. A non-significant reduction in the 'use one or more red blood cell transfusions' [typical RR 0.91 (95% CI 0.78, 1.06); typical RD - 0.07 (95% CI -0.18, 0.04)] favouring early EPO was noted. Both studies (n = 262) reported on "number of transfusions per infant"; early EPO administration resulted in a non-significant reduction compared to late EPO [typical WMD - 0.32 (95% CI -0.92, 0.29)]. There was no significant reduction in total volume of blood transfused per infant or in the number of donors to whom the infant was exposed. Retinopathy of prematurity (ROP) (all stages) was assessed in 191 infants. Early EPO led to a significant increase in the risk of ROP [(typical RR 1.40 (95% CI 1.05, 1.86); typical RD 0.16 (95% CI 0.03, 0.29); NNTH 6 (95% CI 3 -33)]. There was statistically significant heterogeneity for this outcome. Both studies (n = 191) reported on ROP stage > 3. No statistically significant increase in risk was noted [typical RR 1.56 (95% CI 0.71, 3.41); typical RD was 0.05 (95% CI - 0.04, 0.14)]. There was no statistically significant heterogeneity for this outcome for either RR or for RD. No other important favourable or adverse neonatal outcomes or side effects were reported.. The use of early EPO did not significantly reduce the primary outcome of "use of one or more red blood cell transfusions", or "number of transfusions per infant" compared to late EPO administration. Currently there is lack of evidence that early EPO vs. late EPO confers any substantial benefits with regard to any donor blood exposure as a large proportion (14 - 30 %) of infants enrolled in these studies were exposed to donor blood prior to study entry. The finding of a statistically significant increased risk of ROP (any grade) and a similar trend for ROP stage > 3 with early EPO treatment is of great concern. No further studies comparing early vs. late administration of EPO are warranted.

Topics: Age Factors; Anemia, Neonatal; Erythrocyte Transfusion; Erythropoietin; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Randomized Controlled Trials as Topic; Retinopathy of Prematurity

Hematocrit falls after birth in preterm infants due to physiological factors and blood letting. Low plasma levels of erythropoietin (EPO) in preterm infants provide a rationale for the use of EPO to prevent or treat anemia.. To assess the effectiveness and safety of late initiation of EPO (initiated at 8 days after birth or later) in reducing the use of red blood cell transfusions in preterm and/or low birth weight infants.. Subgroup analyses of low (< 500 IU/kg/week) and high (> 500 IU/kg/week) doses of EPO and within these subgroups analyses of the use of low (< 5 mg/kg/day) and high (> 5 mg/kg/day) doses of supplemental iron, in reducing the use of red blood cell transfusions in these infants.. MEDLINE, EMBASE, CINAHL, abstracts from scientific meetings published in Pediatric Research and reference lists of identified trials and reviews were searched in November 2005/April 2006 and the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2006). No language restrictions were applied.. Randomised or quasi-randomized controlled trials of late initiation of EPO treatment (started at eight days of age or later) vs. placebo or no intervention in preterm (< 37 weeks) and/or low birth weight (< 2500 g) neonates. For inclusion the studies needed to provide information on at least one outcome of interest.. Data were abstracted by the two authors on pre-tested data collection forms. Data were entered by one review author (AO) and checked for accuracy by the other (SA). Data were analysed using RevMan 4.2.8. The statistical methods included relative risk (RR), risk difference (RD), number needed to treat to benefit (NNTB), number needed to treat to harm (NNTH) for dichotomous outcomes and weighted mean difference (WMD) for continuous outcomes reported with their 95% confidence intervals (CI). A fixed effects model was used for meta-analyses. Heterogeneity tests including the I squared (I(2)) statistic were performed to assess the appropriateness of pooling the data.. Twenty-eight studies enrolling 1302 preterm infants in 21 countries were included. The quality of the trials varied. Most trials were of small sample size. Only one study clearly stated that infants were excluded if they had received red blood cell transfusion prior to study entry (Samanci 1996). A total of 19 studies including 912 infants reported on the primary outcome of "Use of one or more red cell transfusions". The meta-analysis showed a significant effect [typical RR; 0.66 (95% CI; 0.59, 0.74); typical RD -0.21 (95% CI; -0.26, -0.16); typical NNTB of 5 (95% CI 4, 6)]. There was statistically significant heterogeneity [for RR (p < 0.00001), I(2 )= 74.0% and for RD (p = 0.0006), I(2 )=58.9%]. Similar results were obtained in secondary analyses based on different combinations of high/low doses of EPO and iron supplementation. There was a significant reduction in the total volume (ml/kg) of blood transfused per infant (four studies enrolling 177 infants) [typical WMD = -7 ml (95% CI -12, -3)] and in the number of transfusions per infant (nine studies enrolling 567 infants); [typical WMD -0.78 (-0.97, -0.59)]. The effect size was less in a post hoc analyses of high quality studies compared to studies in which the quality was uncertain and in studies that used strict guidelines for red blood cell transfusions vs. studies that did not. There were no significant differences in mortality, retinopathy of prematurity, sepsis, intraventricular haemorrhage, periventricular leukomalacia, necrotizing enterocolitis, bronchopulmonary dysplasia, SIDS, neutropenia, hypertension, or length of hospital stay. Long-term neurodevelopmental outcomes were not reported.. Late administration of EPO reduces the use of one or more red blood cell transfusions, the number of red blood cell transfusions per infant and the total volume of red blood cell transfused per infant. The clinical importance of the results for the latter two outcomes is marginal (< 1 transfusion per infant and 7 ml/kg of transfused red blood cells). Any donor exposure is likely not avoided as most studies included infants who had received red cell transfusions prior to trial entry. Late EPO does not significantly reduce or increase any of many important neonatal adverse outcomes including mortality and retinopathy of prematurity. Further research of the use of late EPO treatment to prevent donor exposure is not indicated. Research efforts should focus on limiting donor exposure during the first few days of life in sick neonates, when red blood cell requirements are most likely to be required and cannot be prevented by late EPO treatment.

Topics: Age Factors; Anemia, Neonatal; Cause of Death; Erythrocyte Transfusion; Erythropoietin; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Randomized Controlled Trials as Topic

Topics: Administration, Oral; Anemia, Neonatal; Dietary Supplements; Erythropoietin; Humans; Infant, Newborn; Iron; Recombinant Proteins

Erythropoietin (EPO) treatment for anemia of prematurity is still controversial. Large multicentric trials demonstrate that administration of EPO+Fe cannot prevent early transfusions, particularly in very low birth weight newborns and in infants with severe neonatal diseases, but may have some beneficial effect to prevent late transfusions. Current treatment of anemia of prematurity should be multifactorial trying to minimize all causes that reduce erthrocytic mass (phlebotomies, use of noninvasive procedures) and promoting all factors that increase it (placental transfusion, adequate nutrition support). To evaluate the real impact of EPO treatment it is mandatory to follow similar transfusion protocols for preterm infants in all the studies. The aim of EPO+Fe administration should be to avoid new late transfusions in very low birth weight preterm infants or to prevent the first transfusion after the second week of life in less immature premature with the objective of reducing the number of donors rather than the number of transfusions. We have limited the use of EPO+Fe to infants <30 weeks gestational age and birth weight

Topics: Anemia, Neonatal; Blood Transfusion; Child Development; Erythropoiesis; Erythropoietin; Female; Humans; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Pregnancy; Recombinant Proteins

The introduction of recombinant human erythropoietin (RHuEPO) has dramatically changed the therapeutic approach to the anemia of chronic renal failure. Clinical studies have also demonstrated that RHuEPO is effectiveness in various non-uremic conditions, such as anemia associated with onco-hematological disorders, prematurity, HIV infection and to reduce the exposure to allogeneic blood in surgical patients. In this review, we briefly analyze the main clinical applications of RHuEPO, with particular attention to the potential complications deriving from its use.

Topics: Adult; Anemia; Anemia, Neonatal; Blood Transfusion, Autologous; Child; Clinical Trials as Topic; Erythropoietin; Female; HIV Infections; Humans; Infant, Newborn; Infant, Premature, Diseases; Kidney Failure, Chronic; Male; Multicenter Studies as Topic; Neoplasms; Randomized Controlled Trials as Topic; Recombinant Proteins

Human recombinant erythropoietin has been studied extensively as treatment for a variety of anemias. Since in vitro studies showed the primary etiology of the anemia of prematurity to be insufficient serum erythropoietin concentrations, clinical trials have evaluated the administration of human recombinant erythropoietin to preterm infants to treat this indication. These studies were followed by pharmacokinetic determinations in animal models and preterm infants, which revealed that preterm infants required greater doses of human recombinant erythropoietin because of a more rapid clearance and greater volume of distribution. Recent studies have focused on the administration of human recombinant erythropoietin in the first weeks of life to alleviate the anemia caused by excessive phlebotomy losses, and to prevent the anemia of prematurity. In addition, human recombinant erythropoietin has been tried clinically in a variety of neonatal populations in an attempt to decrease or eliminate transfusions. Although much information has been accumulated about the clinical use of human recombinant erythropoietin in preterm infants over the last 15 years, many questions remain unanswered. The evolution of clinical practice in the care of extremely low birthweight infants continues to affect the number of transfusions. It is likely that human recombinant erythropoietin administration in combination with instituting rigorous transfusion guidelines and decreasing phlebotomy losses will have the greatest impact in decreasing transfusion requirements in all preterm and term neonates, regardless of the etiology of their anemia.

Topics: Anemia, Neonatal; Erythropoietin; Half-Life; Humans; Infant, Newborn; Infant, Premature; Randomized Controlled Trials as Topic; Recombinant Proteins; Treatment Outcome

Physiologic anemia is a common and normal finding in newborn infants. In preterm infants, anemia of prematurity is the result of this normal physiologic process compounded by the morbidity of prematurity. Premature infants reach their nadir hematocrit sooner and at a lower level than term. This article reviews the physiology of stem cell differentiation and the structure and function of the red blood cell, as well as examining red blood cell indices. It also addresses the etiology, symptomatology, diagnostic workups and treatment/prevention modalities of anemia of prematurity. Treatment for and prevention of anemia of prematurity remain controversial, and specific criteria are lacking.

Topics: Anemia, Neonatal; Blood Transfusion; Cell Differentiation; Erythrocyte Count; Erythrocyte Indices; Erythropoietin; Ferrous Compounds; Hematopoiesis; Hematopoietic Stem Cells; Humans; Infant, Newborn; Infant, Premature, Diseases; Risk Factors

Transfusion-dependent anemia remains a problem for preterm infants, particularly those with a birth weight less than 1.0 kg. Several studies have documented the efficacy and safety of transfusing red blood cells stored up to 42 days as a means to diminish donor exposures. Recombinant erythropoietin therapy has not been widely adopted because it does not consistently reduce the need for red blood cell transfusions in very low-birth weight preterm infants.

Topics: Anemia, Neonatal; Erythrocyte Transfusion; Erythropoietin; Hematocrit; Humans; Infant, Newborn; Infant, Premature, Diseases; Recombinant Proteins

Anemia of prematurity is a hyporegenerative anemia usually appearing after the second week, reaching highest intensity in the second month of life. It's normocytic and normochromic with low reticulocyte count. It has been attributed to EPO deficiency. The low EPO levels detected in premature infants and the proper response to synthetic erythropoietin suggested that EPO administration in premature of < or =32 weeks gestational age could be of benefit trying to maintain or increase the hematocrit levels. Protocols of EPO administration to premature babies should always be considered as EPO+Fe, keeping ferritin levels over 100 ng/ml. Failures to EPO+Fe treatment in very small premature babies, measured as no decrease in the need of blood transfusions, may be due to the amount of blood looses that should be restricted.

Topics: Anemia, Neonatal; Erythropoietin; Ferritins; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Iron

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 likely decreases transfusion need even further; however, the direct impact of each of these actions has not been studied prospectively. It is likely that the combination of instituting rigorous and standardized transfusion guidelines, decreasing phlebotomy losses, and the appropriate use of Epo will have the greatest impact in decreasing transfusion requirements in all preterm and term neonates, regardless of the cause of their anemia.

Topics: Anemia, Neonatal; Blood Transfusion; Clinical Trials as Topic; Erythropoietin; Humans; Infant, Newborn; Infant, Premature

Human recombinant erythropoietin was first cloned in 1985, and is currently available for clinical use for a variety of anemias. Following successful clinical trials using erythropoietin to treat adults with the anemia of end-stage renal disease, the first clinical trial evaluating the use of erythropoietin in preterm infants to treat anemia was published in 1990. Since that initial report, numerous clinical trials have reported various levels of success in the treatment of this anemia. Most recently, erythropoietin has been used in the first weeks of life in an attempt to prevent the anemia of prematurity. This review describes mechanisms of erythropoiesis in the fetus and neonate, and focuses on recent clinical trials evaluating the use of erythropoietin to prevent and treat anemia in preterm infants.

Topics: Anemia, Neonatal; Clinical Trials as Topic; Erythropoietin; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases

Topics: Anemia, Neonatal; Blood Transfusion; Clinical Trials as Topic; Erythropoietin; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Recombinant Proteins; Time Factors

Controversies about medical practices usually arise from lack of definitive scientific studies. In the presence of continuing controversy about the appropriate hemoglobin level for ventilated (or nonventilated) infants, we can attempt to derive as much useful information as possible. In this article, the authors focus on four subjects: the physiologic role of red cells, the clinical effects of anemia and the proposed clinical benefit of red cell transfusions in preterm infants, the risks associated with transfusions, and the use of recombinant erythropoietin as an alternative to transfusion therapy.

Topics: Anemia, Neonatal; Blood Transfusion; Erythrocytes; Erythropoietin; Hemoglobins; Humans; Infant, Newborn; Infant, Premature; Respiration, Artificial; Transfusion Reaction

Neonatal erythropoiesis is limited by a relatively inadequate production of erythropoietin. This is likely the result of dependence on the hepatic production of erythropoietin and an incomplete switchover to renal production. The present model of neonatal erythropoiesis suggests that the use of exogenous erythropoietin should correct the early anemia of prematurity that is observed at 6 weeks of age in premature newborns. Randomized, controlled trials of erythropoietin use in very low birthweight infants are reviewed. The data support the conclusion that erythropoietin at doses of > or = 750 u/kg/wk started at less than 7 days of age results in improved reticulocyte counts and hemoglobin levels, but does not reduce the number of infants who will be exposed to blood products. Erythropoietin at doses of > or = 600 u/kg/wk started at an average of 21 days of life improves reticulocyte counts and hemoglobin levels, and reduces the number of infants will will require late transfusion, but does nothing for the bulk of infants who are transfused before that age.

Topics: Anemia, Neonatal; Erythropoiesis; Erythropoietin; Humans; Infant, Newborn; Infant, Premature, Diseases; Randomized Controlled Trials as Topic

Anemia of prematurity (AOP) is an exaggerated form of the normal physiologic anemia of infancy. The primary pathophysiologic abnormality implicated in the development of AOP is inadequate production of erythropoietin, whose function is the regulation of red blood cell production. Recent studies into the safety and efficacy of recombinant human erythropoietin in infants with AOP have demonstrated consistently a rise in hematocrits and reticulocyte counts, fewer blood transfusions, reduced transfused volume of blood per kilogram body weight, and a decrease in bioavailable iron. Current dose recommendations are 200 U/kg subcutaneously or intravenously daily or every other day.

Topics: Anemia, Neonatal; Erythropoietin; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Recombinant Proteins

Recombinant human erythropoietin (rHuEpo) has been increasingly used in preterm infants in the last 3 to 4 years. Recent studies have indicated a reduction in blood transfusion requirements in infants receiving rHuEpo. No significant adverse effects have emerged, apart from iron deficiency (if iron supplementation is inadequate), and the risk of transfusion-related infection is decreased. Nevertheless, rHuEpo is relatively expensive (a 6-week course costs approximately the same as 2 blood transfusions), so its use requires careful consideration; it is logical to target rHuEpo therapy to those babies who are most likely to be transfused. Using this strategy, 1 study involving stable growing preterm infants has shown that direct costs of blood transfusion and rHuEpo were similar, and the use of rHuEpo was recommended. In addition, use of high-dosage rHuEpo early in the course of management on the neonatal intensive care unit has been shown to reduce direct treatment costs in ill preterm infants. Further studies will continue to identify infants who are likely to benefit from rHuEpo therapy and to define its cost effectiveness in more detail.

Topics: Anemia, Neonatal; Erythropoietin; Humans; Infant; Infant, Newborn; Infant, Premature, Diseases; Recombinant Proteins

Topics: Anemia, Neonatal; Erythropoietin; Humans; Infant, Newborn; Infant, Premature, Diseases; Recombinant Proteins; Risk Factors

Anemia of prematurity (AOP) affects almost all infants that are born prematurely. Excessive phlebotomy in the NICU setting has exacerbated this condition. Until recently, erythrocyte transfusion has been the only therapy for AOP. Recombinant human erythropoietin (rh-EPO) has been shown to be effective in reducing erythrocyte transfusions in premature infants with AOP. Various studies have utilized rh-EPO as a treatment modality or as prophylaxis for AOP. The results of these studies have shown that rb-EPO is a complementary strategy along with restriction of phlebotomy and less liberal transfusion policies, to decreasing the number of transfusions that an infant may need. Trials are necessary to document the cost-effectiveness of rh-EPO as well as its long term effects on the premature infant.

Topics: Anemia, Neonatal; Erythrocyte Transfusion; Erythropoietin; Humans; Infant, Newborn; Infant, Premature, Diseases; Neonatal Nursing

In order to prevent or to treat anemia of prematurity, more than 800 preterm infants were enrolled into controlled studies with recombinant erythropoietin (rhEPO) during the past five years. The effective dosage seems to be within the range of 300 to 1200 IU/kg per week, markedly higher than in adults or children with anemia due to renal failure. No adverse events nor impairment of granulopoiesis or platelet formation could be attributed to erythropoietin. Statistical metaanalysis of eight controlled trials revealed an 18% reduction of transfused infants. The preventive effect was scarce in very small and very sick preterm infants, and during the first two weeks of life, when hemorrhagic anemia due to diagnostic blood loss is predominant. rhEPO treatment is one step in the concept to prevent anemia of prematurity. This concept should also include placental transfusion, minimizing of diagnostic sampling, miniaturized laboratory tests, adequate iron supplementation, and optimal nutritive protein administration.

Topics: Anemia, Neonatal; Blood Transfusion; Clinical Trials as Topic; Erythropoiesis; Erythropoietin; Humans; Infant, Newborn; Infant, Premature; Recombinant Proteins

It has been well established that erythropoietin (EPO) in the dosage range of 500 units/kilo/week and perhaps slightly lower doses will produce a brisk reticulocyte response in infants with anemia of prematurity. Controlled clinical trials to demonstrate that this therapy can result in significant reductions in transfusion in these babies face several complex issues of experimental design. 1. Should the study population be relatively bigger, healthier babies (< 1500 grams birth weight, not on ventilatory support) who have lower transfusion requirements, or smaller sicker infants (< 1250 grams birth weight and on ventilators) who have higher transfusion requirements? These infants will need adequate nutrition and liberal supplementation with iron if they are to respond adequately, but the sicker smaller infants will take longer to meet these nutritional goals. 2. Timing is important because spontaneous recovery occurs at about 35 to 36 weeks of corrected gestational age, so to be effective, therapy must start before 33 weeks of gestational age and preferably earlier than that. 3. Since the end point is transfusion, the criteria used for transfusions become a critical issue. If liberal transfusion criteria are used, the study will be doubly biased in favor of EPO efficacy. There will be an increased number of transfusion events in the control population and spontaneous recovery from the anemia of prematurity will be overly suppressed in the control population. It's likely that the current transfusion criteria are too liberal thus introducing these biases to experimental design.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Anemia, Neonatal; Blood Transfusion; Clinical Trials as Topic; Erythropoietin; Humans; Infant, Newborn; Infant, Premature, Diseases; Recombinant Proteins; Research Design

Increased understanding of the pathophysiology of anemia of prematurity (AOP) has emerged over the past years. It is apparent that low levels of endogenous erythropoietin (Epo) is the basis for this phenomenon. This has resulted in an effective therapeutic approach for this condition. Administration of Epo can ameliorate the signs and symptoms of AOP and lessen, and in many cases avoid, the necessity for blood transfusion.

Topics: Anemia, Neonatal; Blood Transfusion; Erythropoietin; Humans; Infant, Newborn; Recombinant Proteins

To review and evaluate current research on the use of recombinant human erythropoietin (rhEPO) for the treatment of anemia of prematurity (AOP).. A MEDLINE search (1985-September 1994) was used to identify and retrieve pertinent data about erythropoietin's use in premature neonates. Bibliographies in the relevant literature and International Pharmacy Abstracts were reviewed as well.. The authors extrapolated data from trials and other literature in which the entire paper or abstract was published. Because of the paucity of data on the use of rhEPO in neonates, all available literature was reviewed and cited, regardless of study methodology.. Most data support that rhEPO is efficacious in treating AOP. Until recently, the published investigations have included only small numbers of patients. Larger, multicenter, placebo-controlled trials suggest that infants weighing less than 1500 g benefit from rhEPO therapy. Questions remain concerning the rhEPO dose and nutrient requirements for optimal efficacy.. Published clinical trials that have examined the efficacy of rhEPO in the treatment of AOP vary considerably with regard to methodology, rhEPO dose, nutrient doses, and outcome measurement. At present, many questions remain to be answered including ascertaining rhEPO's long-term benefit versus cost/risk as well as its potential contribution to improving the care of the premature neonate.

Topics: Anemia, Neonatal; Clinical Trials as Topic; Economics, Pharmaceutical; Erythropoietin; Female; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Male; Randomized Controlled Trials as Topic; Recombinant Proteins

Anemia of prematurity (AOP) results from several interacting processes, including phlebotomy losses, a temporary failure to release erythropoietin in response to anemia, a short life span of erythrocytes, and rapid growth of body mass and, hence, blood volume after the first few weeks of life. Infants with AOP have erythroid progenitors that respond to erythropoietin in vitro, suggesting that treatment with recombinant erythropoietin might reduce the need for transfusions for AOP. Many pilot studies were needed to define the dose of recombinant erythropoietin (500 to 750 U/kg/wk) that stimulated the early onset of erythropoiesis in infants with AOP. Three large controlled trials have demonstrated that recombinant erythropoietin therapy reduces transfusions in AOP and is apparently safe. Unresolved issues include the ideal dose, the optimal nutrition needed during therapy, the target population, and timing of the start of treatment.

Topics: Anemia, Neonatal; Clinical Trials as Topic; Erythropoietin; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Recombinant Proteins

Topics: Anemia, Neonatal; Costs and Cost Analysis; Drug Therapy; Erythropoietin; Humans; Infant, Newborn; Infant, Premature; Randomized Controlled Trials as Topic; Recombinant Proteins

Recombinant human erythropoietin (r-HuEPO) is a new therapeutic modality for the treatment of neonatal anemia. The results of three large controlled trials were published within the past year. This article reviews the physiologic rationale underlying the use of r-HuEPO in preterm infants, addresses how the design of clinical trials affects outcomes and conclusions, and discusses the recent trials in this context. The article concludes with a summary of questions that require further investigation.

Topics: Anemia, Neonatal; Clinical Trials as Topic; Erythropoietin; Humans; Infant, Newborn; Infant, Premature, Diseases; Recombinant Proteins

Topics: Anemia, Neonatal; Erythropoietin; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Recombinant Proteins

Topics: Anemia, Neonatal; Erythrocyte Transfusion; Erythropoietin; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Recombinant Proteins; Risk

Topics: Anemia, Neonatal; Blood Transfusion; Erythropoietin; Humans; Infant, Newborn; Infant, Premature, Diseases; Recombinant Proteins; Research Design

Topics: Anemia, Neonatal; Blood Transfusion; Contraindications; Erythropoietin; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Recombinant Proteins

The anemia of prematurity is defined by a progressive decline in hemoglobin level occurring over the first 2 months of life. Unlike term newborns whose "physiologic anemia" rarely if ever necessitates any treatment, preterm infants may become anemic enough to have clinical symptoms that indicate a need for red blood cell transfusions. Various factors contribute to the development of this anemia. Some of these factors, such as the short life span of erythrocytes in preterm infants, increased sensitivity of the erythrocytes to oxidative injury, and the blood losses caused by repeated phlebotomies, would normally be expected to induce corrective reticulocytosis. Characteristically, however, this anemia is hyporegenerative. Thus, it is associated with relative reticulocytopenia, low serum erythropoietin levels, and bone marrow erythroid hypoplasia. The recent availability of recombinant human erythropoietin has opened new perspectives in the management of a variety of anemias. Based on current knowledge of the regulation and pathophysiology of fetal and neonatal erythropoiesis, recombinant erythropoietin may represent a logical and efficient alternative to giving red blood cell transfusions in the treatment of the anemia of prematurity. Clinical trials have been initiated in several countries using different approaches and methodology. At this early stage these trials do not yet fully affirm that recombinant erythropoietin can be used as the first-line therapy in infants with the anemia of prematurity. Our own observations, however, suggest that this agent is well tolerated by preterm infants and may exert a corrective effect on the anemia of prematurity.

Topics: Anemia, Neonatal; Blood Cell Count; Blood Transfusion; Combined Modality Therapy; Drug Evaluation; Erythropoiesis; Erythropoietin; Hematocrit; Humans; Immunologic Factors; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Injections, Subcutaneous; Iron; Iron Deficiencies; Longitudinal Studies; Pilot Projects; Recombinant Proteins; Reticulocytes

At no other time of life is the decision to transfuse potentially as difficult as in the newborn period. Superimposed upon complex "physiologic" changes in the ability to deliver and release oxygen are varying requirements among infants in terms of oxygen need. These are compounded by changes brought about as a direct consequence of frequent phlebotomy in the most ill of preterm infants. Despite the confusion overlying many of the changes occurring at this time of life, certain principles can be applied. Unlike that of the adult, an infant's ability to make oxygen available in response to a specific demand is almost as dependent upon the modifiers of oxygen uptake and release by hemoglobin as upon the hemoglobin concentration itself. These modifiers are constantly changing, sometimes in a predictable fashion, sometimes not. As discussed, some attention to the status of a particular infant's capability in providing oxygen relative to need will assist in the decision when to transfuse. If specific parameters of these assessments can not be determined, it may be necessary to proceed with transfusion based on the clinical presentation of an infant. With regard to the above, any infant sufficiently ill to require frequent blood sampling should have such blood losses replaced, certainly before ten percent of blood volume has been exceeded. This is particularly true in infants who are unable to maintain adequate arterial oxygen tensions with or without the use of supplemental inspired oxygen. At several weeks of age, when the clinical status of a preterm infant may have stabilized, transfusion may or may not be needed during the nadir of the anemia of prematurity. Infants who had been previously transfused or who had earlier received frequent simple transfusions should be able to tolerate lower levels of hemoglobin. Infants without compromised cardiopulmonary function and in whom no unusual metabolic needs exist are unlikely to be aided by transfusions when the hemoglobin concentration is greater than 10 to 11 g/dl. At lower levels of hemoglobin, simple calculations of "available oxygen" may be helpful when it is difficult to determine whether clinical signs and symptoms of anemia exist. Such signs and symptoms may include poor feeding, dyspnea, tachycardia, tachypnea, diminished activity, and pallor. Apnea has not unequivocably been shown to improve following transfusion. Clearly, our current concepts regarding indications for transfusion, even when based upon

Topics: Anemia, Neonatal; Blood Transfusion; Erythropoietin; Hematocrit; Hemoglobins; Humans; Infant, Newborn; Infant, Premature, Diseases; Oxygen; Risk

Topics: Anemia, Neonatal; Blood Transfusion; Erythropoiesis; Erythropoietin; Hemoglobins; Humans; Infant; Infant, Newborn; Infant, Premature, Diseases; Oxygen; Oxygen Consumption; Regional Blood Flow

Topics: Anemia, Hemolytic; Anemia, Neonatal; Bilirubin; Birth Weight; Blood Group Antigens; Diet; Erythrocytes; Erythrocytes, Abnormal; Erythropoiesis; Erythropoietin; Folic Acid Deficiency; Gestational Age; Hemoglobinometry; Hemorrhage; Humans; Immunization; Infant; Infant, Newborn; Isoantigens; Kinetics; Rh-Hr Blood-Group System; Thalassemia; Vitamin E Deficiency

Although many controversies exist regarding the risk of red blood cell (RBC) transfusions, half of preterm infants born at <32 weeks of gestational age receive such transfusions because of anemia of prematurity. Because of the costs and risks associated with multiple transfusions, it has been suggested that a large transfusion volume reduces the number of transfusions. However, there have been persistent concerns that RBC transfusion might lead to volume overload.. We examined the impacts of large (20 mL/kg) compared to standard volume (15 mL/kg) transfusions on the hemodynamic variables of stable, electively transfused, preterm infants, by serially measuring echocardiographic parameters and plasma B-type natriuretic peptide levels.. A total of 39 infants born at <34 weeks of gestation and aged >2 weeks at the time of enrollment were randomly allocated to either a standard volume (15 mL/kg) or a large volume (20 mL/kg) group. Significant reductions in cardiac output and transient increases in plasma B-type natriuretic peptide levels were found after RBC transfusion in both the standard and large volume (20 mL/kg) groups. However, these changes were not significantly different between the two groups.. Large-volume transfusions could be tolerable in stable preterm infants with anemia.

Topics: Age Factors; Anemia, Neonatal; Erythrocyte Transfusion; Erythropoietin; Hemodynamics; Humans; Infant, Newborn; Infant, Premature

To estimate the blood level of Erythropoietin(EPO) in neonates with anemia of prematurity (APO) and in late hypo-regenerative anemia and to clarify role of EPO in correction of anemia and reducing the number of blood transfusions.. This study was carried out on 60 neonates divided into; group I (30 preterm neonates) with AOP received EPO (250 IU/kg/dose subcutaneously 3 times weekly for 4 weeks), compared to group II (30 neonates) with AOP treated only with blood transfusion. CBC parameters and transfusion requirements were followed during therapy. Serum level of EPO was measured by ELISA technique.. By the end of the 4th week of therapy, there was significant increase in group I post r-Hu EPO compared to group II regarding reticulocyte counts (P < 0.001) leading to rise of the Hb (P < 0.001), Hct levels (P < 0.001) with subsequent reduction in the overall number of blood transfusions (P < 0.001).. EPO therapy in conjunction with iron, vitamin E and folic acid, stimulated erythropoiesis and significantly reduced the need for blood transfusion in AOP.

Topics: Anemia, Neonatal; Blood Transfusion; Child, Preschool; Erythropoietin; Female; Humans; Infant; Infant, Newborn; Injections, Subcutaneous; Male; Prospective Studies; Reticulocyte Count

We explored the clinical efficacy of vitamin A combined with vitamin B in the prevention and treatment of premature infants with anemia.. One hundred fifty cases of premature infants were divided into three groups. Vitamin A combined with recombinant human erythropoietin (group A), vitamin B combined with recombinant human erythropoietin (group B), vitamin A combined with vitamin B combined with recombinant human erythropoietin treatment (recorded as group C). Levels of serum ferritin (SF), hemoglobin (Hb), hematocrit (Hct) and reticulocyte (Ret) in the serum of children before and after treatment were compared with those of three different treatments.. After treatment, the levels of SF, Hb and Ret in group C were higher than those in group A and B, and the level of Hct in group C was lower than that in group A and B (P<0.05) There was no significant difference in SF, Hb, Hct and Ret between the two groups (P>0.05). The ratio of blood transfusion in group C was lower than that in group A and B (P<0.05). There was no significant difference between the two groups (P>0.05).. Vitamin A combined with vitamin B can effectively prevent anemia in premature infants, which has important clinical significance.

Topics: Anemia, Neonatal; Drug Therapy, Combination; Erythropoietin; Female; Ferritins; Hematocrit; Hemoglobins; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Male; Recombinant Proteins; Reticulocytes; Treatment Outcome; Vitamin A; Vitamin B Complex

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).. 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.. 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.. 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.

Topics: Anemia, Neonatal; Darbepoetin alfa; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Erythrocyte Transfusion; Erythropoietin; Female; Guideline Adherence; Hematinics; Humans; Infant, Extremely Low Birth Weight; Infant, Newborn; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Injections, Subcutaneous; Male; Reticulocyte Count; Therapeutic Equivalency

Premature infants especially those with birth weight < 1500 g suffer from Anaemia of prematurity (AOP) and associated problems. Erythropoietin therapy is a safe effective way to prevent and to treat anaemia of prematurity. To evaluate the effect of short-term administration of recombinant human erythropoietin (rHuEPO) with iron and folic acid in very low birth weight (VLBW) neonates in the prevention of anaemia of prematurity. A randomized controlled trial was carried out at Dhaka Shishu Hospital. Sixty preterm very low birth weight (PTVLBW) babies were enrolled in this study. Thirty were assigned to rHuEPO group and 30 as control. Baseline haematologic values were estimated before administration of rHuEPO. From day 7 of life rHuEPO-200 IU/kg/dose subcutaneously every alternate day for 2 weeks was administered to rHuEPO group. All infants in both groups have received oral iron, folic acid from day 14. Clinical and haematological assessment was done at 6 and 10 weeks of life. Baseline clinical characteristics and haematologic values were almost similar in both groups. This study has shown increase in haematological values (haemoglobin and haematocrit) and reduction in the number of blood transfusions during both the 1st and 2nd follow up in rHuEPO group in comparison to control group (p < 0.01). Short-term rHuEPO appears to be very effective in prevention of Anaemia of prematurity.

Topics: Anemia, Neonatal; Bangladesh; Erythropoietin; Female; Folic Acid; Humans; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Intensive Care Units, Neonatal; Iron; Male; Outcome Assessment, Health Care; Time Factors

To compare reticulocyte responses of once-per-week erythropoietin (EPO) dosing with 3-times-a-week dosing in preterm infants.. 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.. 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.. 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.

Topics: Anemia, Neonatal; Blood Cell Count; Cross-Over Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythrocyte Count; Erythropoiesis; Erythropoietin; Female; Follow-Up Studies; Hematocrit; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Injections, Subcutaneous; Intensive Care Units, Neonatal; Iron Compounds; Male; Pilot Projects; Risk Assessment; Severity of Illness Index; Treatment Outcome; Vitamins

High-dose recombinant human erythropoietin (rEpo) has first been administered in clinical trials for neuroprotection in very preterm neonates at high risk of brain injury and in (near-) term neonates with hypoxic-ischemic encephalopathy. However, recent trials in adults raised concerns about the safety of high-dose rEpo for neuro- and cardioprotection.. To evaluate the putative accumulation or renal leakage of Epo as a function of developmental stage after repetitive early short-term infusion of high-dose rEpo (3 × 3,000 U/kg within 42 h after birth; NCT00413946) for neuroprotection in very preterm infants.. Epo concentrations were measured using the ELISA technique in the first two consecutive urine specimens after each rEpo infusion.. Renal Epo excretion was significantly higher in preterm infants with gestational ages <29 weeks than in more mature infants and reached up to 23% of the administered rEpo within 8 h after each infusion. The urinary Epo concentration did not increase after three repetitive infusions of high-dose rEpo. The ratio of urinary Epo to total protein concentrations was the same in infants with gestational ages <29 weeks and in those with gestational ages ≥29 weeks.. Our data suggest that the higher renal Epo excretion in more immature infants may be attributed to a higher glomerular filtration leakage due to the lower maturation of the kidneys and argue against saturation kinetics after multiple doses of 3,000 U/kg rEpo. This information should be considered in future trials on the use of rEpo for neuroprotection in neonates.

Topics: Anemia, Neonatal; Cytoprotection; Dose-Response Relationship, Drug; Double-Blind Method; Erythropoietin; Female; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn; Infant, Premature; Infusion Pumps; Male; Neurons; Neuroprotective Agents; Osmolar Concentration; Placebos; Recombinant Proteins; Time Factors

To compare transfusion requirements and erythropoietic response in preterms between schedules of rEPO administration once or three times per week, using the same weekly dose.. Prospective, randomized trial including infants weighing <1500 g at birth and/or were 32 weeks' gestation: Group 1 (60 infants) received subcutaneous rEPO at 250 units kg(-1) per dose, three times weekly for 6 weeks; Group 2 (59 infants), at 750 units kg(-1) per dose, once weekly for 6 weeks. Efficacy was evaluated based on the transfusion requirement, hemoglobin changes, reticulocyte counts, serum transferrin receptor (sTfR) and serum ferritin. The frequency of adverse effects was registered in both groups.. A total of 13 infants were transfused in each group (relative risk: 0.98; 95% confidence interval: 0.4 to 2.3). Phlebotomy loss and red blood cell transfusion volumes received were similar in both groups. Hemoglobin levels were lower at end of study in Group 2 (10.6±1.5 g dl(-1) versus 11.5±1.4 g dl(-1); P<0.003). At end of study, reticulocyte counts and sTfR values increased and serum ferritin values decreased, without significant differences between the two groups. Incidence of complications was similar in both groups.. The once-weekly rEPO schedule for very low birth weight infants proved as effective as the three-times-weekly schedule, in relation to erythropoietic stimulus and transfusion requirement.

Topics: Anemia, Neonatal; Blood Transfusion; Drug Administration Schedule; Drug Monitoring; Erythropoiesis; Erythropoietin; Ferritins; Hemoglobins; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Injections, Subcutaneous; Receptors, Transferrin; Recombinant Proteins; Reticulocyte Count; Thrombocytosis; Transfusion Reaction; Treatment Outcome

Red blood cell (RBC) transfusions can suppress erythropoiesis. On this basis, RBC transfusions administered to very low birth weight (VLBW) neonates potentially render them more likely to qualify for a subsequent transfusion.. We hypothesized that 'late' (>14 days after birth) RBC transfusions given to VLBW neonates result in a decrease in reticulocyte count persisting for at least 7 to 10 days. We also hypothesized that a single dose of darbepoetin given along with the transfusion would have the opposite effect, increasing the reticulocyte count for at least 7 to 10 days. To test this, we conducted a single-centered randomized trial with 20 VLBW neonates who, according to our transfusion guidelines, qualified for a late transfusion.. VLBW infants about to receive a late RBC transfusion were randomized (1:1) to also receive vs not receive (controls) a single subcutaneous dose of darbepoetin (10 μg kg(-1)). Reticulocyte counts diminished significantly in the controls (a drop of 85±62 × 10(3) μl(-1) (mean±s.d.) at 7 to 10 days), but increased significantly in the darbepoetin recipients (an increase of 177±120 × 10(3) μl(-1) at 7 to 10 days, P<0.0001). At 7 to 10 days after the transfusion, hematocrits of the controls were 8.1±4.9 points above their pre-transfusion values and of the darbepoetin group were 12.4±2.7 points above their pre-transfusion values (P=0.033).. This was a limited-scope, single-centered, randomized trial intended to pilot-test a new concept in neonatal transfusion practice. Namely, we tested whether a late RBC transfusion suppressed reticulocytosis and whether a concomitant single dose of darbepoetin counteracted that suppression. Using the pilot data presented in this study, larger trials can now be designed to address meaningful clinical outcomes such as transfusion avoidance using this approach.

Topics: Anemia, Neonatal; Darbepoetin alfa; Erythrocyte Transfusion; Erythropoiesis; Erythropoietin; Humans; Infant, Newborn; Infant, Very Low Birth Weight; Injections, Subcutaneous; Reticulocyte Count

Early recombinant erythropoietin therapy and iron therapy would decrease the need for red blood cells transfusions and prevents anemia of prematurity.. Fifty-eight preterm infants in newborn services at Ghaem Medical Center randomly were assigned, among them 18 patients were excluded. A total of 40 preterm infants with gestational age 28-34 weeks, birth weight 1000-1750 g followed the study: 20 infants in treatment group and 20 infants in control group were randomized to treatment (rhu EPO, 500u per kg, per week, 2 times weekly, subcutaneous) and control (no treatment). Therapy was initiated 4 days after birth and continued throughout the 4 weeks. All infants on enteral feeds received supplements: iron 3 mg/kg/d, vitamins and folat. Complete blood cells and reticulocyte counts were measured weekly. Transfusions and phlebotomy data were recorded. Statistical significance was determined by chi-square test, student t test and Mann-Whitney. A P value of < 0.05 was considered statistically significant.. The reticulocyte counts were higher in treated infants during the study (p: 0.009). Final hematocrits were higher in treated infants (p: 0.02).The volume of packed red blood cells transfusions mililiter per infant significantly reduced (p: 0.05), the average number of transfusion per infant was also lower for treated infant than control [2 (10 % )vs 8 (40%) respectively]. No adverse effects of EPO or supplemental iron occurred.. The combination of early rhu EPO and iron as administered in the present study stimulated erythropoiesis and decreased red blood cells transfusion in premature infants who were 1000-1750 g at birth. The enrollments of the larger and healthier preterm infants, who are at lower risk for transfusion, are limitation of the present study.

Topics: Anemia, Neonatal; Erythrocyte Transfusion; Erythropoiesis; Erythropoietin; Female; Humans; Infant, Newborn; Infant, Premature; Iron; Male; Recombinant Proteins

Hematopoietic and non-hematopoietic effects of recombinant erythropoietin (Epo) given to preterm infants are controversially discussed. Because renal loss of Epo was significantly higher after intravenous versus subcutaneous Epoetin-beta administration, we suggest a reconsideration of whether subcutaneous recombinant Epo is more efficient and safer because of lower peaks of circulating Epo.

Topics: Anemia, Neonatal; Erythropoietin; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Injections, Intravenous; Injections, Subcutaneous; Longitudinal Studies; Recombinant Proteins

Suppression of erythropoiesis due to low plasma erythropoietin levels is an important factor in the development of anaemia of prematurity. Premature infants may therefore be treated with recombinant human erythropoietin (rhEPO). This prospective, randomised and controlled study was designed to find out whether rhEPO treatment improves erythrocyte deformability in preterm infants.. Sixteen infants were treated with rhEPO (250 IU/kg three times weekly) a total of 15 times beginning on day of life 5 whereas fifteen infants served as controls. Haemoglobin concentration, haematocrit, reticulocyte count, ferritin level and erythrocyte deformability were measured on days 5, 14, 28, 42 and 63. Erythrocyte elongation was determined as an indicator of erythrocyte deformability using a shear stress diffractometer (Rheodyn SSD) at shear forces of 0.3 to 60 Pa.. Haemoglobin concentration was significantly higher on days 28 and 42 and reticulocyte percentage on day 28 in the rhEPO group compared to the controls. Serum ferritin was lower in the rhEPO group on day 28. Erythrocyte deformability was significantly increased on days 28 and 42 in the infants receiving rhEPO. We found a strong relationship between erythrocyte elongation and reticulocyte count.. RhEPO markedly increases the erythropoiesis in preterm infants in the critical first weeks of life and the anaemia of prematurity is obviously reduced. The erythrocyte deformability improved under rhEPO treatment. Erythrocyte deformability was significantly related to the reticulocyte count indicating that the improvement of erythrocyte deformability was due to the formation of well-deformable young erythrocytes.

Topics: Anemia, Neonatal; Erythrocyte Deformability; Erythropoietin; Hematinics; Hematocrit; Hemoglobins; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Prospective Studies; Recombinant Proteins; Reticulocyte Count

The aim of the present study is to define criteria for erythropoietin therapy of hyporegeneratory anemia in premature newborns according to hemoglobin (Hb) and hematocrit (Hct) concentration, and reticulocyte count (Ret).. The prospective study includes two groups of 20 newborns with anemia of prematurity, body weight at birth below 1500 grams and gestation age below 33 gestation week. The newborns in the first group have been treated with beta-erythropoietin for four weeks--750-1000 E/kg weekly dose, divided q48h. Hb, Hct and Ret have been monitored and compared with that of control group newborns. The therapy of newborns in the control group consisted of blood transfusions.. The hematological parameters in the newborns from the first group have been increased permanently after the first week of therapy, with Ret being most sensitive to the therapy. In the second group of newborns, due to blood transfusions, transient increase of Hb and Hct, and decrease of Ret have been observed in next days after the blood transfusions.. The erythropoietin therapy of hyporegeneratory anemia in preterm newborns leads to rise in Hb, Hct and Ret. The therapy with blood transfusions suppresses erythropoiesis. This leads to decrease in Ret and transient rise in Hb, Hct and erythrocytes. That's why each blood transfusion leads to another one.

Topics: Anemia, Neonatal; Blood Transfusion; Erythropoietin; Gestational Age; Hematocrit; Hemoglobins; Humans; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Prospective Studies; Recombinant Proteins; Reticulocyte Count; Reticulocytes; Treatment Outcome

Premature infants, especially those with birth weights of <1500 g, often suffer from anemia of prematurity and associated problems. Erythropoietin therapy is a safe effective way to prevent and to treat anemia of prematurity. We hypothesized that combined administration of vitamin B12 and folate with erythropoietin and iron would enhance erythropoietin-induced erythropoiesis.. In a randomized, controlled trial, 64 premature infants (birth weight: 801-1300 g) receiving erythropoietin and iron supplementation were assigned randomly to receive either vitamin B12 (3 microg/kg per day) and folate (100 microg/kg per day) (treatment group) or a lower dose of folate (60 microg/kg per day) (control group).. During the 4-week observation period, vitamin B12 and folate enhanced erythropoietin-induced erythropoiesis significantly, as indicated by a 10% increase in red blood cell counts, compared with folate alone. Hemoglobin and hematocrit levels remained stable in the treatment group, whereas they decreased in the control group. Vitamin B12 levels in the treatment group increased over baseline and control values, whereas red blood cell folate levels were comparable between the groups. Subsequent analysis showed slight nonsignificant differences in baseline red blood cell count, hemoglobin level, hematocrit level, and mean corpuscular volume values, which must be addressed as a limitation.. With the limitation of a slight imbalance in baseline data between the study groups, combined therapy with vitamin B12, folate, erythropoietin, and orally and intravenously administered iron seemed more effective in stimulating erythropoiesis among premature infants, compared with erythropoietin, iron, and low-dose folate alone. Additional trials are necessary to confirm these data.

Topics: Anemia, Neonatal; Blood Transfusion; Drug Therapy, Combination; Erythrocyte Indices; Erythropoiesis; Erythropoietin; Folic Acid; Gestational Age; Hematocrit; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Parenteral Nutrition; Vitamin B 12; Vitamin B Complex

To determine the effectiveness of a 10-day subcutaneous erythropoietin (rHuEpo) course of 300 units per kg per dose plus oral iron compared to oral iron alone in anemic infants during their convalescent phase of illness.. Prospective, randomized trial performed at a 40-bed, teaching, referral, level III, neonatal intensive care unit. Infants with a gestational age at birth of less than 32 weeks, hematocrit of less than or equal to 28% with a corrected reticulocyte count of less than or equal to 5%, postconceptual age of less than 48 weeks or 5 months chronological age, and a diagnosis of anemia of prematurity were considered for inclusion. Major outcome parameters included hematocrit, corrected reticulocyte count and red cell transfusion requirements.. A total of 60 infants were enrolled (n=30 per group). Infants randomized to rHuEpo had a significantly higher post-treatment hematocrit and corrected reticulocyte count than infants in the iron only group (p<0.001). There was a trend towards fewer red cell requirements in the rHuEpo group.. The rHuEpo regimen studied here was associated with an acute improvement in hematocrit and corrected reticulocyte counts. This study did not demonstrate a statistically significant decrease in transfusion therapy, in part related to increased subsequent use of rHuEpo in the control group. Taken together, these data demonstrate that this regimen can effectively treat anemia in convalescent premature infants.

Topics: Anemia, Neonatal; Convalescence; Drug Administration Schedule; Epoetin Alfa; Erythrocyte Transfusion; Erythropoietin; Hematinics; Hematocrit; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Injections, Subcutaneous; Prospective Studies; Recombinant Proteins; Reticulocyte Count; Treatment Outcome

Erythropoietin (Epo) is frequently administered to premature infants to stimulate erythropoiesis. There is evidence from studies in animals and healthy adults that Epo also interacts with thrombopoiesis and platelet function. This study investigates the effect of Epo therapy on platelet reactivity, peripheral platelet counts and thiazole orange-positive (TO+) platelets in extremely low birth weight (ELBW) infants. In a randomised-controlled trial, ELBW infants with a birth weight < or =800 g and a gestational age < or =32 weeks were either randomised to a group receiving Epo during the first weeks of life or to a control group. Our results show that thrombin receptor-activating peptide (TRAP-6) -induced expression of P-selectin increased significantly during the first two weeks of Epo treatment. With the exception of week five, the number of TO+ platelets was significantly higher during the first eight weeks in Epo-treated infants compared to controls. The increase of TO+ platelets was not paralleled by an increase in total platelet count. We can conclude that Epo therapy has a short-lasting effect on platelet reactivity toTRAP-6 in ELBW infants during the first two weeks of life. Furthermore, Epo therapy is associated with an increase in the number of TO+ platelets compared to controls.

Topics: Anemia, Neonatal; Blood Transfusion; Erythropoietin; Humans; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Platelet Activation; Platelet Function Tests; Reticulocyte Count; Thrombopoiesis

This study aimed to detect the effectiveness of recombinant human erythropoietin therapy in preventing premature anemia in low-birthweight preterm infants.. A total of 292 premature infants who were born earlier than 33 gestational weeks and smaller than 1500 g birthweight were enrolled into the study. In addition to their conventional supportive therapy (medications), recombinant human erythropoietin 200 U/kg twice a week, subcutaneously, was given to randomly selected 142 premature infants for 6 weeks. The blood count variables and need for transfusions were compared with the remaining 150 premature infants during 6 months follow up.. Serum erythropoietin levels were 11.3 +/- 6.1 mU/mL and 38.3 +/- 19.1 mU/mL in the erythropoietin group before and at the fourth week of the study, respectively (P < 0.001). Reticulocyte counts of the group treated with erythropoietin were 146 x 10(6) +/- 28 x 10(6)/mL and 122 x 10(6) +/- 27 x 10(6)/mL at the fourth and seventh week of the study, respectively, and these values were significantly higher when compared with the control group (P < 0.001 and P < 0.001). At the same period, hematocrit values were also found to be higher in the treatment group than the control group (P < 0.001). Serum ferritin levels were lower in the treatment group compared with the control group at the fourth week of the study. No side-effects related to erythropoietin usage were encountered. The need for packed cell transfusions were 47% in the group treated with erythropoietin and 62.6% in the control group. A statistically significant difference was found for transfusion needs between the control and treatment groups (P < 0.001).. Recombinant erythropoietin is effective therapy for maintaining stable hematocrit levels in low-birthweight preterm infants and prevents the need for blood transfusions.

Topics: Anemia, Neonatal; Erythropoietin; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Prospective Studies; Recombinant Proteins

Premature infants<1500 g were randomly assigned to study and control groups. In the study group, 42 premature infants received recombinant human erythropoietin (r-Hu EPO) 750 U/kg per week subcutaneously from day 5 to 40 and enteral iron supplementation of 2 to 6 mg/kg/d beginning on day 14 provided that they were receiving at least 50% energy intake orally. In the control group, 51 infants received the same dose of enteral iron supplementation beginning at the end of the fourth week. At the end of a 12-week monitoring period, r-Hu EPO combined with early enteral iron reduced transfusion needs only in the subgroup<1000 g. r-Hu EPO and early iron treatment had no effect on the development of severe retinopathy of prematurity, intraventricular hemorrhage, necrotizing enterocolitis, and bronchopulmonary dysplasia. We suggest that r-Hu EPO combined with early enteral iron is both effective and safe in infants<1000 g.

Topics: Anemia, Neonatal; Child Development; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Female; Follow-Up Studies; Humans; Infant Mortality; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Injections, Subcutaneous; Male; Recombinant Proteins; Risk Assessment; Treatment Outcome

It is not known whether a moderate dose of oral iron supplementation would further enhance erythropoiesis in recombinant human erythropoietin (EPO)-treated very low-birthweight (VLBW) infants.. In total, 24 preterm infants with birthweights 750-1499 g were enrolled at the age of 14-28 days to receive 400 IU/kg per week EPO subcutaneously for 8 weeks. The infants were randomly allocated either to receive oral iron supplementation 4 mg/kg per day or to serve as controls.. Hemoglobin and the absolute reticulocyte count in the iron supplementation and the control groups remained identical throughout the study period, whereas serum ferritin was significantly lower in the control group at study exit and follow up. Rates of treatment success (no need for transfusion and hemoglobin never below 8 g/dL) also did not differ between the groups.. In this study we did not find a clear advantage in a moderate dose of oral iron supplementation on erythropoiesis in EPO-treated VLBW infants. Whether a higher dose would lead to enhanced erythropoiesis remains to be answered.

Topics: Administration, Oral; Anemia, Neonatal; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Erythropoietin; Female; Ferric Compounds; Ferritins; Follow-Up Studies; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Injections, Subcutaneous; Male; Probability; Recombinant Proteins; Reticulocyte Count; Risk Assessment; Severity of Illness Index; Treatment Outcome

To evaluate the effects of vitamin E supplementation on haemoglobin concentration and the requirement for transfusion in premature infants treated with erythropoietin and iron.. Randomised, double blind, placebo controlled trial. Thirty infants

Topics: Anemia, Neonatal; Double-Blind Method; Erythrocyte Transfusion; Erythropoietin; Hemoglobins; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Iron; Recombinant Proteins; Reticulocyte Count; Treatment Failure; Vitamin E

The purpose of this study was to evaluate the effectiveness of early treatment with erythropoietin (EPO) in two different treatment regimes (high vs. low dose) in comparison to the conventional treatment of packed red blood cell (PRBC) transfusions in the management of anaemia of prematurity in a country with limited resources. An open controlled trial was conducted on 93 preterm infants (7 days postnatal age, 900-1500 g birthweight). Patients were randomly assigned either to a low dose (250 IU/kg), a high dose (400 IU/kg), or a control group. EPO was administered subcutaneously three times a week and all infants received 6 mg/kg iron orally from study entry to endpoint of therapy. Haematological parameters were measured and compared. The success was defined as an absence of transfusions and a haematocrit that did not fall below 30 per cent during the time period that the infants were in the study. The three groups were statistically comparable at study entry with respect to gestational age, birthweight, Apgar scores, and haematological values. Over the period that the infants were in the study, 75 per cent of the low dose group and 71 per cent of the high dose group met the criteria for success compared with 40 per cent in the control group (p < 0.001). However, there was no significant difference in the number of transfusions when the low and high EPO dose groups (9.5 per cent) were combined and compared with the control group (26.7 per cent) p = 0.0587. It was concluded that in stable infants, 900-1500 g, where phlebotomy losses are minimized and stringent transfusion guidelines are adhered to, EPO does not significantly decrease the number of transfusions. A conservative approach in the management of anaemia of prematurity, is a viable alternative in areas with limited resources.

Topics: Anemia, Neonatal; Chi-Square Distribution; Developing Countries; Dose-Response Relationship, Drug; Erythrocyte Transfusion; Erythropoietin; Female; Follow-Up Studies; Humans; Infant, Newborn; Infant, Premature; Injections, Subcutaneous; Male; Probability; Recombinant Proteins; Reference Values; South Africa; Treatment Outcome

To identify the effect of early parental recombinant human erythropoietin and iron administration on the blood transfusion requirement of premature infants.. In a controlled clinical trial conducted at the neonatal intensive care unit of Al-Hada Military Hospital, Taif, Kingdom of Saudi Arabia over a 16 months period, we assigned 20 very low birth weight infants with gestational age of (mean +/- standard error of mean) 28.4 +/- 0.5 weeks and birth weight of (mean +/- standard error of mean) 1031 +/- 42 gm, to receive either intravenous recombinant human erythropoietin 200 U/kg/day and iron 1mg/kg/day or conventional therapy over a 21 day study period. Blood transfusion administration undergoes a strict protocol in our nursery.. During the 3 week study period, the hemoglobin and hematocrit remained similar in the 2 groups while the reticulocyte counts were greater in the recombinant human erythropoietin recipients on day 14. The number and volume of blood transfusions were similar in both groups.. Very low birth weight infants receive fewer blood transfusions than the number previously reported. Strict phlebotomy and transfusion criteria could minimize the need for human recombinant erythropoietin.

Topics: Anemia, Neonatal; Blood Transfusion; Drug Therapy, Combination; Erythropoietin; Female; Humans; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Infusions, Intravenous; Iron; Male; Recombinant Proteins; Saudi Arabia

To investigate the effect of early erythropoietin treatment on induction of erythropoiesis and the need for transfusion in Very Low Birth Weight (VLBW) infants with acute neonatal problems.. The study group consisted of 14 VLBW prematures with gestational ages less than 32 weeks who were given subcutaneous erythropoietin (600 U/kg per week) and oral iron (3 mg/kg per day) during the first 7-8 weeks of their life, while 13 other VLBW prematures that were given placebo constituted the control group. Weekly hematocrit, (Hct) reticulocyte (Ret) values and the volume of blood drawn and transfused were recorded in the both groups.. The groups were comparable regarding with birth weights and gestational ages. The volume of the blood drawn (76.8 +/- 42.5 and 37.0 +/- 15.2) was higher and the volume of the transfusions (51.84 +/- 49.30 and 68.84 +/- 41.2) was lower in the study group but the differences between the groups were not significant (p>0.05). The hematocrit, the reticulocyte and the ferritin values were similar in both the groups at the end of the therapy.. Under the neonatal intensive care circumstances of developing countries where blood volumes needed for laboratory analysis are still very high, phlebotomy losses can not be avoided. Thus early erythropoietin and iron therapy at these doses are not effective in decreasing the need for transfusion and induction of endogenous erythropoiesis.

Topics: Anemia, Neonatal; Blood Transfusion; Erythropoietin; Gestational Age; Hematocrit; Humans; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Injections, Subcutaneous; Iron; Recombinant Proteins; Time Factors; Treatment Outcome

To investigate whether recombinant erythropoietin (rhEPO) reduces the need for transfusion in extremely low birth weight (ELBW) infants (birth weight 500-999 g) and to determine the optimal time for treatment.. In a blinded multicenter trial, 219 ELBW infants were randomized on day 3 to one of 3 groups: early rhEPO group (rhEPO from the first week for 9 weeks, n = 74), late rhEPO group (rhEPO from the fourth week for 6 weeks, n = 74), or control group (no rhEPO, n = 71). All infants received enteral iron (3-9 mg/kg/day) from the first week. The rhEPO beta dose was 750 IU/kg/week. Success was defined as no transfusion and hematocrit levels never below 30%.. Success rate was 13% in the early rhEPO group, 11% in the late rhEPO group, and 4% in the control group (P =.026 for early rhEPO versus control group). Median transfusion volume was 0.4 versus 0.5 versus 0.7 mL/kg/day (P =.02) and median donor exposure was 1.0 versus 1.0 versus 2.0 (P =.05) in the early rhEPO group, the late rhEPO group, and the control group, respectively. Infection risk was not increased and weight gain was not delayed with rhEPO beta.. Early rhEPO beta treatment effectively reduces the need for transfusion in ELBW infants.

Topics: Anemia, Neonatal; Blood Transfusion; Cross Infection; Double-Blind Method; Erythropoietin; Europe; Female; Hematocrit; Humans; Infant, Newborn; Infant, Very Low Birth Weight; Iron; Male; Proportional Hazards Models; Recombinant Proteins; Statistics, Nonparametric; Survival Rate; Time Factors

Topics: Anemia, Neonatal; Double-Blind Method; Erythropoietin; Humans; Infant, Newborn; Infant, Premature, Diseases; Recombinant Proteins; Treatment Outcome

To assess whether a high intake of oral iron would increase the effect of recombinant human erythropoietin (rHuEPO) on hemoglobin synthesis.. 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 microg/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.. 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 microg/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).. 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.

Topics: Administration, Oral; Analysis of Variance; Anemia, Neonatal; Drug Synergism; Erythropoietin; Female; Ferritins; Hematocrit; Humans; Infant, Newborn; Infant, Premature, Diseases; Iron; Male; Recombinant Proteins

Infants of

Topics: Anemia, Neonatal; Blood Transfusion; Child Development; Erythropoiesis; Erythropoietin; Female; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Iron; Male; Placebos

Topics: Anemia, Neonatal; Erythropoietin; Ferrous Compounds; Gestational Age; Humans; Infant, Newborn; Recombinant Proteins; Treatment Outcome

The administration of recombinant human erythropoietin (rHuEPO), started after the first 2 weeks of life, reduces the transfusion requirement in premature infants. However, its use throughout the first 2 weeks of life, when anemia results predominantly from phlebotomy losses, remains controversial. We investigated whether early use of rHuEPO would reduce the total transfusion requirement and/or the number of transfusions throughout the first 2 weeks of life.. We randomized 114 infants with birth weight (BW) <1250 g to receive rHuEPO (1250 units/kg/week; IV; early group: n = 57) or placebo (late group: n = 57) from day 2 to day 14 of life; subsequently, all the patients received rHuEPO (750 units/kg/week, subcutaneously) for 6 additional weeks. All infants were given oral iron (6 mg/kg/day) and folic acid (2 mg/day).. The early group showed higher hematocrit and reticulocyte counts than the late group in the first 3 weeks of life, but there was no difference in the total number of transfusions (early: 1.8 +/- 2.3 vs late: 1.8 +/- 2.5 transfusion/patient) or the transfusion requirement throughout the first 2 weeks of life (early:.8 +/- 1.1 vs late:.9 +/- 1.3) could be demonstrated. In infants with BW <800 g and total phlebotomy losses >30 mL/kg (n = 29), a lower number of transfusions was received by infants in the early group, compared with late group, from the second week to the end of the treatment (early: 3.4 +/- 1.1 vs late: 5.4 +/- 3.7 transfusion/patient). No clinical adverse effects were observed. Thrombocytosis was detected during the treatment with rHuEPO in 31% of the infants.. In the whole population, the early administration of rHuEPO induced a rise of reticulocyte counts, but not enough to reduce the transfusion requirement. The most severely ill infants (BW <800 g and phlebotomy losses >30 mL/kg) seemed to benefit from early use of rHuEPO, and this deserves additional study.

Topics: Anemia, Neonatal; Blood Transfusion; Erythropoietin; Humans; Infant, Newborn; Infant, Premature, Diseases; Iron; Recombinant Proteins; Time Factors

The aim of this study was to investigate the effect of recombinant human erythropoietin (rHu-EPO) on oxygen affinity and adequate oxygen delivery to the tissues of stable premature infants. 36 very-low-birth-weight infants were randomly assigned to either receive rHu-EPO (200 units/kg every other day) or not, and both groups were supplemented with iron, folic acid and vitamin E. Arterial blood gases, oxygen saturation, complete blood counts, fetal haemoglobin, 2,3-diphosphoglycerate (2,3-DPG) and blood lactate were analysed weekly, from the 1st week till discharge. Patients in the two groups were comparable. There was a trend in increasing lactate values towards the 4th to 5th weeks of life, which did not reach statistical significance. There was no correlation between lactate values and the studied variables (pH, BE, oxygen saturation). In 35 transfusions, pre- and 24 h post-transfusion blood lactate status was studied. In 23 of them, a decrease in post-transfusion lactate was noticed, whilst an increased post-transfusion level was shown in 10 cases and no change in 2 cases. The mean pre-transfusion lactate value was significantly higher than the post-transfusion one (24.04 +/- 11.9 mg/dl before and 16.27 +/- 8.5 mg/dl after transfusion; p = 0.0025). In both groups there was a steady rise in 2,3-DPG concentration over the period of study, and the 2,3-DPG values at the end of our study were significantly increased in the rHu-EPO group (rHu-EPO 5.98 +/- 0.9, control 4.84 +/- 0.7; p = 0.04). In conclusion, the use of rHu-EPO did not affect blood lactate levels compared to the control group. Regarding oxygen affinity, it seems that rHu-EPO causes a shift of the oxy-haemoglobin dissociation curve to the right. This is a previously unreported effect of rHu-EPO and its clinical use may, thus, confer to preterm babies an added advantage.

Topics: 2,3-Diphosphoglycerate; Anemia, Neonatal; Blood Transfusion; Erythropoietin; Fetal Hemoglobin; Humans; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Lactic Acid; Prospective Studies; Recombinant Proteins

Anemia is common among very low birth weight newborns and requires frequent blood transfusions. Erythropoietin was been reported to be useful in the prevention of this anemia.. To assess the benefits of early (before the third week of life) Human recombinant Erythropoietin (r-EPO) administration to reduce the requirement of blood transfusions in very low birth weight newborns.. Sixty newborns under 1500 g of birthweight were randomly assigned to receive r-EPO (n = 29) or placebo (n = 31) three times per week, during four weeks. Packed red cell volume and reticulocyte counts were measured weekly. Serum erythropoietin was measured prior to eighth dose. Transfusion requirements were recorded.. r-EPO reduced transfusions from 1.41 +/- 1.1 to 0.69 +/- 1 transfusions/newborns (p < 0.001). At the fourth week of treatment, reticulocyte count was 14.8 +/- 7 and 6.4 +/- 4.9% in the active treatment group and placebo group respectively (p < 0.001).. r-EPO reduces the requirement of transfusions in low birth weight infants.

Topics: Anemia, Neonatal; Blood Transfusion; Double-Blind Method; Erythropoietin; Female; Humans; Infant, Low Birth Weight; Infant, Newborn; Male; Recombinant Proteins; Time Factors

The in vivo influence of recombinant human erythropoietin (rhEpo) and iron on human neutrophil (PMN) antimicrobial function was assessed. A total of 21 preterm infants were randomized to receive either 200 U/kg/other day of rHuEPO+12 mg/kg/day of iron (EPO+high Fe, seven infants) or 200 U/kg/other day of rhEPO+4 mg/kg/day of iron (EPO+standard Fe, 9 infants) or 4 mg/kg/day of iron only (standard Fe, five infants). PMNs were isolated from blood of these infants 60+/-5 days after birth and from eight healthy adults. No differences between infants and adults were found in PMN random migration and chemotactic activity to N-formylmethionyl leucyl phenylalanine (FMLP), superoxide anion production in response to FMLP and phagocytosis of Staphylococcus aureus. In contrast, percentage phagocytosis was significantly lower in EPO+standard Fe as compared to both EPO+high Fe and standard Fe groups (P<0.01). This modest impairment of phagocytic activity of neonatal PMNs found in association with administration of rhEPO and standard iron may be related to consumption of iron during rhEPO-enhanced erythropoiesis.

Topics: Age Factors; Anemia, Neonatal; Cell Count; Chemotaxis, Leukocyte; Erythropoietin; Humans; Infant, Newborn; Iron; Neutrophils; Phagocytosis; Recombinant Proteins; Respiratory Burst

A few years ago recombinant human erythropoietin (rh-EPO) has been introduced for the prophylaxis of anaemia of prematurity. Aim of this controlled study was a cost-effectiveness analysis of the prophylaxis with rh-EPO versus sole transfusion with packed red blood cells. In the study group 33 infants (gestational age 30 +/- 2 weeks, birthweight 1217 g +/- 244 g) were treated with rh-EPO beginning on the fifth day of life for a six week period. They received 750 IE rh-EPO/kg/week and transfusion with packed red blood cells when indicated. In the historic control group 33 infants (gestational age 29.2 +/- 1.9 weeks, birthweight 1181 g +/- 205 g) did not receive rh-EPO, patients were only transfused. Indication and guidelines for transfusion were identical for both groups. The number of transfusions was registered after 2 and 4 weeks of life and by the time of hospital discharge. The cost analysis was carried out by using current prices for packed red blood cells including material and processing and prices for rh-EPO (Neo-Recormon, Boehringer Mannheim). Infants in the study group received 1.39 +/- 1.94 transfusions per patient while patients in the control group needed 2.7 +/- 1.93 transfusions per patient (p < 0.05). Cost for treatment was slightly increased in the study group (DM 536,- vs. DM 459,-). Prophylaxis of anaemia of prematurity with recombinant human erythropoietin proved to be effective. Compared with sole blood transfusion treatment, expenses for the prophylaxis with rh-EPO were only little higher.

Topics: Anemia, Neonatal; Cost-Benefit Analysis; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythrocyte Transfusion; Erythropoietin; Female; Humans; Infant, Newborn; Infant, Premature, Diseases; Male; Recombinant Proteins

There is no consensus regarding protein intake and the doses of recombinant human erythropoietin (r-HuEpo) and iron in the treatment of anaemia of prematurity (AOP). This open, randomized study has compared the effectiveness of 50 IU r-HuEpo/kg with that of 100 IU/kg, both given subcutaneously thrice weekly. In addition, two different protein supplements have been compared; lyophilized human milk protein and a commercial cow's milk product. Total protein intake was 3 g/kg per day. Daily iron dose was 18-36 mg. "Healthy" preterm infants (n = 32, birth weight: 800-1400 g, gestational age < or = 31 weeks) were studied from age 3 to 8 weeks. The two protein regimens yielded no differences in body growth, reticulocyte count or Hb concentration. In both r-HuEpo dose groups increased number of reticulocytes followed start of treatment; higher levels were, however, found in the group receiving 100 IU/kg. Mean Hb concentration plateaued at 12 g/dl for infants receiving 100 IU/kg, at 11 g/dl in the 50 IU/kg group. Even though serum levels of ferritin and transferrin saturation indicated no iron deficiency, soluble transferrin receptor increased in both groups, more rapidly and to higher levels in the 100 IU/kg group. In addition, the number of infants having more than 8% hypochromic red cells increased in both groups.. Commercial cow's milk protein added to human milk was as good as human milk protein supplementation in supporting growth and erythropoiesis. Fifty IU/kg r-HuEpo thrice weekly during AOP stimulated erythropoiesis significantly, but less so than 100 IU/kg. Even when using high oral doses of iron to preterms receiving r-HuEpo, our data suggested a certain degree of iron deficient erythropoiesis.

Topics: Anemia, Neonatal; Animals; Combined Modality Therapy; Dietary Proteins; Erythropoiesis; Erythropoietin; Female; Growth; Hemoglobins; Humans; Infant Nutritional Physiological Phenomena; Infant, Newborn; Infant, Premature; Iron; Linear Models; Logistic Models; Male; Milk; Milk, Human; Receptors, Transferrin; Recombinant Proteins; Reticulocyte Count

Topics: Anemia, Neonatal; Double-Blind Method; Erythrocyte Transfusion; Erythropoietin; Humans; Infant, Newborn; Pilot Projects; Recombinant Proteins

The purpose of this study was to test the therapeutic effect of human recombinant erythropoietin (rH-EPO) on anemia of prematurity.. Fifty-eight preterm infants less than 34 weeks of gestational age from three different hospitals were studied. Transfusional policies were similar in all three centers. Infants with ABO or Rh incompatibility were excluded. At 28 days after birth, 28 infants (48.3%) had hemoglobin levels under 10.5 g/dL and were randomized to receive rH-EPO or standard care. Those infants ascribed to the treatment group received 200 U/kg of body weight of rH-EPO subcutaneously once a day, three days a week for 4 weeks together with oral supplements of ferrous sulfate at a dosage of 4 mg/kg/day. Both groups received daily doses of 50 micrograms of folic acid and 5U of vitamin E per os. Erythropoietin and ferritin were determined at randomization and at 60 days of age. Hemoglobin, reticulocytes, leucocytes, granulocytes and platelets were measured once a week, from the beginning of the treatment until 60 days of age.. At randomization into treatments, there were no significant differences between the groups with respect to weight, gestational age, hemoglobin (9.42 +/- 0.73 vs 9.26 +/- 0.68 g/dL), reticulocytes (61.7 +/- 32.2 vs 68.0 +/- 61.0 x 10(9)/L), ferritin, EPO1 leucocytes or platelets. At 60 days of age, the treatment group showed higher hemoglobin values (10.5 +/- 1.73 vs 9.1 +/- 1.0 g/dL, p < 0.05). There were no significant differences between reticulocyte counts (176.4 +/- 91.1 vs 112.6 +/- 85.0 x 10(9)/L), granulocytes (2,351 +/- 868 vs 2,075 +/- 856 x 10(9)/L), platelets (400 +/- 138 vs 316 +/- 164 x 10(9)/L) or ferritin (209 +/- 177 vs 393 +/- 328 micrograms/mL). Of the infants in the nontreated group, 13.3% received blood transfusions between 30 and 60 days of age, while only 6.7% of the treatment group did (p = 0.31).. We have been able to find 11 controlled studies in the medical literature which deal with the clinical usage of rH-EPO in newborns. Six use the hormone in an early phase and 5 in a posterior one. Our study should be included in the later and, as happens in most of them, demonstrates the efficacy of rH-EPO in the treatment of late anemia of the preterm newborn as shown by an increment in the hemoglobin levels and a trend towards the diminution in the use of blood transfusions. We have not observed substantial adverse effects.

Topics: Anemia, Neonatal; Erythropoietin; Humans; Infant, Newborn; Infant, Premature, Diseases

To examine the effect of protein intake on the erythropoietic response of very low birth weight infants to treatment with recombinant human erythropoietin (rHuEPO).. Twenty very low birth weight infants were enrolled in the study and 19 completed the 6 weeks of study. Weekly absolute reticulocyte counts, protein intakes, and growth, as well as selected markers of protein metabolism--prealbumin, albumin, and transferrin--were analyzed. Iron stores were estimated for each infant to exclude iron deficiency as a cause of anemia. The relationship between protein intake and absolute reticulocyte count was evaluated with a linear breakpoint analysis to account for any plateau in the relationship at higher protein intakes.. Adequate iron stores were present in all infants, and transferrin concentrations correlated with measured total iron-binding capacity (r = 0.95, p = 0.0001). In the rHuEPO-treated infants, absolute reticulocyte count was significantly associated with protein intake up to 3.1 gm/kg per day and extending to 3.5 gm/kg per day (p = 0.041 to 0.032); beyond this point there was no longer any effect. Moreover, in comparison with the infants who received placebo, the rHuEPO-treated infants had a better daily percent weight gain for a protein intake up to 3.5 gm/kg per day (p = 0.016).. In VLBW infants treated with rHuEPO, higher protein intake up to 3.1 to 3.5 gm/kg per day improved the erythropoietic response, and protein utilization for growth was improved. During treatment with rHuEPO, infants who receive adequate protein to achieve satisfactory growth also receive sufficient protein for erythropoiesis.

Topics: Anemia, Neonatal; Dietary Proteins; Double-Blind Method; Erythropoiesis; Erythropoietin; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Recombinant Proteins

In a double-blind placebo-controlled study we showed a 3-fold decrease in blood transfusions (BTFs) given to preterm infants with anaemia of prematurity who received recombinant erythropoietin. However, only 50% of placebo recipients required a BTF. Data from the placebo group indicated that either mean daily weight gain < or = 7.5 g/day before study entry or haematocrit < or = 50% at birth was associated with BTFs (P < 0.001). We calculated that giving erythropoietin to patients in the treatment group with either of these variables prevented 24 of 28 BTFs and that it would cost R184 to prevent 1 BTF. The cost of each BTF was R187 (blood filtered to remove white cells and reduce cytomegalovirus transmission). Therefore, the costs of the two treatments were similar, but as the risk of transmitting infection is lower with erythropoietin, we recommend its use in selected preterm infants.

Topics: Anemia, Neonatal; Blood Transfusion; Combined Modality Therapy; Cost-Benefit Analysis; Double-Blind Method; Erythropoietin; Humans; Infant, Newborn; Infant, Premature, Diseases; Recombinant Proteins; Treatment Outcome

The effect of recombinant human (r-Hu) erythropoietin (Epo) (300 IU/Kg per week for 4 weeks) was studied in healthy preterm infants (n = 14) fed human milk with additional milk protein and high doses of iron. The controls (n = 15) were in themselves a study group and were used to follow the natural course of anaemia of prematurity on such nutrition. Serum immunoreactive Epo (SiEpo) increased significantly 24 h after r-HuEpo injections (range 36 to > 128 mU/ml) and remained at these levels throughout the treatment period. r-HuEpo in such moderate doses kept haemoglobin above 11 g/dl. Bodyweight gain, protein and iron parameters indicated adequacy of dietary protein and iron. In controls, siEpo increased during the first weeks after nutritional supplementation, with a concommitant rise in reticulocyte count. At age 3 weeks, despite low siEpo levels, reticulocyte counts indicated active erythropoiesis. Following further moderate increases in siEpo, the reticulocyte count increased to high levels (7%). The reticulocyte response suggests that erythropoiesis in preterm infants is less dependent upon Epo levels than in adults.

Topics: Anemia, Neonatal; Combined Modality Therapy; Dietary Proteins; Erythropoietin; Ferrous Compounds; Growth; Humans; Infant; Infant, Newborn; Infant, Premature, Diseases; Recombinant Proteins; Reticulocyte Count

Erythropoietin (rHuEPO) therapy has been shown to be beneficial in preventing and treating anaemia of prematurity and to decrease the need for blood transfusions. There is, however, only scanty data on the effect of rHuEPO therapy on iron metabolism. We studied 29 preterm infants (age 34 +/- 14 days) who were randomly assigned to receive either rHuEPO 900 U kg-1 week-1 with 6 mg kg-1 day-1 of iron for 4 weeks (n = 15) or no therapy. The following parameters were evaluated and compared between and within groups at the beginning, during and at the end of the study: Haematocrit (SI), reticulocytes (10(9) micrograms l-1), serum ferritin (microgram 1-1) and iron (mumol l-1). The results were as follows. At the baseline, erythropoietin levels were similar in both groups: 7.2 +/- 5.6 versus 6.2 +/- 3.2 mU ml-1 (NS). In the treated infants the haematocrit remained stable during the study and was significantly higher than in the control group by the end of the study: 0.34 +/- 0.03 versus 0.28 +/- 0.05 (p = 0.001). rHuEPO therapy increased the reticulocyte count from 130 +/- 70 to 430 +/- 200 (p = 0.0002). However, rHuEPO therapy depleted both serum ferritin and iron levels from 321 +/- 191 to 76 +/- 58 micrograms l-1 (p = 0.04) and from 18 +/- 5 to 13 +/- 4 mumol l-1 (p = 0.03), respectively. We conclude that rHuEPO therapy prevented anaemia and its sequelae; however, serum ferritin and iron levels were depleted. We suggest that the effect of rHuEPO may be further increased by higher iron supplementation.

Topics: Anemia, Neonatal; Body Weight; Combined Modality Therapy; Erythropoietin; Ferritins; Ferrous Compounds; Hematocrit; Humans; Infant; Infant, Newborn; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Iron; Recombinant Proteins; Reticulocyte Count

To determine whether intravenously administered iron supplements would improve the hematologic response to recombinant erythropoietin in stable preterm infants.. Forty-two preterm infants (<33 weeks' gestation, birth weight < 1500 gm, hematocrit <38%) were treated with recombinant human erythropoietin (Eprex), 600 U/kg per week, and randomly assigned to receive either an oral preparation of ferrous lactate (elemental iron, 12 mg/kg per day) or an intravenous preparation of iron sucrose (6 mg/kg per week).. Hematocrits, reticulocyte counts, and transfusions were similar in the oral group (OG) and the intravenous group (IVG). However, markedly higher serum ferritin concentrations were noted in the IVG (p <0.001), and by completion of the study the arithmetic mean values were 265 +/- 127 microg/L versus 137 +/- 65 microg/L in the IVG and the OG, respectively. The numbers of hypochromic erythrocytes increased in both groups during the study but were significantly higher in the OG (p = 0.04). Mean daily weight gain in the IVG (27 +/- 6.4 gm/day) was greater than in the OG (22.9 +/- 4.78 gm/day; p = 0.04).. High doses of both orally administered iron and intravenously administered iron sucrose appear to supply sufficient iron for erythropoiesis in stable infants. Storage iron may become depleted after oral supplementation. The intravenous preparation appears to be safe and maintains serum ferritin concentrations, and it may be indicated for patients with low ferritin levels and for those not established on enteral feedings.

Topics: Administration, Oral; Anemia, Neonatal; Blood Cell Count; Blood Transfusion; Erythrocyte Count; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Ferric Compounds; Ferric Oxide, Saccharated; Ferritins; Ferrous Compounds; Glucaric Acid; Hematocrit; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Injections, Intravenous; Iron; Lactates; Male; Recombinant Proteins; Reticulocytes

Topics: Anemia, Neonatal; Dose-Response Relationship, Drug; Erythropoietin; Female; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Injections, Subcutaneous; Male; Prospective Studies; Recombinant Proteins; Treatment Outcome

Treatment with recombinant human erythropoietin (rHuEPO) stimulates erythropoiesis and reduces the need for transfusions in hospitalized preterm infants. The aim of our study was to follow very low birth weight infants after the initial 6 weeks of rHuEPO treatment.. We randomly assigned 97 very low birth weight infants with a gestational age of 31 weeks or less and birth weight of 1500 gm or less to receive rHuEPO, 300 units/kg per week (erythropoietin (EPO) 300, n = 33), rHuEPO, 750 units/kg per week (EPO 750; n = 28), or no treatment (control, n = 36). The rHuEPO was administered from the first week of life for 6 weeks. After EPO therapy was discontinued, 75 neonates were followed weekly until discharge and at 3, 6, and 12 months of age.. Mean numbers (+/- SD) of packed erythrocyte transfusions per patient from the time rHuEPO therapy was discontinued until discharge were 0.38 +/- 0.64 (EPO 300), 0.23 +/- 0.52 (EPO 750), 0.9 +/- 1.1 (control) (p < 0.05 in both EPO groups vs control). Mean reticulocyte counts at the sixth week were 6% +/- 2.2% (EPO 300), 6.9% +/- 2.2% (EPO 750), and 3.1% +/- 2.6% (control) in the three groups (p < 0.01 in both EPO groups vs control), and at the eighth week were 4.7% +/- 2.8% (EPO 300), 5.4% +/- 2.7% (EPO 750), and 2.6% +/- 2.2% (control) (p < 0.01 in both EPO groups vs control). Serum ferritin levels were significantly higher at the sixth week, and the percentage of hemoglobin F was significantly lower at 6, 8, and 10 weeks in the control group versus EPO groups. At 3, 6, and 12 months of age, there were no differences in reticulocytes, ferritin, HbF, and growth among groups.. Preterm infants who received rHuEPO had a normal pattern of erythropoiesis after the drug was discontinued. These data provide strong evidence that the anemia of prematurity is the result of a transient developmental abnormality in EPO production.

Topics: Anemia, Neonatal; Drug Administration Schedule; Erythropoiesis; Erythropoietin; Ferritins; Follow-Up Studies; Hematocrit; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature, Diseases; Recombinant Proteins; Time Factors; Treatment Outcome

Seventy premature infants (birthweight 1.75 kg or less, gestational age 33 weeks or less) with hemoglobin less than 10 g/dL and hematocrit less than 30% were studied and randomly divided into three groups. All of them received oral elemental iron 3 mg/kg/day and vitamin E 5 mg/kg/day during the study period. Recombinant human erythropoietin (rHuEPO) 150 U/kg was administered intravenously twice a week for 4 weeks in group A (26 infants). Infants in group A received a total of 4 erythrocyte transfusions because of frequent apnea. Infants in group B (25 infants) received erythrocyte transfusion when their hemoglobin levels was less than 10 g/dL with signs and symptoms (including tachycardia, tachypnea, poor feeding, apnea, poor weight gain) attributed to anemia or who had a hemoglobin less than 8 g/dL even if asymptomatic. Infants in group B received a total of 36 erythrocyte transfusions. Infants in group C (19 infants) were assigned to a non-rHuEPO and nontransfusion group. Three of the 19 premature infants in group C received erythrocyte transfusions later because of frequent and prolonged apneic episodes and were excluded from this study. Our data revealed that reticulocyte and serum erythropoietin values were higher (p < 0.01) in rHuEPO-treated group than transfusion group and hemoglobin and hematocrit values were lower in group C than the other two groups during the rHuEPO treatment period. No significant difference (p > 0.05) was found in neutrophil and platelet counts among these three groups. Serum ferritin values were found lower in the rHuEPO-treated group than the other two groups. Lower weight gain was found in infants in group C. We conclude that rHuEPO administration can reduce the need for blood transfusion. Poor weight gain can be found in infants with anemia of prematurity who do not receive rHuEPO or blood transfusion therapy.

Topics: Anemia, Neonatal; Erythrocyte Transfusion; Erythropoietin; Ferritins; Hematocrit; Hemoglobins; Humans; Infant, Newborn; Infant, Premature, Diseases; Iron; Leukocyte Count; Neutrophils; Platelet Count; Recombinant Proteins; Reticulocyte Count; Vitamin E

We evaluated the results of administering recombinant human erythropoietin (rHuEPO) and iron in 19 randomly selected premature infants, who had no infections, did receive oxygen support or aminophylline. rHuEPO was administered intravenously from days to 37 (biweekly) in a dose of 100 U/kg (group I) or 400 U/kg (group II). Also, infants in both groups were supplemented with 10 mg/kg/week of iron intravenously. Seven of 19 infants did not receive either rHuEPO or iron (group III). Infants of all groups had similar birth weights, gestational age and hematocrit, RBC count as well as total and fetal hemoglobin concentrations in blood obtained within the first hour of life. However, infants treated with 400 U/kg of rHuEPO required a significantly (p < 0.04) lower volume of packed erythrocytes in comparison to untreated infants, both between days 7 and 37 of life (18.6 ml vs 46.8 ml; p < 0.04) and between day 7 of life and the day of discharge (35.8 ml vs 94.2 ml; p < 0.04). No difference in neutrophil count, fetal hemoglobin concentration and no toxicity were observed in infants treated with rHuEPO in comparison to untreated prematures.

Topics: Anemia, Neonatal; Drug Administration Schedule; Erythropoietin; Humans; Infant; Infant, Newborn; Infant, Premature, Diseases; Injections, Intravenous; Iron; Recombinant Proteins

Anemia of prematurity is characterized by low reticulocyte counts and inadequate erythropoietin response, for which many very-low-birth-weight infants receive multiple blood transfusions. We investigated whether early treatment of such infants with recombinant human erythropoietin would reduce their need for transfusions.. We performed a controlled, blinded trial in 241 infants with very low birth weights at 12 centers in six European countries. When three days old, the infants were randomly assigned either to the epoetin group or to the control group. Those in the epoetin group received 250 IU of epoetin beta per kilogram of body weight subcutaneously three times a week from day 3 to day 42 (for a total of 17 doses); those in the control group did not receive this drug. Infants in both groups received oral iron (2 mg per day) from day 14 onward.. The control infants needed a mean of 1.25 transfusions each, as compared with 0.87 transfusion for epoetin-treated infants (P = 0.013). The median cumulative volume of blood transfused per kilogram per day was 0.41 ml in the control group (first quartile, 0 ml; third quartile, 0.8 ml) and 0.09 ml in the epoetin group (first quartile, 0 ml; third quartile, 0.8 ml) (P = 0.044). The rate of success, defined as an absence of need for transfusions and a hematocrit that never fell below 32 percent, was 4.1 percent in the control group and 27.5 percent in the epoetin group (P = 0.008). Epoetin was most beneficial in boys with birth weights of 1200 g or more and a base-line hematocrit of 48 percent or more. No toxic effects were observed in the epoetin group; as compared with the control group, the epoetin group had an increased incidence of septicemia (14 vs. 7 episodes, P not significant) and reduced weight gain (520 vs. 571 g, P = 0.02).. Infants with very low birth weights have less need of transfusions if given epoetin beta during the first six weeks of life (250 IU per kilogram three times a week). We recommend early epoetin treatment for all such infants, but further studies of nutrition and iron supplementation during treatment are needed.

Topics: Anemia, Neonatal; Blood Transfusion; Cost-Benefit Analysis; Erythropoietin; Female; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature, Diseases; Injections, Subcutaneous; Iron; Male; Recombinant Proteins; Treatment Outcome

To assess the efficacy of recombinant human erythropoietin (rHuEpo) in the treatment of the anemia of prematurity.. A double-blind, placebo-controlled study was conducted on 80 preterm infants (< or = 32 weeks; postnatal age, 2 to 8 weeks; central hematocrit < or = 35%). Patients were randomly assigned to receive subcutaneous rHuEpo (Eprex, 600 U/kg per week) or an equivalent volume of placebo, for up to 6 weeks. All patients received supplements of vitamin E (25 IU) and iron (3 mg/kg per day). The iron supplement was increased if declining serum ferritin measurements were noted.. Treatment and placebo groups did not differ significantly with respect to mean gestational age, birth weight, hematocrit, or reticulocyte count at study entry. Fewer transfusions were administered to those receiving erythropoietin (7 compared with 21; P = .002). Compared with the placebo group, the infants receiving rHuEpo had a higher mean hematocrit (32.3 +/- 4% vs 29.3 +/- 6.2%; P = .014) and absolute reticulocyte count (223 +/- 73 vs 124.9 +/- 73 x 10(9)/L; P < .001) at the end of the study. The mean neutrophil count was not significantly reduced at study exit (P = .8), nor at any other period during the trial in the rHuEpo group. Intercurrent events (mostly infections) were not increased in the treatment group, although there was one case of sudden infant death syndrome at age 4 months.. Using a dose of rHuEpo of 600 U/kg per week, this study has shown a clear reduction in the requirement for blood transfusion in preterm infants.

Topics: Anemia, Neonatal; Blood Cell Count; Blood Transfusion; Double-Blind Method; Erythropoietin; Hematocrit; Humans; Infant; Infant, Newborn; Infant, Premature, Diseases; Iron; Recombinant Proteins; Vitamin E

To evaluate the costs relative to the benefits of using recombinant human erythropoietin (rHuEPO) therapy as an alternative to red blood cell (RBC) transfusions in infants with anemia of prematurity.. A cost-benefit analysis of rHuEPO therapy was performed based on its use in very-low-birth-weight premature infants.. Data were drawn from published studies or were provided by the University of Iowa Hospitals and Clinics, Iowa City.. Costs and benefits were analyzed as a comparison of incurred costs to averted costs. Incurred and averted costs of rHuEPO therapy and RBC transfusions included direct product costs and estimates of costs of adverse events. The analysis was viewed in terms of net savings. Sensitivity analysis was performed.. The base case analysis yielded a net loss of $299.48 per infant. A 54% reduction in the direct product costs of rHuEPO therapy yielded a break-even point. No other variations in the sensitivity analysis resulted in a net savings.. Using assumptions based on the current state of clinical research, it appears that routine use of rHuEPO with supplemental RBC transfusions would not generate any cost savings as an alternative to RBC transfusions alone. As further evidence is compiled on the efficacy of rHuEPO therapy in very-low-birth-weight premature infants, the true costs may be better established.

Topics: Anemia, Neonatal; Costs and Cost Analysis; Delivery of Health Care; Drugs, Investigational; Erythrocyte Transfusion; Erythropoietin; Health Care Costs; Humans; Infant, Newborn; Infant, Premature, Diseases; Recombinant Proteins; Treatment Outcome

To assess whether erythropoietin (EPO) treatment is safe and reduces the need for transfusion, we randomized 44 preterm infants to an EPO group and a comparable control (CON) group. EPO 150 U/kg was given s.c. twice weekly for 6 wk from the 1st wk of life. Hematologic parameters, transfusion requirements, and growth were followed during therapy and for 6 mo thereafter. To better assess in which neonates EPO treatment was effective, we classified retrospectively the EPO and CON groups into uncomplicated neonates (EPO A: n = 9, birth weight = 1247 +/- 126 g, gestational age = 29.8 +/- 1.5 wk; CON A: n = 7, birth weight = 1217 +/- 145 g, gestational age = 29.9 +/- 1.5 wk) and neonates requiring artificial ventilation (EPO B: n = 16, birth weight = 1169 +/- 249 g, gestational age = 28.1 +/- 2 wk; CON B: n = 12, birth weight = 1173 +/- 215 g, gestational age = 28.3 +/- 2 wk). There were significant differences in reticulocytes between both uncomplicated and ventilated neonates in the EPO group compared with respective control groups. However, the need for transfusion was significantly less in the uncomplicated EPO group (EPO A: 0.44 +/- 0.73 versus CON A: 1.28 +/- 0.75, p < 0.05) but not in the neonates on ventilation (EPO B: 8.25 +/- 5 versus CON B: 7.75 +/- 3.7). In conclusion, early EPO administration reduces the need for transfusion in uncomplicated premature neonates.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Age Factors; Anemia, Neonatal; Blood Transfusion; Erythropoietin; Ferritins; Humans; Infant; Infant, Newborn; Infant, Premature; Recombinant Proteins; Reticulocyte Count

The effectiveness of recombinant human erythropoietin (r-HuEpo) in raising haemoglobin concentrations in very low birthweight infants was examined in a randomised multicentre study. Twenty nine 'healthy' appropriate for gestational age infants with birth weights 900-1400 g entered the study at 3 weeks of age. All infants received breast milk supplemented with 9 g/l human breast milk protein from 3 to 8 weeks of age. Eighteen mg iron was given daily from week 3 and was doubled if serum iron concentration fell below 16.0 mumol/l. Fourteen infants were randomised to receive 100 U/kg r-HuEpo subcutaneously three times a week from week 3 to week 7; 15 infants served as controls. After one week reticulocyte and haemoglobin concentrations were significantly higher in the r-HuEpo treated group and the haemoglobin values remained significantly higher throughout r-HuEpo treatment and at the concentrations observed in full term infants. No adverse effects were associated with the treatment. In stable very low birthweight infants with optimal iron and protein intakes, moderate dose r-HuEpo can produce significant gains in red cell production that may be clinically useful.

Topics: Anemia, Neonatal; Cell Count; Erythropoietin; Female; Hemoglobins; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Iron; Male; Proteins; Recombinant Proteins; Reticulocytes

The specific objectives of this study were (1) to assess the safety and efficacy of recombinant human erythropoietin (rhEPO) in reducing postnatal hemoglobin decline in premature infants of less than 33 weeks' gestation, and thus reducing the need for transfusion; and (2) to determine the optimal dosage of rhEPO.. Three groups of premature infants of less than 33 weeks' gestation were treated with rhEPO: group 1 (n = 10) received 300 U/kg per week; group 2 (n = 11), 600 U/kg per week; and group 3 (n = 10), 900 U/kg per week. These three groups were compared to a reference group of 20 infants of the same gestational age and birth weight. Treatment started on the 10th day of life and lasted 6 weeks. All infants were given oral iron and vitamin E supplements.. Treated infants had significantly higher reticulocyte counts, and the effect was dose dependent (P = .009). Postnatal decline of hemoglobin and hematocrit was lessened in the treated groups; the percent of decrease of hemoglobin and hematocrit was significantly reduced in the treated infants at 35 days of age (P = .0025 and P = .0036, respectively). The need for blood transfusion was also reduced in the rhEPO-treated groups: 19% of treated vs 45% of reference infants received transfusions, and the treated infants received less blood. Serum iron and transferrin saturation percentage dropped significantly during the study and a dose-dependent relationship in treated infants was displayed, suggesting high iron consumption (P = .0008 and P = .006, respectively). No dose effect on hemoglobin level and the need for blood transfusion was found, possibly because of the higher degree of illness severity and iron consumption in groups 2 and 3. No side effects related to rhEPO therapy were observed.. It is concluded that rhEPO therapy is safe in premature babies when given in the three dosages used in this study; in addition, it enhances erythropoiesis and reduces the need for blood transfusions. rhEPO therapy seems more efficient when given in higher dosages; however, illness severity and iron consumption represent major limiting factors. Controlled, randomized studies are warranted to confirm these data and to determine precise modalities and indications of rhEPO therapy in premature infants.

Topics: Anemia, Neonatal; Blood Transfusion; Dose-Response Relationship, Drug; Erythropoietin; Hematocrit; Hemoglobins; Humans; Infant, Newborn; Infant, Premature, Diseases; Iron; Pilot Projects; Recombinant Proteins

Twenty four infants between 27 and 33 weeks' gestation were recruited into a double blind study to investigate the use of recombinant human erythropoietin (r-HuEpo) for the prevention of anaemia of prematurity. Between 50 and 150 U of r-HuEpo (n = 16) or placebo was administered subcutaneously twice a week from 7 days of age until discharge. There was a significant increase in the reticulocyte count in infants receiving r-HuEpo sustained from the second week of treatment until discharge compared with placebo. There was a reduction in the number of transfusions required in the r-HuEpo group with only 47% requiring a transfusion compared with 87% in the placebo group. During treatment with r-HuEpo there was a significant rise in the red cell folate concentration, a significant fall in the ferritin concentration, and a significantly higher percentage of haemoglobin F at discharge suggesting active erythropoiesis. The study provides strong evidence for the efficacy of r-HuEpo in stimulating erythropoiesis and reducing the requirement for transfusions for anaemia of prematurity.

Topics: Anemia, Neonatal; Double-Blind Method; Drug Administration Schedule; Erythropoietin; Female; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Injections, Subcutaneous; Male; Recombinant Proteins

We randomly assigned eight concurrently symptom-free premature infants (birth weight less than or equal to 1250 gm) at high risk of requiring erythrocyte transfusions for anemia of prematurity to 6 weeks of intensive treatment with either subcutaneous recombinant human erythropoietin (r-HuEPO group) or a placebo (control group). Treatment with r-HuEPO was initiated at a dose of 100 units/kg per day 5 days a week, and was increased to 200 units/kg per day after 2 or 3 weeks if target reticulocyte counts were not achieved. All patients were given supplemental oral iron therapy at a dose of 6 mg/kg per day, as tolerated. Mean reticulocyte counts in r-HuEPO-treated and control infants were 64,600 versus 67,500 cells/mm3 at entry; were 245,600 versus 78,000 cells/mm3 after 1 week; and averaged 262,600 versus 136,400 cells/mm3 during the study. Mean reticulocyte counts in r-HuEPO-treated infants were 251,200 cells/mm3 during the week when r-HuEPO, 100 units/kg per day, was given, and were 269,500 cells/mm3 after the dose was increased to 200 units/kg per day. Mean hematocrit values at entry were 33.4% in babies who received r-HuEPO versus 33.6% in the control subjects, and were 31.4% in r-HuEPO-treated and 25.2% in the control subjects at the end of treatment. One r-HuEPO-treated and three control babies received transfusions during the study; the total volume of blood given was 17 ml in the r-HuEPO group and 101 ml in the control subjects. The percentage of hemoglobin F increased in infants not given transfusions. We conclude that r-HuEPO stimulates endogenous erythropoiesis in small premature babies who are receiving supplemental oral iron therapy. A controlled multicenter trial has been undertaken to confirm these promising preliminary observations.

Topics: Anemia, Neonatal; Blood Transfusion; Body Weight; Erythrocyte Transfusion; Erythropoiesis; Erythropoietin; Female; Fetal Hemoglobin; Hematocrit; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Iron; Leukocyte Count; Male; Neutrophils; Pilot Projects; Platelet Count; Random Allocation; Recombinant Proteins; Reticulocytes

The anemia of prematurity is defined by a progressive decline in hemoglobin level occurring over the first 2 months of life. Unlike term newborns whose "physiologic anemia" rarely if ever necessitates any treatment, preterm infants may become anemic enough to have clinical symptoms that indicate a need for red blood cell transfusions. Various factors contribute to the development of this anemia. Some of these factors, such as the short life span of erythrocytes in preterm infants, increased sensitivity of the erythrocytes to oxidative injury, and the blood losses caused by repeated phlebotomies, would normally be expected to induce corrective reticulocytosis. Characteristically, however, this anemia is hyporegenerative. Thus, it is associated with relative reticulocytopenia, low serum erythropoietin levels, and bone marrow erythroid hypoplasia. The recent availability of recombinant human erythropoietin has opened new perspectives in the management of a variety of anemias. Based on current knowledge of the regulation and pathophysiology of fetal and neonatal erythropoiesis, recombinant erythropoietin may represent a logical and efficient alternative to giving red blood cell transfusions in the treatment of the anemia of prematurity. Clinical trials have been initiated in several countries using different approaches and methodology. At this early stage these trials do not yet fully affirm that recombinant erythropoietin can be used as the first-line therapy in infants with the anemia of prematurity. Our own observations, however, suggest that this agent is well tolerated by preterm infants and may exert a corrective effect on the anemia of prematurity.

Topics: Anemia, Neonatal; Blood Cell Count; Blood Transfusion; Combined Modality Therapy; Drug Evaluation; Erythropoiesis; Erythropoietin; Hematocrit; Humans; Immunologic Factors; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Injections, Subcutaneous; Iron; Iron Deficiencies; Longitudinal Studies; Pilot Projects; Recombinant Proteins; Reticulocytes

To assess the risks and benefits of erythropoietin versus erythrocyte transfusion in the treatment of the anemia of prematurity, we randomly assigned 19 anemic preterm infants (birth weight 988 +/- 227 gm; gestational age 27.6 +/- 1.2 weeks; age 41 +/- 15 days; all values mean +/- SD) to receive either transfusion or subcutaneously administered erythropoietin (200 units/kg every other day for 10 doses). In the 10 erythropoietin recipients, corrected reticulocyte counts increased from 2% +/- 1% to 7% +/- 2% (p less than 0.001) and hematocrits increased from 27% +/- 2% to 30% +/- 4% (p less than 0.05). In the nine infants who underwent transfusion, reticulocyte counts did not increase, but hematocrits increased from 28% +/- 4% to 41% +/- 2% after initial transfusion (p less than 0.001) and had decreased to 34% +/- 5% by day 20. Signs attributed to anemia (tachycardia, apnea with bradycardia, and poor weight gain) declined in both the erythropoietin recipients and those who underwent transfusion. However, five of nine infants who underwent transfusion had symptoms within 10 to 14 days and were given further transfusions. Marrow aspiration performed after 7 to 10 days of treatment showed that infants receiving erythropoietin had greater percentages of erythropoietic precursors (p less than 0.01), greater concentrations of mature erythroid progenitors (p less than 0.001), and higher cycling rates of erythroid progenitors (p less than 0.001). The percentage of mature stored neutrophils in marrow was lower in the erythropoietin group than in the transfusion group, resulting in an inverse myeloid/erythroid ratio (0.5:1 vs 6.2:1; p less than 0.001). After 20 days, absolute blood neutrophil counts were lower in the erythropoietin recipients (1.8 +/- 0.9 x 10(3) cells/microliters) than in the infants who underwent transfusion (3.9 +/- 1.9 x 10(3) cells/microliters; p less than 0.05). Administration of erythropoietin thus stimulated erythropoiesis and relieved signs attributed to anemia; the significance of the relative neutropenia remains to be determined. We conclude that erythropoietin administration offers promise as an alternative to erythrocyte transfusion in neonates with symptomatic anemia of prematurity.

Topics: Anemia, Neonatal; Blood Cells; Blood Component Transfusion; Bone Marrow; Erythropoietin; Ferritins; Hematocrit; Hematopoietic Stem Cells; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Prospective Studies; Recombinant Proteins; Recurrence; Risk Factors

To study the safety and efficacy of administering human recombinant erythropoietin (rHuEPO) to infants with anaemia of prematurity, a combined phase I/II trial of weekly intravenous injections for 4 weeks was undertaken. We treated 16 infants with 10, 25, 50, 100 or 200 units/kg body weight in groups of two to four patients per dose level. They were all born prematurely (mean gestational age: 29 weeks; range 27-32), had a mean post-natal age of 42 days (range: 25-59) and haemoglobin concentration of 87 g/l (range: 72-94) when treatment was started. Four patients (25%) needed a transfusion during the trial, one at day 7 treated with 10 units/kg and 3 at days 15, 25, 29 with 100 units/kg. In the others, a progressive rise in mean haemoglobin values was seen in each group after 21 days of treatment, without a dose-dependent effect. A positive change in absolute reticulocyte counts with a peak after 7-14 days of therapy was observed with low (25-50 units/kg) but not with higher doses, with a significant difference at day 14 between 25 and 100 units/kg (P less than 0.01). A dose-limiting severe neutropenia (absolute neutrophil count less than 0.5 x 10(9)/l) occurred transiently in five patients, with doses greater than 25 units/kg. No infectious complication and no sign of iron deficiency were observed. Weekly low doses of rHuEPO appear safe, convenient to administer and able to induce a reticulocytic response in infants with anaemia of prematurity. A phase III placebo-controlled trial is needed to confirm these results. Neutropenia associated with rHuEPO administration in infants might be related to their stage of human ontogeny.

Topics: Anemia, Neonatal; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Evaluation; Erythropoietin; Humans; Infant; Infant, Newborn; Infant, Premature, Diseases; Injections, Intravenous; Iron; Neutropenia; Recombinant Proteins

Experimental and clinical data implicate inadequate erythropoietin production as an important reason that infants acquire this anemia and suggest that recombinant human erythropoietin (r-HuEPO) might be used to treat or prevent it. We therefore randomly assigned 20 small premature infants (birth weight less than or equal to 1250 gm) who were highly likely to require erythrocyte transfusions for anemia of prematurity to receive 6 weeks of treatment with either intravenously administered r-HuEPO (at a dose of 100 units/kg twice each week) or a placebo. Hematologic measurements, transfusion requirements, and growth were followed during therapy and for 6 months thereafter. Treated (EPO) and control babies did not differ with respect to weight, hematocrit, overall mean absolute reticulocyte count, calculated erythrocyte mass, or rate of growth. However, reticulocyte counts increased earlier in patients given r-HuEPO. Six of ten babies in the EPO group, and 8 of 10 assigned to the control group, received at least one erythrocyte transfusion during treatment. For all infants the amount of blood sampled for laboratory tests was strongly predictive of the volume of packed erythrocytes transfused (r = 0.890; p = 0.0001). Of nine infants who had less than 20 ml packed erythrocytes removed for laboratory tests, none of four given r-HuEPO received a transfusion, whereas three of five infants assigned to the placebo group received one. No toxic effects were attributable to r-HuEPO, and no significant changes in leukocyte or platelet counts occurred during treatment. Reticulocyte counts were correlated with simultaneous platelet counts and were inversely related to absolute neutrophil counts in both study groups. We conclude that r-HuEPO administration is safe and feasible at the dose studied. Additional controlled trials utilizing higher doses of r-HuEPO and larger numbers of patients are justified.

Topics: Anemia, Neonatal; Blood Transfusion; Erythrocyte Count; Erythropoietin; Female; Hematocrit; Humans; Infant, Newborn; Infant, Premature; Leukocyte Count; Male; Pilot Projects; Placebos; Platelet Count; Recombinant Proteins; Regression Analysis; Reticulocytes

To determine if trial-related blood sampling increases the risk of later red blood cell (RBC) transfusion in very preterm infants, we compared the volume of clinical- and trial-related blood samples, in a specific trial and correlated to subsequent RBC transfusion.. For 193 very preterm infants, participating in the FortiColos trial (NCT03537365), trial-related blood volume drawn was in accordance with ethical considerations established by the European Commission. Medical records were reviewed to assess the number and accumulated volume (mL/kg) of blood samples (both clinical- and trial-related). Data were compared with the need of RBC transfusions during the first 28 days of life.. Mean (SD) gestational age and birth weight was 28 ± 1 weeks and 1168 ± 301 g. In total, 11% of total blood volume was drawn for sampling (8.1 ± 5.1 mL/kg) and trial-related sampling accounted for 1.6 ± 0.6 mL/kg. Trial-related blood sampling had no impact on RBC transfusion (p = 0.9).. Clinical blood sampling in very preterm infants is associated with blood loss and subsequent need for RBC transfusions. In a specific trial requiring blood samples, we found no additional burden of trial-related blood sampling. The study suggests that trial-related sampling is safe if European criteria are followed.

Topics: Anemia, Neonatal; Erythrocyte Transfusion; Erythropoietin; Humans; Infant; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infant, Very Low Birth Weight

Retinopathy of prematurity (ROP) is a major morbidity in preterm infants causing visual impairment including blindness. Prevention and timely treatment are critical. We investigated the potential role of red blood cell (RBC) transfusions as risk factor for ROP development.. Retrospective cohort study of data from 68 tertiary level neonatal intensive care units in Germany. Preterm infants born at 22 + 0 to 28 + 6 weeks of gestation between January 2009 and December 2021 were enrolled.. We included n = 12 565 infants. Prevalence of any ROP was 49.2% with most infants being diagnosed with stage 1 (21.5%) and 2 disease (17.2%). ROP stage 3 was present in 10.2%, stage 4 in 0.3%, and ROP requiring treatment in 6.6%. Infants with ROP had significantly more frequently a history of RBC transfusions. Adjusting for confounders, RBC transfusions were associated with increased odds of ROP (OR 1.4, p < 0.001), ROP progression (OR 2.1, p < 0.01) and ROP requiring treatment (OR 3.6, p < 0.001). Restrictive transfusion approaches correlated with decreased (OR 0.7, p < 0.001), liberal regimes with increased odds (OR 1.2, p = 0.001).. The present study confirmed an association of RBC transfusions and ROP. Our findings emphasise the need for anaemia prevention and critical re-evaluation of transfusion practices in preterm infants.

Topics: Anemia, Neonatal; Erythrocyte Transfusion; Erythropoietin; Gestational Age; Humans; Infant; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Retinopathy of Prematurity; Retrospective Studies; Risk Factors

New biomarkers that predict later neurodevelopmental morbidity are needed. This study evaluated the associations between umbilical cord serum erythropoietin (us-EPO) and neurodevelopmental morbidity by the age of 2-6.5 years in a Finnish cohort.. This study included 878 non-anomalous children born alive in 2012 to 2016 in Helsinki University Hospitals and whose us-EPO concentration was determined at birth. Data of these children were linked to data from the Finnish Medical Birth Register and the Finnish Hospital Discharge Register. Neurodevelopmental morbidity included cerebral palsy, epilepsy, intellectual disability, autism spectrum disorder, sensorineural defects, and minor neurodevelopmental disorders.. In the cohort including both term and preterm children, us-EPO levels correlated with gestational age (r = 0.526) and were lower in premature children. High us-EPO levels (>100 IU/l) were associated with an increased risk of severe neurodevelopmental morbidity (OR: 4.87; 95% CI: 1.05-22.58) when adjusted for the gestational age. The distribution of us-EPO levels did not differ in children with or without the later neurodevelopmental diagnosis.. Although high us-EPO concentration at birth was associated with an increased risk of neurodevelopmental morbidity in early childhood, the role of us-EPO determination in clinical use appears to be minor.. We determined whether endogenous umbilical cord serum erythropoietin would be a new useful biomarker to predict the risk of neurodevelopmental morbidity. This study evaluated the role of endogenous erythropoietin at birth in neurodevelopmental morbidity with a study population of good size and specific diagnoses based on data from high-quality registers. Although high umbilical cord serum erythropoietin concentration at birth was associated with an increased risk of neurodevelopmental morbidity in early childhood, the clinical value of erythropoietin determination appears to be minor.

Topics: Anemia, Neonatal; Autism Spectrum Disorder; Child; Child, Preschool; Erythrocyte Transfusion; Erythropoietin; Female; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Morbidity; Neurodevelopmental Disorders

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.. This is a retrospective cohort study of infants discharged from 2008 to 2017 using the Pediatrix Clinical Data Warehouse.. 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.. 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.

Topics: Anemia, Neonatal; Drug Evaluation; Erythropoietin; Female; Gestational Age; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn; Infant, Small for Gestational Age; Intensive Care Units, Neonatal; Male; Neuroprotection; Retrospective Studies; United States

The majority of extremely low birth weight (ELBW) neonates receive red blood cell (RBC) transfusions; at least 50% receive multiple transfusions. Anemia care bundles could be the most effective approach to reduce transfusion rates. We conducted a quality improvement non-controlled before-and-after retrospective study involving 345 ELBW infants admitted over a 5-year period in two consecutive epochs before and after implementation of an anemia care bundle in January 2017. Bundle components included (a) prophylactic subcutaneous erythropoietin twice each week (600 IU/kg/week) from day 7 through 8 weeks of age and (b) blood sampling stewardship in the first five postnatal weeks. Early postnatal blood sampling losses were significantly reduced following the implementation of the care bundle (21.2 ml/kg vs 25 ml/kg, P < 0.001). We found a 50% reduction in the rate of multiple RBC transfusions (adjusted RR 0.45, 95% CI: 0.34-0.59) and a reduced odds of necrotizing enterocolitis (NEC) (4% vs 10%, adjusted OR 0.38 (95% CI: 0.15-0.78)) among infants that received the anemia care bundle (n = 182 infants). The overall transfusion rate, number and volume of transfusions, and multiple donor exposures were also significantly reduced.Conclusion: The combination of extended subcutaneous erythropoietin administration and reduced early postnatal blood sampling was associated with a significant reduction in the rate of multiple erythrocyte transfusions and NEC in ELBW neonates. What is known: • The majority of extremely low birth weight neonates continue to require blood transfusions despite advances in standardized transfusion practices; at least 50% require multiple transfusions. • Anemia care bundles, employing a combination of anemia prevention strategies, can effectively reduce the RBC transfusion rates in ELBW infants. What is new: • A combination of extended subcutaneous erythropoietin supplementation and blood sampling stewardship practices reduced the rate of multiple RBC transfusions in ELBW neonates by 50%. • Implementation of the anemia care bundle was associated with a significant reduction in the rates of necrotizing enterocolitis.

Topics: Anemia, Neonatal; Erythropoietin; Humans; Infant, Extremely Low Birth Weight; Infant, Newborn; Infant, Premature; Quality Improvement; Retrospective Studies

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.. 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.. 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.

Topics: Anemia, Neonatal; Erythropoietin; Female; Humans; Immunologic Factors; Infant, Newborn; Infusions, Intravenous; Maternal-Fetal Exchange; Multiple Sclerosis, Relapsing-Remitting; Natalizumab; Pregnancy

Topics: Anemia, Neonatal; Combined Modality Therapy; Erythrocyte Transfusion; Erythropoietin; Hematinics; History, 20th Century; History, 21st Century; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Iron

Kidneys are physiologically hypoxic due to huge oxygen consumption for tubular reabsorption. The physiological hypoxia makes the kidney an appropriate organ for sensitively detecting oxygen levels and producing erythropoietin (EPO). In preterm neonates, immature kidneys cannot produce sufficient EPO, which results in anemia of prematurity (AOP). The cause of EPO insufficiency in AOP has been unclear, therefore current therapeutic options are transfusion and injection of recombinant human EPO. This report shows that the cause of insufficient EPO production in AOP is elevated renal oxygen levels due to poor oxygen consumption by immature tubules. Neonatal mice with AOP showed low tubular transporter expression and elevated renal oxygen levels compared with those without AOP. Enhancing transporter expression in AOP mice induced renal hypoxia and EPO production. In preterm neonates, red blood cell counts, hemoglobin levels, and hematocrit levels correlated with tubular function, but not with serum creatinine, gestational age, or birth weight. Furthermore, pharmacological upregulation of hypoxia signaling ameliorated AOP in mice. These data suggest that tubular maturation with increased oxygen consumption is required for renal EPO production.

Topics: Anemia, Neonatal; Animals; Animals, Newborn; Cell Hypoxia; Creatinine; Disease Models, Animal; Erythropoietin; Humans; Infant, Newborn; Kidney; Mice; Oxygen; Oxygen Consumption

Infantile pyknocytosis is a neonatal hemolytic disorder which causes anemia and icterus and is characterized by the presence of an increased number of distorted red blood cells called pyknocytes. Resolution spontaneously occurs in the first semester of life. It has been generally described as a rare entity, with an occasional family history. We report seven cases of infantile pyknocytosis observed in our hospital in 3 years. Most of the infants presented with hemolytic icterus and profound anemia that was reaching its peak by the 3rd week of life. Three neonates received one to three red blood cell transfusions, according to former recommendations. However, the following four received a treatment with recombinant erythropoietin administered subcutaneously. Only one of these four cases required a transfusion. All of them were free of hematological disease 2-3 months after completion of treatment. Infantile pyknocytosis is a recognized cause of neonatal hemolytic anemia, which requires careful examination of red cell morphology on a peripheral blood smear. The cause of this transient disorder remains unknown. Our observations show that recombinant erythropoietin therapy is effective in treating infantile pyknocytosis and increases the reticulocyte response, thus improving the hemoglobin level.

Topics: Anemia, Hemolytic; Anemia, Neonatal; Erythrocyte Transfusion; Erythrocytes, Abnormal; Erythropoietin; Female; Humans; Infant; Infant, Newborn; Male

To evaluate the short-term effects of blood transfusion on iron status [hemoglobin, ferritin, soluble transferrin receptor (sTfR), and reticulocyte count], hepcidin, and erythropoietin in stable preterm infants.. Sixty-three preterm infants treated with red blood cell transfusions (RBCTs) were included. Venous blood samples were collected before and within 24 h after each transfusion.. Hemoglobin concentration increased after RBCT (7.2±1.2 g/dL vs. 13.7±2.3 g/dL, P=0.02), as well as ferritin [131 (63-110.4) ng/mL vs. 211 (125.7-299.2) ng/mL, P=0.05); reticulocyte count decreased. sTfR did not change. Hepcidin serum levels increased from 37.5 (21.3-84.7) ng/mL to 72.6 (31.3-126.2) ng/mL, (P=0.04) and erythropoietin decreased (48±19 pg/mL vs. 29±17 pg/mL, P=0.06) after RBCT. A positive linear correlation was found (R2=0.76, P=0.0001) between hepcidin and ferritin levels of post-minus-pre RBCT. Hepcidin levels increased significantly in preterm infants who received RBCT after 1 month of age compared to those who received RBCT at <1 month (P=0.03). No correlation was found between gestational age, weight appropriate for age, or length of blood storage and hepcidin levels.. Preterm infants can control iron levels by regulating hepcidin and decreasing erythropoietin. This ability varies with postnatal age.

Topics: Anemia, Neonatal; Erythrocyte Transfusion; Erythropoietin; Female; Ferritins; Hemoglobins; Hepcidins; Homeostasis; Humans; Infant; Infant, Newborn; Infant, Premature; Infant, Small for Gestational Age; Iron; Male; Receptors, Transferrin; Reticulocyte Count

Topics: Anemia, Neonatal; Erythrocyte Transfusion; Erythropoietin; Humans; Infant, Extremely Low Birth Weight; Infant, Premature

Anemia in preterm infants is the pathophysiological process with greater and more rapid decline in hemoglobin compared to the physiological anemia in infants. There is a need for transfusions and administration of human recombinant erythropoietin.. To determine the frequency of anemia in premature infants at the Pediatric Clinic, University Clinical Center Sarajevo, as well as parameter values in the blood count of premature infants and to explore a relationship between blood transfusions with the advent of intraventricular hemorrhage (determine treatment outcome in preterm infants).. Research is retrospective study and it included the period of six months in year 2014. Research included 100 patients, gestational age < 37 weeks (premature infants). Data were collected by examining the medical records of patients at the Pediatric Clinic, UCCS.. The first group of patients were premature infants of gestational age ≤ 32 weeks (62/100) and the second group were premature infants of gestational age 33-37 weeks (38/100). Among the patients, 5% were boys and 46% girls. There was significant difference in birth weight and APGAR score among the groups. In the first group, there were 27.42% of deaths, while in the second group, there were only 10.53% of deaths. There was a significant difference in the length of treatment. There was a statistically significant difference in the need for transfusion among the groups. 18 patients in the first group required a transfusion, while in the second group only 3 patients.. Preterm infants of gestational age ≤ 32 weeks are likely candidates for blood transfusion during treatment. Preterm infants of gestational age ≤ 32 weeks have the risk of intracranial bleeding associated with the application of blood transfusion in the first week of life.

Topics: Anemia, Neonatal; Blood Transfusion; Cerebral Hemorrhage; Erythropoietin; Female; Gestational Age; Hemoglobins; Hospitals, University; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Male; Retrospective Studies; Severity of Illness Index; Treatment Outcome

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.

Topics: Adrenergic beta-Antagonists; Anemia, Neonatal; Erythropoietin; Gestational Age; Hemangioma; Humans; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Joint Instability; Magnetic Resonance Imaging; Male; Phimosis; Propranolol; Skin Abnormalities

Preterm infants are at risk for neurodevelopmental sequelae even in absence of major cerebral lesions. The hypothesis that Human Recombinant Erythropoietin (rEpo) could improve the neurodevelopmental outcome in risk neonates has raised the highest interest in recent years.. A group of preterm neonates born at a gestational age ≤ 30 weeks and free from major cerebral lesions or major visual impairment, were included in the study if they had a complete neurologic evaluation for at least 24 months of postmenstrual age. They were assigned to group I in the case they had been treated with rEpo or group II if untreated. The aim was to evaluate whether rEpo, given at the high cumulative doses utilized for hematologic purposes, is able to improve the neurodevelopmental outcome in preterm infants born at a gestational age ≤ 30 weeks. A group of 104 preterm neonates were studied: 59 neonates who received rEpo for 6.9 ± 2.4 weeks at a median cumulative dose of 6300 UI/Kg (6337 ± 2434 UI/Kg), starting at a median age of 4 days and 45 neonates who were born in the period preceding the routine use of rEpo. The neurodevelopmental quotient at 24 month postmenstrual age was assessed utilizing the Griffiths' Mental Developmental Scales.. Our results failed to show any difference in the Developmental Quotient at 24 month. Bronchopulmonary dysplasia, minor intraventricular hemorrhages and blood transfusions were the clinical features significantly related to the Developmental Quotient.. Our results do not support the hypothesis that rEpo, administered with the schedule utilized for hematologic purposes, improve the neurodevelopmental outcome of preterm neonates, at least those preterm infants free from major impairments.

Topics: Anemia, Neonatal; Child Development; Developmental Disabilities; Dose-Response Relationship, Drug; Erythropoietin; Female; Follow-Up Studies; Humans; Infant, Newborn; Infant, Premature; Male; Neurologic Examination

Exogenous human erythropoietin (EPO) artificially synthesised through recombinant DNA technology (rHuEPO) is currently used as a substitute for blood transfusion in preterm and low birth weight neonates. The objective of this study is to determine whether the use of rHuEPO is associated with an increased severity of retinopathy of prematurity (ROP) in preterm neonates.. This retrospective review studies neonates who were admitted to a tertiary perinatal unit and screened for ROP during the 10-year period from January 2003 to December 2012.. : During the 10-year period, 688 preterm neonates underwent ROP screening, with 198 identified as having ROP. The incidence of stage 1 ROP was 51.5% (102/198), followed by 35.9% (71/198) for stage 2, and 12.6% (25/198) for stage 3 and greater. Plus disease was seen in 14 neonates (7.1%). Treatment (laser photocoagulation) was administered in 64% of neonates (16/25) with stage 3 of the disease and above because of progression to threshold ROP. Twenty-six (13%) of the neonates received rHuEPO treatment. There were no statistically significant differences in birth weight (910.4 vs 885 g; P=0.71), gestational age (26.5 vs 25.8 weeks; P=0.09), and duration of ventilation (512 vs 501.4 h; P=0.92) between neonates who did not receive rHuEPO compared with those who were treated with rHuEPO. Multivariate regression analysis showed that the use of EPO was associated with increased severity of ROP.. EPO therapy appears to increase the risk of development and worsening of ROP.

Topics: Anemia, Neonatal; Birth Weight; Epoetin Alfa; Erythropoietin; Female; Gestational Age; Hematinics; Humans; Infant, Newborn; Infant, Premature; Laser Coagulation; Male; Recombinant Proteins; Retinopathy of Prematurity; Retrospective Studies; Risk Factors; Severity of Illness Index

Topics: Anemia, Neonatal; Erythropoietin; Female; Hematinics; Humans; Infant, Premature, Diseases; Male

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.. 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.. 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.. 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.

Topics: Anemia, Neonatal; Birth Weight; Blood Transfusion; Blood Volume; Blood Volume Determination; Computer Simulation; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Male; Models, Cardiovascular; Phlebotomy; Pregnancy

Topics: Anemia, Neonatal; Blood Transfusion, Intrauterine; Erythropoietin; Humans; Infant, Newborn; Male; Recombinant Proteins; Rh Isoimmunization

To evaluate associations between conditions of maternal new-onset gestational hypertension (mHTN) and the features imparting risk of severe retinopathy of prematurity (ROP) in preterm infants.. Hospital databases and charts of all preterm inborn infants at the University of North Carolina from 1996 to 2007 were retrospectively reviewed. The presence or absence of mHTN (e.g., pre-eclampsia) and infant factors (birthweight, gestational age, erythropoietin use, and zone and stage of ROP) were analyzed for independence of association.. Of the 5143 infants, 323 had ROP and 76 had mothers with mHTN. Infants with ROP were more likely to have mothers with mHTN and to be younger and smaller at birth. At initial examination, more infants of mothers with mHTN had vascularization into the lower zones than did infants of mothers without mHTN (P < 0.001). However, at the examination in which the most severe ROP was present, there was no association between mHTN and ROP stage (P = 0.2342). Analysis of stage and zone together showed that infants born to mothers with mHTN were more likely to have ROP at initial examination, after adjustment for gestational age, but not for birth weight. The use of erythropoietin was not associated with ROP zone or stage, even after adjustment for maternal condition, infant birth weight, or gestational age.. Although larger avascular areas or higher severity scores were associated with mHTN after adjustment for gestational age at initial examination, no associations were found between mHTN and ROP severity score at the examination when ROP was most severe. There were no associations between ROP severity and treatment with erythropoietin.

Topics: Anemia, Neonatal; Erythrocyte Transfusion; Erythropoietin; Female; Gestational Age; Humans; Hypertension, Pregnancy-Induced; Infant, Low Birth Weight; Infant, Newborn; Pregnancy; Recombinant Proteins; Retinopathy of Prematurity; Retrospective Studies; Risk Factors

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.. 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%.. 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.. 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.

Topics: Anemia, Neonatal; Erythrocyte Transfusion; Erythropoietin; Hematocrit; Hemoglobinometry; Humans; Hypoxia; Hypoxia-Inducible Factor 1; Infant, Newborn; Infant, Premature; Lactic Acid; Recombinant Proteins

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.. 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.. 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).. r-hu EPO treatment has effect on changes in Hb, Ht, Ret and reduces the number of inevitable blood transfusions for anaemia of prematurity.

Topics: Anemia, Neonatal; Blood Cell Count; Blood Transfusion; Erythropoietin; Female; Hematocrit; Hemoglobinometry; Humans; Infant, Newborn; Infant, Premature; Male; Recombinant Proteins

Very-low-birth-weight (VLBW) infants often require blood transfusions for anemia. Studies have investigated the preventative effect of delayed cord clamping, high-dose iron, and costly recombinant erythropoietin. As part of our unit clinical governance framework to improving patient care, we audited the effect of a preventative management guideline that combines delayed cord clamping for 30 seconds with early protein intake and early oral iron supplementation (6 mg/kg from days 7 to 10 of life, if milk feeds 60 mL/kg/d) combined with a restrictive transfusion policy in infants < 32 weeks' gestation and < 1500 g birth weight. Data on blood transfusions in VLBW infants during the first 6 weeks of life collected before the start of the new regimen (period I) were compared with data in consecutively born VLBW infants after the introduction of the management guideline (period II). Age (in days) when milk feeds and oral iron supplements were introduced was recorded. Statistical analysis used Wilcoxon signed-rank test. VLBW infants in period I ( N = 18, median birth weight 1001 g [727; 1158]) received a median of four transfusions (0.75; 9) compared with 1.5 (0.75; 5, P = 0.01) VLBW infant transfusions in period II ( N = 22, median birth weight 967 g [792; 1131]). Milk feeds of 60 mL/kg/d were achieved on median day 12 (6; to 16), and iron was introduced on median day 38 (21; to 44) in period I compared with milk feeds on day 9 (7; 15, P = 0.05) and oral iron on day 16 (11; 21, P < 0001) in period II. The combination of a 30-second delay in cord clamping, early protein and iron, and a change of transfusion thresholds reduced the number of blood transfusions by half.

Topics: Anemia; Anemia, Neonatal; Blood Transfusion; Constriction; Erythropoietin; Female; Gestational Age; Humans; Infant, Newborn; Infant, Very Low Birth Weight; Iron Compounds; Male; Practice Guidelines as Topic; Recombinant Proteins; Time Factors; Treatment Outcome; Umbilical Cord

Oxygen-carrying capacity of blood is reduced in anemic infants because of low hemoglobin levels. Red blood cell transfusions become necessary if low hematocrit causes tissue hypoxia. No reliable parameters exist for detecting chronic tissue hypoxia. Vascular endothelial growth factor is upregulated by hypoxia; hence, elevated vascular endothelial growth factor levels may be a marker for tissue hypoxia and may indicate the need for red blood cell transfusions.. In a prospective study, plasma vascular endothelial growth factor levels were measured in 3 groups of infants suspected of requiring red blood cell transfusions to find a vascular endothelial growth factor cutoff value indicative of tissue hypoxia. The 3 groups were acute anemic (an episode of acute bleeding [hematocrit drop > 5%] per day); chronic anemic (hematocrit drop < 5% per day); and nontransfused (hematocrit drop < 5% per day) but not meeting clinical criteria for a transfusion. Blood was sampled before transfusion and again 48 hours after transfusion if required. Plasma vascular endothelial growth factor and erythropoietin concentrations were measured.. Vascular endothelial growth factor concentrations were lower in acutely anemic compared with chronically anemic infants, whereas erythropoietin levels did not differ between these groups. The vascular endothelial growth factor concentration was <140 pg/mL in all acutely anemic infants, and this was deemed the threshold level indicating sufficient tissue oxygenation in subsequent analysis. We found that 30% of chronically anemic and 43% of nontransfused infants had vascular endothelial growth factor levels of >140 pg/mL. In transfused infants, with elevated vascular endothelial growth factor levels, red blood cell transfusion resulted in lowering of vascular endothelial growth factor concentrations.. Vascular endothelial growth factor concentrations of >140 pg/mL may indicate insufficient oxygen delivery to tissues and may serve as a marker of the need for transfusion or of tissue hypoxia in other diseases.

Topics: Anemia, Neonatal; Biomarkers; Erythrocyte Transfusion; Erythropoietin; Female; Hematocrit; Hemorrhage; Humans; Hypoxia; Infant, Newborn; Infant, Premature, Diseases; Male; Predictive Value of Tests; Prospective Studies; Reference Values; Vascular Endothelial Growth Factor A

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.. 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.. 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.. 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.

Topics: Anemia, Neonatal; Animals; Erythropoietin; Humans; Infant, Newborn; Pilot Projects; Recombinant Proteins; Sheep

Anemia of prematurity is seen in infants of less than 32 weeks' gestation. This anemia is due to low erythropoietin level and endogenous insufficiency of iron and vitamins. Administering of recombinant human erythropoietin, iron and vitamins in time is logic prevention alternative. The aim of our study is to examine the frequency of late haemotransfusions as an indicator of this prevention. We have investigated 181 children, who were born before the 32nd gestational week and who were distributed in two groups: group A (with prevention) and group B (without prevention). We found no significant difference in the frequency of the late transfusions between the two groups, but the results of the prevention in the most mature infants were better than those of the infants who were born before the 30th gestational week.

Topics: Anemia, Neonatal; Blood Transfusion; Erythropoietin; Humans; Infant, Newborn; Infant, Premature; Iron; Recombinant Proteins; Treatment Outcome; Vitamins

Topics: Anemia, Neonatal; Blood Transfusion; Erythropoietin; Hematopoiesis; Humans; Infant, Newborn; Infant, Premature; Iron; Recombinant Proteins

Recombinant human erythropoietin (rhEPO) is used for the treatment of anemia of prematurity. However, it has also been found to have properties similar to vascular endothelial growth factor (VEGF), the major angiogenic factor implicated in the pathogenesis of retinopathy of prematurity (ROP). We sought to determine whether rhEPO is an independent risk factor for the development of ROP.. Data were analyzed from 264 infants admitted to the Loma Linda University Children's Hospital neonatal intensive care unit in 1994 and 2002. The data included demographic characteristics, incidence of major morbidities, rhEPO treatment, number of red blood cell transfusions received, and incidence and severity of ROP. A multiple logistic regression model was used to determine the relation of the studied risk factors to the incidence (any stage) and severity (threshold ROP requiring cryotherapy or laser photocoagulation) of ROP.. The risk of developing ROP increased among infants who received >20 doses of rhEPO was higher compared with those who received < or =20 doses (OR, 3.53; 95% CI, 1.59, 7.85). These infants were also more likely to require laser photocoagulation (OR, 4.31; 95% CI, 1.99, 9.33). The age at which rhEPO was started was also a significant risk factor, with those starting rhEPO after 20 days of age having almost fourfold the risk of ROP compared with those starting it on or before 20 days of age (OR, 3.57; 95% CI, 1.59, 8.03).. rhEPO was found to be a significant independent risk factor for the development of ROP.

Topics: Age Factors; Anemia, Neonatal; Birth Weight; California; Dose-Response Relationship, Drug; Erythropoietin; Follow-Up Studies; Humans; Incidence; Infant, Newborn; Models, Statistical; Prognosis; Recombinant Proteins; Regression Analysis; Retinopathy of Prematurity; Retrospective Studies; Risk Factors

Determination of factors related to the need for transfusion in premature infants.. Descriptive.. The need for transfusion in premature infants was determined in 2 academic centres: University Medical Center Utrecht and Leiden University Medical Center, The Netherlands. The data had been acquired in another study. The factors under study were: hospital, pregnancy duration, birth weight, gender, time of clamping of the umbilical cord, total volume of blood sampled for diagnostic purposes, number of days of mechanical ventilation, total duration of admission and duration of the admission to the Neonatal Intensive care unit. Both hospitals followed the national interdisciplinary practice guideline 'Blood transfusion'.. The total volume ofsampled blood for diagnosis, the duration of the mechanical ventilation and the admission period were related to a greater need for transfusion. On the other hand, the chance of transfusions diminished with longer pregnancy duration or increased birth weight. The difference in need for blood transfusion between both centres was significant. The total volume of transfused erythrocytes showed a strong correlation with the volume sampled for diagnostic procedures.. Anaemia in neonates is strongly related to the amount of blood taken for diagnostic procedures. Alternatives for blood transfusions in premature infants, and consequently for the reduction of the number of donors per child, are to be sought in delayed clamping of the umbilical cord, use of erythropoietin and use ofautologous umbilical cord blood.

Topics: Anemia, Neonatal; Blood Transfusion; Diagnosis, Differential; Erythropoietin; Female; Fetal Blood; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Male; Time Factors; Umbilical Cord

To evaluate the frequency and severity of retinopathy of prematurity in extremely low-birth-weight (ELBW) infants who received recombinant human erythropoietin (rHuEPO), and to compare the frequency of blood cell transfusions these infants required with a matched control group who did not receive rHuEPO.. Retrospective cohort analysis.. Level III neonatal intensive care unit in a large academic medical center.. One hundred thirty-eight ELBW infants who received rHuEPO and 138 ELBW infants who did not (control group) but who were matched by birth weight, gestational age, sex, and year of birth and who survived to the first ophthalmologic examination.. The rHuEPO was started before the 8th day of life in 115 (83%) of the 138 infants. Stages III-V retinopathy of prematurity occurred with similar frequency in both groups of infants (rHuEPO group 19% [26 infants] vs control group 20% [27 infants], p>0.05). Infants in the rHuEPO group received fewer transfusions on average during their hospitalization compared with those in the control group (4.2 vs 6.1 transfusions, p<0.01).. Use of rHuEPO for prevention or treatment of anemia of prematurity in ELBW infants does not increase the frequency of severe retinopathy of prematurity and reduces the number of transfusions.

Topics: Anemia, Neonatal; Birth Weight; Blood Transfusion; Cohort Studies; Erythropoietin; Female; Gestational Age; Humans; Infant, Extremely Low Birth Weight; Infant, Newborn; Male; Pregnancy; Pregnancy Outcome; Recombinant Proteins; Retinopathy of Prematurity; Retrospective Studies; Risk Assessment

Topics: Anemia, Neonatal; Animals; Disease Progression; Dose-Response Relationship, Drug; Erythropoietin; Humans; Infant, Newborn; Infant, Very Low Birth Weight; Prognosis; Recombinant Proteins; Retinopathy of Prematurity; Risk Factors

Topics: Administration, Oral; Anemia, Neonatal; Dose-Response Relationship, Drug; Erythropoietin; Female; Ferrous Compounds; Follow-Up Studies; Humans; Infant, Newborn; Infant, Very Low Birth Weight; Male; Recombinant Proteins; Risk Assessment

Erythropoietin (EPO) is commonly used in very low birth weight neonates to minimize blood transfusions during hospitalization. Data are limited comparing the use of EPO along with a restricted transfusion schedule versus a restricted transfusion schedule alone. We compared the effects of a restricted transfusion schedule with EPO versus a restricted transfusion schedule alone during two consecutive 6-month periods.. In period I, infants born at <30 weeks gestational age (GA) or <1,500 g birth weight (BW) were treated prophylactically for six weeks with EPO 1,000 U/kg/wk in three divided doses and blood transfusions were given using a restricted transfusion schedule. This was the called the EPO Group. In period II, a restricted transfusion schedule was utilized, but EPO was not administered. This constituted the No EPO Group. No other changes in clinical practice were introduced in either period.. There were 30 neonates in the EPO Group and 20 in the No EPO Group. There were no significant differences in sex, race, mean birth weight (1,074 +/- 283 versus 965 +/- 330 g), mean gestational age (28.9 +/- 2.96 versus 27.8 +/- 2.86 wks), 5 minute Apgar score (7.8 +/- 1.2 versus 7.6 +/- 1.1), or mean hematocrit (48.2% +/- 6.05 versus 48.6% +/- 6.31) at admission. There were no significant differences in the total number of transfusions between the two periods. In the EPO Group, 8/30 patients received 27 transfusions. Six transfusions violated guidelines based on hematocrit level. EPO was discontinued in three infants secondary to treatment-related neutropenia. There were two deaths unassociated with EPO treatment. Excluding deaths, 6 patients received 16 transfusions. In the No EPO Group, 8/20 patients received 13 transfusions. Two transfusions violated guidelines based on hematocrit. There were three deaths and one patient transfer. Excluding these four patients, 6 infants received 11 transfusions (P < or = 1.) Among survivors, there were no significant differences in mean total length of stay (49.3 +/- 22.7 versus 53.2 +/- 26.4 d), mean discharge weight (2,144 +/- 405 versus 2,358 +/- 458 g), or average weight gain/d (20.7 +/- 5.44 versus 22.6 +/- 6.81 g), between the two groups respectively, nor were there significant differences when all babies were included in the analysis. There was a significant difference in mean hematocrit at discharge, respectively, (38.3% +/- 6.84 versus 31.4% +/- 6.26; P = 0.003) in survivors.. A restricted transfusion schedule without EPO use was associated with lower mean hematocrit at discharge, but not with an increased frequency of transfusions, nor significant differences in length of stay, discharge weight, or average daily weight gain. A restricted transfusion schedule alone avoided side effects and costs associated with EPO. Indications for transfusion and what constitutes appropriate levels of hemoglobin still require clinical investigation, including long-term clinical outcomes.

Topics: Anemia, Neonatal; Blood Transfusion; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Female; Follow-Up Studies; Hematocrit; Humans; Infant, Newborn; Infant, Very Low Birth Weight; Male; Retrospective Studies; Treatment Outcome

The purpose of the present paper was to detect the clinical factors most predictive of red blood cell (RBC) transfusion in extremely low-birthweight (ELBW) infants in the recombinant human erythropoietin era.. Between 1995 and 2000, 66 ELBW infants were admitted to a level III neonatal intensive care unit. Fifty-four of 66 infants were eligible for enrollment in the present study. Infants were treated with erythropoietin 200 IU/kg per dose s.c. twice a week with 4-6 mg/kg per day iron supplement.. The mean gestational age and birthweight were 26.5 +/- 2.1 weeks and 776 +/- 134 g, respectively. Ten of 54 ELBW infants (18.5%) died during the first 21 days. Eight of 10 dead infants (80.0%) and 27 of 44 surviving infants (61.4%) received one or more RBC transfusions. The overall requirement for RBC transfusions in the surviving infants was 3.0 +/- 3.2 per infant/hospital course (range: 0-9) . There were significant differences in gestational weeks, birthweight, initial hemoglobin value, 5 min Apgar score, phlebotomy loss, phlebotomy loss/birthweight, duration of mechanical ventilation, duration of oxygen supplement, and incidence of both intraventricular hemorrhage and chronic lung disease between the transfused and non-transfused group. The predictive variables, initial hemoglobin level (odds ratio [OR] 2.61; 1 g/dL), birthweight (OR 3.00; 100 g), and gestational week (OR 1.89; 1 week), were found to be most predictive for transfusion on logistic regression analysis.. ELBW infants are still the population at greatest risk for repeated blood transfusions after introduction of erythropoietin treatment. If labor develops, it is often impossible to extend the pregnancy period, therefore efforts should be made to increase hemoglobin level at birth.

Topics: Algorithms; Anemia, Neonatal; Erythrocyte Transfusion; Erythropoietin; Female; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Intensive Care Units, Neonatal; Japan; Male; Practice Guidelines as Topic; Predictive Value of Tests; Recombinant Proteins; Retrospective Studies; Risk Factors; Survival Analysis; Treatment Outcome

Anaemia of prematurity is a common problem encountered in most special care baby units warranting often repeated blood transfusions with its inherent dangers. We present three patients in Nigeria who were very low birth weight premature babies on whom recombinant erythropoietin was used as an efficient replacement for blood transfusions. All three patients showed a progressive drop in haemoglobin concentration from the first to the sixth to eight week of life with development of heamic murmurs and insignificant reticulocyte responses, and were planned for transfusion therapy. The parents of all the patients strongly refused transfusion therapy (one on religious grounds) warranting the use of recombinant erythropoietin to which there was a significant response in all three patients with elevation of haemoglobin concentration, PCV, and reticulocyte counts, and obviating the planned transfusions. No significant side effects were also noticed. We suggest further controlled trials to establish this mode of therapy.

Topics: Anemia, Neonatal; Erythropoietin; Female; Hemoglobins; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Male; Nigeria; Recombinant Proteins; Reticulocyte Count

Darbepoetin is longer acting and more potent than recombinant erythropoietin (rEpo). In certain situations, preterm neonates might benefit from rEpo, and for such patients darbepoetin would require fewer doses at a lower cost. However, the proper dose and dosing interval have not been established.. We performed a prospective trial in two level III Neonatal Intensive Care Units. Patients <32 weeks gestation at birth, with a birth weight (BW) <1500 g, were eligible for participation if they were >21-days-old and had a hemoglobin (Hgb) concentration

Topics: Anemia, Neonatal; Area Under Curve; Biological Availability; Darbepoetin alfa; Erythropoietin; Half-Life; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Pilot Projects; Prospective Studies; Reticulocyte Count

Anaemia of prematurity (AOP) is caused by a deficiency of erythropoietin, which stimulates differentiation, and growth of erythroid progenitors. The previous standard of therapy of AOP was erythrocyte transfusions. Following successful clinical trials using recombinant human eryrthropoietin (rHuEpo) to treat adults, the rHuEpo has been used to prevent and treat anaemia in preterm infants. The aim of the study was to evaluate the influence of rHuEpo treatment on parameters of the erythrocytic system in peripheral blood, iron concentration, and unsaturated iron bind capacity (UIBC), as well as on erythrocyte transfusion requirements, in preterm infants with AOP, having no infection and not receiving oxygen support. Twenty-four children with AOP, that were hospitalized during one year, with no signs of infection and without any form of oxygen therapy, were investigated. The rHuEpo was administered subcutaneously 700 U/kg/week, in two doses. Infants: also received oral iron. The percentage of children with AOP treated by supplementary transfusions was compared in two one-year periods, before and after the introduction of rHuEpo therapy. In over 50% of children, satisfactory improvement of erythrocytic picture was achieved after administration of 4-7 doses of rHuEpo. In the year prior to the introduction of rHuEpo therapy, 91% of children with AOP required supplementary red cells transfusions, while only 13% when rHuEpo was applied.. The rHuEpo is the drug of choice in the treatment of anaemia of prematurity. Therapeutic use of rHuEpo markedly diminished quantity of supplementary transfusions in children with AOP.

Topics: Anemia, Neonatal; Erythrocyte Transfusion; Erythropoietin; Hemoglobins; Humans; Infant, Newborn; Iron; Recombinant Proteins

Topics: Anemia, Neonatal; Erythropoietin; Humans; Infant, Newborn; Infant, Very Low Birth Weight; Infusions, Intravenous; Injections, Subcutaneous; Recombinant Proteins

Topics: Anemia, Neonatal; Erythropoietin; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Recombinant Proteins

Topics: Anemia, Neonatal; Blood Transfusion; Erythropoietin; Humans; Infant, Newborn; Infant, Very Low Birth Weight; Recombinant Proteins; Time Factors

To determine the impact of two different recombinant human erythropoietin (epoetin alfa) dosing strategies on the number of red blood cell (RBC) transfusions, and explore relationships between specific patient and drug regimen variables with epoetin alfa therapy outcomes.. Retrospective cohort study.. Level III university neonatal intensive care unit.. Infants who received epoetin alfa therapy three times weekly for more than one week were categorized into two epoetin alfa dosing strategy groups: group A (300-749 units/kg/wk) and group B (750-1200 units/kg/wk). The following patient variables were collected and their relationship to therapy outcomes (corrected reticulocyte count [%], hematocrit [%], and number of RBC transfusions after therapy was started) were evaluated using independent Student's t-test, correlation analysis, and stepwise linear regression: birth weight (kg), gestational age (weeks), postnatal age at therapy onset (days), duration of mechanical ventilation (days), number of RBC transfusions before epoetin alfa therapy, phlebotomy loss (mL/kg), epoetin alfa dosage (units/kg/dose), iron dosage (mg/kg/d), duration of therapy (days), and postconceptional age at therapy discontinuation (weeks).. The charts of 44 patients were reviewed. No significant impact on outcome was attributed to overall dosing strategy (group A vs. group B). Linear regression identified postnatal age at therapy onset as a significant contributor to mean hematocrit (R2 = 2 0.116; p = 0.023) and postconceptional age at therapy discontinuation as a significant contributor to number of transfusions during and after epoetin alfa use (R2 = 0.118; p = 0.022). A significant positive correlation was found between weekly mean epoetin alfa dosage and mean reticulocyte count (r = 0.326; p = 0.046), mean iron dosage and mean reticulocyte count (r = 0.439; p = 0.006), and ventilator days and total number of transfusions (r = 0.606; p < 0.001). A significant negative correlation was found between number of transfusions and reticulocyte count (r = -0.367; p = 0.023).. Epoetin alfa dosing strategy, as defined in our study, did not significantly affect the number of transfusions. However, postnatal age at therapy initiation, postconceptional age at therapy discontinuation, mean epoetin alfa dosage, and iron dosage correlate with specific outcomes of epoetin alfa therapy in premature infants.

Topics: Anemia, Neonatal; Cohort Studies; Dose-Response Relationship, Drug; Epoetin Alfa; Erythrocyte Transfusion; Erythropoietin; Hematinics; Humans; Infant, Newborn; Infant, Premature; Iron; Recombinant Proteins; Retrospective Studies; Treatment Outcome

To evaluate the effectiveness of recombinant human erythropoietin (rH-EPO) in the prophylactic treatment of anemia of prematurity.. We performed a non-randomised, retrospective case control study of 108 premature babies with birth weights of less than 1500 grams and gestational age of less than 34 weeks. Infants with hemolytic or hemorrhagic disease and those who died in the first days of life were excluded. Fifty-four patients were treated with rH-EPO (250 U/kg subcutaneously, 3 times a week) for 6 weeks. A ferrous sulfate supplement was also administered orally (4-6 mg/kg/day) with a multivitamin complex.. There were no differences between groups in gestational age, birth weight, ferritin levels, hematocrit and hemoglobin on admission, amount of blood sampled and days with ventilatory support. The number of transfusions per patient were 1.46 +/- 1.38 in control group versus 0.69 +/- 1.19 in rH-EPO-treated infants (p < 0.002). Sixty-three percent of infants in the treated group did not require blood transfusions compared with only 29.7% in the nontreated group (p < 0.001). The lowest mean hemoglobin was 8.72 +/- 2.62 gr/dl in the control group versus 9.70 +/- 2.08 gr/dl in the rH-EPO group.. Prophylactic treatment with rH-EPO was effective in reducing the number of transfusions, mainly in stable newborn infants with a birth weight greater than 1000 grams.

Topics: Anemia, Neonatal; Case-Control Studies; Erythropoietin; Female; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Male; Recombinant Proteins; Retrospective Studies

Chronic anemia is very frequent in very low birth weight (VLBW) infants. Lowered red cells life span, hemolysis, low production of erythropoietin, phlebotomies, excessive body growth are its most important causes. A reduction of the number of transfusions to babies with chronic anemia was obtained through r-HuEpo. A serie accounting for 89 newborns < 1500 g (18 < 1000 g) with a mean weight of 1069 g (+/- 238) in whom early treatment with r-HuEpo was performed (from 9.55 +/- 3.04 day), 300 UI three times a week s.c., is presented. Therapy with r-HuEpo was carried out for 6 weeks, or until the baby weighed 1800 g. During the treatment, each baby received iron, folic acid, multivitaminic supplements. Patients were monitored with red blood cells count, comprehensive of reticolocytes, ipochromic cells (Ipo-cells), content of hemoglobin of reticolocytes (CHr), each week. Iron, ferritine and transferrine were obtained only twice a month, as they required further blood sampling. 10.1% neonates received transfusions: the percentage of transfused VLBW infants was much higher (55.5%) before than after the introduction of r-HuEpo (p = 0.0002). 33.3% extremely low birth weight (ELBW) infants required transfusions (vs 95.5% in pre r-HuEpo period) (p < 0.0001). Our results confirm the importance of Ipo-cells and CHr to monitor early alterations of iron cellular employment.

Topics: Anemia, Neonatal; Erythropoietin; Humans; Infant, Newborn; Infant, Very Low Birth Weight; Monitoring, Physiologic; Recombinant Proteins

Subcutaneous injection of active principles must be performed through a short and thin needle and an insuline syringe (because of the few quantity of drug to administrate). In our Centre, to prevent preterm chronic anemia wc practice subcutaneous therapy with recombinant human erythropoietin. 300 UI three times a week, to all the newborns weighing < 1500 g at birth. Injections to the newborns are performed in correspondence of their gluteal and deltoid muscles, and in the outer part of their thigh. To prevent atrophy, it is important to change every time the site of Injection. For this goal, we have created the shape of a newborn, nained Puntino, and we have located 24 points on it. Each point has received a number between 0 and 23. During the treatment we have followed the guide of Puntino to locate each time the correct site of injection. Thanks to Puntino's aid, there were no cases of skin adverse reaction and atrophy, even in newborns weighing < 1000 g.

Topics: Anemia, Neonatal; Erythropoietin; Humans; Infant, Newborn; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Injections, Subcutaneous; Recombinant Proteins

Our objective was to analyze the utility of treatment with erythropoietin (EPO) plus iron in decreasing the need of late transfusions and reaching hematocrit > or = 32% in preterm infants of < or = 32 weeks of gestation.. Between March 1996 and October 1998, preterm infants of one unit were considered as the control group, while another group in another unit in the same hospital were treated with EPO (250 U/Kg, 3 times a week, subcutaneously) from day 7 of life until 37 weeks 37 post-conception. Oral iron was added to treatment one week later (5 mg/Kg, and increased in order to keep ferritin levels > 100 ng/ml). More strict transfusion criteria were established. Weights were stratified in < 1,000 g, 1,000-1,249 g and > or = 1,250 g.. Blood losses during the first 2 weeks were higher in the control group and that was probably the reason for the increased number of transfusions during the first 10 days of life. Late transfusions decreased in the EPO treated group (p < 0.0003). This was significant after the 3rd week and in the 1,000-1,249 g weight group. The EPO-treated group showed lower hematocrit < or = 32% (p < 0.001). When EPO-treated infants were separately analyzed it was clear that late transfusions were more frequent in infants that were smaller, more immature and sicker and with higher blood losses. The reticulocyte count increase was similar in both groups of late transfused vs. Not transfused EPO-treated infants, being higher at 4 weeks after EPO was started (30/1000). EPO and ferritin values were always higher in late transfused EPO-treated infants than in non-transfused infants.. The EPO plus iron treated group of preterm infants had a 40% decrease in the need for late transfusions in comparison with the control group. The best results were obtained in the 1000-1249 g group of preterm infants.

Topics: Age Factors; Anemia, Neonatal; Birth Weight; Blood Transfusion; Data Interpretation, Statistical; Erythropoietin; Gestational Age; Hematocrit; Humans; Infant, Newborn; Infant, Premature, Diseases; Iron

The effects of anemia of prematurity during bronchopulmonary dysplasia (BPD) as well as on the metabolic and erythropoietic functions were determined before and after a transfusion. Fourteen anemic (Hb range: 65-88 gm/L), oxygen dependent (fraction of inspired oxygen < or = 35%), nonventilated, preterm infants with BPD were studied at a postnatal age of 6 +/- 2 weeks.. Cardiac output, heart rate, mean velocity of circumferential fiber shortening, shortening fraction (SF), and stroke volume were assessed by pulsed and continuous wave Doppler echocardiography. Values for resting oxygen consumption, carbon dioxide production, and energy expenditure were obtained by indirect calorimetry. The affinity of oxygenated hemoglobin was determined by a blood oxygen dissociation analyzer.. An increased hemoglobin level resulted in a suppression of erythropoietin secretion (p < 0.001), whereas heart rate, cardiac output, stroke volume, and SF decreased (p < 0.05). Weight gain before and after transfusion were similar. Plasma lactate levels decreased from 1.6 +/- 0.3 to 1.2 +/- 0.3. Oxygen consumption, carbon dioxide production, and energy expenditure were not affected.. Anemia of prematurity and BPD increase heart rate, cardiac output, stroke volume, and SF. These hemodynamic compensatory responses are normalized by transfusion.

Topics: Adaptation, Physiological; Anemia, Neonatal; Blood Transfusion; Bronchopulmonary Dysplasia; Echocardiography, Doppler; Erythropoietin; Hemodynamics; Humans; Infant; Infant, Newborn; Infant, Premature, Diseases; Myocardium; Oxygen Consumption; Oxygen Inhalation Therapy

Topics: Anemia, Neonatal; Erythropoietin; Humans; Infant, Newborn; Infant, Premature, Diseases

According to an unreliable meta-analysis, epoetin beta reduces the number of premature neonates needing transfusions for anaemia by 18% on average. When such children do require transfusions, two comparative trials have shown a reduction in the frequency of transfusions and total volume of blood transfused, but the clinical consequences were not studied. Thus clinical experience to date is too limited to rule out a risk of possibly severe adverse events. Furthermore, prescription of epoetin beta must be accompanied by iron supplementation, whose optimal dose and route of administration have not been established. The cost-benefit ratio of epoetin beta in the prevention of anaemia in premature infants must be thoroughly assessed in the context of national health systems.

Topics: Anemia, Neonatal; Blood Transfusion; Clinical Trials as Topic; Cost-Benefit Analysis; Erythropoietin; France; Humans; Infant, Newborn; Infant, Premature; Infections; Iron Deficiencies; Iron, Dietary; Meta-Analysis as Topic; Treatment Outcome

Topics: Anemia, Neonatal; Blood Transfusion; Erythropoietin; Evaluation Studies as Topic; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Risk Factors

Topics: Anemia, Neonatal; Erythrocyte Count; Erythropoietin; Humans; Infant, Newborn; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Recombinant Proteins

Topics: Anemia, Neonatal; Erythropoietin; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Recombinant Proteins

Topics: Anemia, Neonatal; Erythrocyte Transfusion; Erythropoietin; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases

The anaemia of prematurity has been attributed to an insufficient erythropoietin (Epo) level. However, haemopoiesis is known to be regulated by a cohort of growth factors including interleukin-3 (IL-3), IL-6, stem cell factor (SCF), granulocyte monocyte-colony stimulating factor (GM-CSF) and insulin-like growth factors-I and -II (IGF-1, IGF-II). Circulating levels of these growth factors were measured in cord blood at the following gestational ages: 25-28 weeks, 29-32 weeks, 33-36 weeks and > 37 weeks. This study indicates that low concentrations of IGFs as well as a low Epo level in early gestational ages may play a role in anaemia of prematurity.

Topics: Anemia, Neonatal; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Fetal Blood; Gestational Age; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; Humans; Infant, Newborn; Infant, Premature, Diseases; Interleukins; Somatomedins

Increased fetal Hb (HbF) synthesis has been shown to occur during fetal hypoxemia and severe anemia. To determine whether increased HbF synthesis occurs during anemia of prematurity, the levels of HbF synthesis were correlated with the degree of anemia and plasma erythropoietin levels. Thirteen newborn infants born at 29.2 +/- 1.7 wk of gestation were studied at a postconceptional age 36.0 +/- 1.1 wk. Hb levels ranged from 65 to 78 g/L. Blood samples were incubated in an amino acid mixture containing [3H]leucine and chromatographed allowing the separation and quantitation of the alpha, beta, and gamma (A gamma T, G gamma, and A gamma I) chains. Erythropoietin was determined by RIA. The mean HbF synthesis was 77.9 +/- 8.9% of total Hb synthesis (range: 61 to 91%). Plasma erythropoietin concentrations were 21.4 +/- 6.4 mU/mL. There was no correlation between the total Hb or HbF synthesis and the level of erythropoietin. There was, however, a significant inverse correlation between the Hb level and HbF synthesis (p < 0.01). Nine infants who had received transfusions during the first few days of life had a mean HbF that was 53.5 +/- 15.2% of total Hb, whereas their HbF synthesis was 78.4 +/- 7.6%. Four of the infants never received transfusions; the total circulating HbF and HbF synthesis in these infants were 87.7 +/- 7.7% and 76.8 +/- 12.7%, respectively. This study shows that there can be a reactivation of HbF synthesis during severe anemia of prematurity.

Topics: Anemia, Neonatal; Erythrocytes; Erythropoietin; Fetal Hemoglobin; Gestational Age; Hemoglobin A; Humans; Infant, Newborn; Infant, Premature; Oxygen

Three neonates (a male and two females of gestational ages 27, 27 and 29 weeks with birthweight 985, 660 and 1130 g), born to parents who are Jehovah's Witnesses, were admitted to our neonatal intensive care unit over a 2 month period in 1992. Human recombinant erythropoietin (rHuEpo, 200 u/kg sc. on alternate days for 6-8 weeks) was started early in conjunction with strict control of blood sampling in an attempt to avoid the need for blood transfusion. The lowest haemoglobin recorded was 95 g/L at 35 days of age in the first infant. The amount of blood withdrawn for sampling was 21.4 mL, 20.7 mL and 5.5 mL, respectively. All were discharged near their expected birthdate, never having received a blood transfusion in the Nursery. It is possible to manage sick, very preterm, very low birthweight neonates in a neonatal intensive care setting without the use of blood transfusions by the early use of rHuEpo in conjunction with strict control of blood sampling.

Topics: Anemia, Neonatal; Blood Transfusion; Erythropoietin; Female; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Male; Recombinant Proteins; Religion and Medicine

We determined the effects of anemia of prematurity on myocardial, metabolic, and erythropoietic functions. Twelve anemic (hemoglobin range, 65 to 78 gm/L) infants without symptoms (gestational age, (mean +/- SD) 28 +/- 2 weeks; birth weight, 1178 +/- 326 gm) were studied at a postconceptional age of 35 +/- 1.6 weeks. All measurements were done before and 36 to 48 hours after a transfusion of packed erythrocytes. Cardiac output, heart rate, and myocardial function were assessed. Oxygen consumption, carbon dioxide production, resting energy expenditure, arterial oxygen pressure for 50% hemoglobin saturation, and the concentrations of erythropoietin and 2,3-diphosphoglycerate were also determined. After transfusion, increased hemoglobin level (75 +/- 4 to 150 +/- 16 gm/L) and decreased oxyhemoglobin affinity (20.8 +/- 1.7 to 23.6 +/- 2.1 gm/L; p < 0.05) caused a decrease in plasma erythropoietin concentration (from 21.1 +/- 6.2 to 5.8 +/- 1.5 mU/ml; p < 0.01). There was a decrease in heart rate (from 155 +/- 10 beats/min to 146 +/- 7 beats/min) and cardiac output (from 281 +/- 73 ml/kg per minute to 199 +/- 62 ml/kg per minute; p < 0.05). Myocardial function indexes, weight gain, and metabolic demands were normal before and after transfusion. These results suggest that oxygenation is adequately maintained in symptom-free infants with anemia of prematurity.

Topics: Anemia, Neonatal; Energy Metabolism; Erythrocyte Transfusion; Erythropoietin; Heart; Hemodynamics; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Oxygen

Topics: Anemia, Neonatal; Erythropoietin; Humans; Infant; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature, Diseases; Recombinant Proteins

Topics: Anemia, Neonatal; Erythropoietin; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature, Diseases; Recombinant Proteins

Topics: Anemia, Neonatal; Erythropoietin; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature, Diseases; Recombinant Proteins

In the human fetus, liver macrophages appear to be the primary source of erythropoietin (Epo). Epo production shifts from the liver to peritubular cells in the kidney sometime during the 3rd trimester. Some preterm infants experience a hyporegenerative anemia that appears to be caused by inadequate Epo production. It is not clear whether this anemia is due to deficient Epo production by liver macrophages or renal peritubular cells. To assess this situation, we measured Epo mRNA and protein in macrophages obtained from cord blood of preterm and term infants and from peripheral blood of adults. Macrophages from preterm infants generated Epo mRNA and protein as effectively as those from term infants and adults. It appears that the anemia of prematurity is not due to defective Epo production by macrophages.

Topics: Adult; Anemia, Neonatal; Erythropoietin; Fetal Blood; Humans; In Vitro Techniques; Infant, Newborn; Infant, Premature; Macrophages; RNA, Messenger

Topics: Anemia, Neonatal; Blood Transfusion; Erythropoietin; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Recombinant Proteins

Topics: Anemia, Neonatal; Clinical Trials as Topic; Conflict of Interest; Erythropoietin; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Recombinant Proteins; Sudden Infant Death

Hemolytic disease of the fetus and newborn has three phases of anemia: in utero, in the first week of life, and in the weeks and months after birth. Intrauterine transfusions can ameliorate the severity of both fetal and early anemia, but late anemia and the need for transfusion remain significant problems. Bone marrow hypoplasia--probably a result of suppression of erythropoiesis from the intrauterine transfusions--was documented in the three patients tested in our study. Because erythropoietin (EPO) levels have been found to be low (i.e., normal) in these previously transfused patients despite the degree of anemia, we treated four affected infants with EPO, 200 microliters/kg subcutaneously three times a week, and noted reticulocytosis and increased hemoglobin values 2 to 4 weeks later. One patient again had reticulocytopenic anemia when the EPO therapy was stopped but responded to retreatment. Our study indicates that EPO treatment may be effective in the management of late anemia and could help to decrease the need for postnatal transfusions.

Topics: Anemia, Neonatal; Blood Transfusion, Intrauterine; Erythroblastosis, Fetal; Erythropoiesis; Erythropoietin; Female; Hemoglobins; Humans; Infant, Newborn; Pilot Projects; Pregnancy; Prenatal Care; Reticulocytes

Topics: Anemia, Neonatal; Blood Transfusion; Clinical Trials as Topic; Erythropoietin; Humans; Infant, Newborn; Infant, Premature, Diseases; Recombinant Proteins

Pharmacokinetics of recombinant human erythropoietin (rHuEPO) were studied in a group of very low birth weight infants after both intravenous and subcutaneous administration. The volume of distribution was larger and the clearance more rapid than those reported in adults. The maximum concentration of erythropoietin after subcutaneous doses of rHuEPO was variable, but bioavailability was high (42%) compared with values reported in adults. These observations could be useful in optimizing treatment of the anemia of prematurity with rHuEPO.

Topics: Anemia, Neonatal; Biological Availability; Erythropoietin; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Injections, Intravenous; Injections, Subcutaneous; Recombinant Proteins

Recombinant human erythropoietin (rHuEPO) was administered subcutaneously three times a week to 18 infants with the anaemia of prematurity at doses of 75, 150, 300, or 600 units/kg per week for 4 weeks, starting at 3-4 weeks of postnatal age. A significant and dose-dependent increase in reticulocyte count was observed from a mean baseline value of 71 x 10(9)/l to 200 x 10(9)/l after 3 weeks of therapy, compared with a change from 69 to 97 x 10(9)/l in 66 historical controls. The haematocrit value remained unchanged during rHuEPO treatment, whereas it steadily declined until 9 weeks of postnatal age in the controls. These effects were accompanied by a marked reduction in serum iron concentration and transferrin saturation in patients receiving standard-dose iron supplements, but not in those given larger doses. Only 3 of 18 patients required a red blood cell transfusion. These infants were among the most anaemic at entry into the study and 2 of them were unable to complete rHuEPO therapy, while the third developed iron deficiency anaemia. These data indicate that rHuEPO with appropriate iron supplementation may accelerate the recovery from anaemia of prematurity. Larger scale placebo-controlled studies are now needed to confirm these findings and verify their impact on transfusion requirements of premature infants.

Topics: Anemia, Neonatal; Blood Component Transfusion; Blood Platelets; Cell Count; Erythropoiesis; Erythropoietin; Hematocrit; Humans; Infant, Newborn; Infant, Premature, Diseases; Iron; Neutrophils; Recombinant Proteins; Reticulocytes

Topics: Adult; Anemia, Neonatal; Animals; Child; Erythropoiesis; Erythropoietin; Humans; Infant; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases

A comparison was carried out between a series of neonates who weighed less than 1500 g at birth and received red cell transfusions for symptomatic anaemia of prematurity (group 1, n = 14) and controls of similar gestational age and weight, who remained well and were not transfused during their nursery stay (group 2, n = 10). Mean (SD) haemoglobin concentrations at birth were 163 (12) g/l and 183 (17) g/l (p = 0.004), respectively. Transfusion resulted in significantly better weight gain in six infants who had been growing poorly:mean (SE) 8.8 (2.8) g/day improved to 23.3 (2.1) g/day (p less than 0.002). Geometric mean (SD) serum immunoreactive erythropoietin (SiEp) concentrations (17.7 (1.3) U/l) for the whole group of infants were similar to those of normal adults (17.4 (4.7) U/l) despite considerably reduced haemoglobin values. There was a significant inverse correlation between haemoglobin and log SiEp concentrations in the infants requiring transfusion (r = -0.43; p less than 0.01), but this was not apparent in the untransfused babies. Moreover, at haemoglobin concentrations below 120 g/l the mean (SE) SiEp concentration of 20 (1.08) U/l in group 1 was significantly higher than in group 2 (14 (1.06) U/l; p = 0.002). These data suggest that an increased concentration of SiEp early in the course of the anaemia of prematurity helps to identify those infants who would benefit from red cell transfusions, but that clinical criteria, although ill defined, do so equally well.

Topics: 2,3-Diphosphoglycerate; Anemia, Neonatal; Blood Cell Count; Blood Transfusion; Chi-Square Distribution; Diphosphoglyceric Acids; Erythrocyte Transfusion; Erythropoietin; Ferritins; Hemoglobins; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Time Factors

Circulating erythroid progenitors (BFU-E) in five anaemic preterm infants (haemoglobin less than 100 g/l) were about 2 and 4.4 times as abundant as in 10 preterm infants who were not anaemic and five healthy adults, respectively, and were significantly more responsive to low concentrations of recombinant human erythropoietin (rHuEpo) than those from healthy adults. These results encourage further studies in the use of rHuEpo for the treatment of the anaemia of prematurity.

Topics: Adult; Anemia, Neonatal; Dose-Response Relationship, Drug; Erythrocyte Count; Erythroid Precursor Cells; Erythropoietin; Fetal Blood; Humans; Infant, Newborn; Infant, Premature, Diseases; Recombinant Proteins

Topics: Anemia, Neonatal; Blood Transfusion; Erythrocyte Transfusion; Erythropoietin; Humans; Infant, Newborn; Infant, Premature; Recombinant Proteins

Topics: Anemia, Neonatal; Erythropoietin; Humans; Infant, Newborn; Infant, Premature, Diseases

We used cells from marrow aspirations that had been performed on 10 infants with the "anemia of prematurity" and tested the responsiveness of their erythroid colony-forming units (CFU-E) to recombinant human erythropoietin. For comparison, we also tested marrow-derived CFU-E from five healthy adults, and circulating CFU-E from cord blood of five healthy neonates. CFU-E from the anemic infants had a 50% maximal response at 0.073 +/- 0.024 U erythropoietin per milliliter (mean +/- SD). They were therefore at least as responsive as were CFU-E from adults, which displayed a 50% maximal response at 0.118 +/- 0.076 U/ml, and as were circulating CFU-E of cord blood origin, which had a 50% maximal response at 0.109 +/- 0.047 U/ml. Because CFU-E from infants with the "anemia of prematurity" appeared highly sensitive to erythropoietin in vitro, we propose that its administration to these patients would likely result in a significant increase in erythrocyte production in vivo.

Topics: Anemia, Neonatal; Bone Marrow; Erythropoietin; Fetal Blood; Humans; In Vitro Techniques; Infant, Newborn; Infant, Premature, Diseases; Stem Cells

Topics: Anemia, Neonatal; Erythropoietin; Humans; Infant, Newborn; Infant, Premature, Diseases

Plasma erythropoietin concentrations were studied in 11 preterm appropriate for gestational age infants at the age of 3-14 weeks. Their birth weights ranged from 860-1 690 g. Erythropoietin was measured by a cell culture technique. Significant concentrations of erythropoietin was detected in 18 out of 29 samples, at all stages of the early anemia. The highest levels were found at 3-9 weeks. Individual erythropoietin values did not correlate with hemoglobin concentrations, hematocrit levels or 'corrected' reticulocyte counts, nor did the 'corrected' reticulocyte count correlate with hemoglobin or hematocrit. The lack of correlation with hemoglobin concentration most likely reflects the importance of other factors as well as the hemoglobin in determining the oxygenation status of the infant. A significant positive correlation (r = 0.60, p less than 0.01) was found between erythropoietin concentration and weight gain in the preceding week. The study shows that small preterm infants are capable of erythropoietin production during their early anemia, and indicates that the hormone plays a role in the regulation of erythropoiesis also at this time of life.

Topics: Anemia, Neonatal; Body Weight; Erythrocyte Count; Erythropoietin; Hemoglobins; Humans; Infant; Infant, Newborn; Infant, Premature, Diseases; Reticulocytes

Erythropoietin (EPO) titres in the serum of premature infants were determined by an in vitro method using radioiron incorporation into haem in fetal mouse liver cells in culture. The serum EPO titres in 12 premature infants at birth were significantly lower than those of normal adults. In those premature infants who developed anaemia the serum EPO titres increased significantly by 4-6 weeks after birth, confirming that EPO production increases in premature infants in early days of life.

Topics: Adult; Anemia, Neonatal; Erythropoietin; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Male; Time Factors

Topics: Adult; Anemia, Neonatal; Bone Marrow; Erythrocyte Aging; Erythrocyte Count; Erythropoiesis; Erythropoietin; Female; Hematopoiesis; Hemoglobins; Humans; Infant; Infant, Newborn; Infant, Premature, Diseases; Pregnancy

Topics: Anemia, Neonatal; Biological Transport; Birth Weight; Cell Survival; Erythrocyte Count; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Folic Acid Deficiency; Hemoglobins; Humans; Infant Nutritional Physiological Phenomena; Infant, Newborn; Infant, Premature; Iron Deficiencies; Oxygen Consumption; Pregnancy; Reticulocytes; Vitamin B 12 Deficiency; Vitamin E Deficiency

Topics: Adolescent; Anemia, Neonatal; Animals; Child; Child, Preschool; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Infant; Infant, Newborn; Infant, Premature, Diseases; Iron Radioisotopes; Mice; Polycythemia; Pregnancy