Early erythropoiesis-stimulating agents in preterm or low birth weight infants.

BACKGROUND: 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 and to provide neuro protection and protection against necrotising enterocolitis (NEC). Darbepoetin (Darbe) and EPO are currently available ESAs. OBJECTIVES: To assess the effectiveness and safety of ESAs (erythropoietin (EPO) and/or Darbe) initiated early (before eight days after birth) compared with placebo or no intervention in reducing red blood cell (RBC) transfusions, adverse neurological outcomes, and feeding intolerance including necrotising enterocolitis (NEC) in preterm and/or low birth weight infants. Primary objective for studies that primarily investigate the effectiveness and safety of ESAs administered early in reducing red blood cell transfusions: To assess the effectiveness and safety of ESAs initiated early in reducing red blood cell transfusions in preterm infants. Secondary objectives: Review authors performed subgroup analyses of low (≤ 500 IU/kg/week) and high (> 500 IU/kg/week) doses of EPO and the amount of iron supplementation provided: none, low (≤ 5 mg/kg/d), and high (> 5 mg/kg/d). Primary objective for studies that primarily investigate the neuro protective effectiveness of ESAs: To assess the effectiveness and safety of ESAs initiated early in reducing adverse neurological outcomes in preterm infants. Primary objective for studies that primarily investigate the effectiveness of EPO or Darbe administered early in reducing feeding intolerance: To assess the effectiveness and safety of ESAs administered early in reducing feeding intolerance (and NEC) in preterm infants. Other secondary objectives: To compare the effectiveness of ESAs in reducing the incidence of adverse events and improving long-term neurodevelopmental outcomes. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 2), MEDLINE via PubMed (1966 to 10 March 2017), Embase (1980 to 10 March 2017), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 10 March 2017). We searched clinical trials databases, conference proceedings, and reference lists of retrieved articles for randomised and quasi-randomised controlled trials. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials of early initiation of EAS treatment versus placebo or no intervention in preterm or low birth weight infants. DATA COLLECTION AND ANALYSIS: We used the methods described in the Cochrane Handbook for Systematic Reviews of Interventions and the GRADE approach to assess the quality of evidence. MAIN RESULTS: This updated review includes 34 studies enrolling 3643 infants. All analyses compared ESAs versus a control consisting of placebo or no treatment. Early ESAs reduced the risk of 'use of one or more [red blood cell] RBC transfusions' (typical risk ratio (RR) 0.79, 95% confidence interval (CI) 0.74 to 0.85; typical risk difference (RD) -0.14, 95% CI -0.18 to -0.10; I2 = 69% for RR and 62% for RD (moderate heterogeneity); number needed to treat for an additional beneficial outcome (NNTB) 7, 95% CI 6 to 10; 19 studies, 1750 infants). The quality of the evidence was low. Necrotising enterocolitis was significantly reduced in the ESA group compared with the placebo group (typical RR 0.69, 95% CI 0.52 to 0.91; typical RD -0.03, 95% CI -0.05 to -0.01; I2 = 0% for RR and 22% for RD (low heterogeneity); NNTB 33, 95% CI 20 to 100; 15 studies, 2639 infants). The quality of the evidence was moderate. Data show a reduction in 'Any neurodevelopmental impairment at 18 to 22 months' corrected age in the ESA group (typical RR 0.62, 95% CI 0.48 to 0.80; typical RD -0.08, 95% CI -0.12 to -0.04; NNTB 13, 95% CI 8 to 25. I2 = 76% for RR (high heterogeneity) and 66% for RD (moderate); 4 studies, 1130 infants). The quality of the evidence was low. Results reveal increased scores on the Bayley-II Mental Development Index (MDI) at 18 to 24 months in the ESA group (weighted mean difference (WMD) 8.22, 95% CI 6.52 to 9.92; I2 = 97% (high heterogeneity); 3 studies, 981 children). The quality of the evidence was low. The total volume of RBCs transfused per infant was reduced by 7 mL/kg. The number of RBC transfusions per infant was minimally reduced, but the number of donors to whom infants who were transfused were exposed was not significantly reduced. Data show no significant difference in risk of stage ≥ 3 retinopathy of prematurity (ROP) with early EPO (typical RR 1.24, 95% CI 0.81 to 1.90; typical RD 0.01, 95% CI -0.02 to 0.04; I2 = 0% (no heterogeneity) for RR; I2 = 34% (low heterogeneity) for RD; 8 studies, 1283 infants). Mortality was not affected, but results show significant reductions in the incidence of intraventricular haemorrhage (IVH) and periventricular leukomalacia (PVL). AUTHORS' CONCLUSIONS: Early administration of ESAs reduces the use of red blood cell (RBC) transfusions, the volume of RBCs transfused, and donor exposure after study entry. Small reductions are likely to be of limited clinical importance. Donor exposure probably is not avoided, given that all but one study included infants who had received RBC transfusions before trial entry. This update found no significant difference in the rate of ROP (stage ≥ 3) for studies that initiated EPO treatment at less than eight days of age, which has been a topic of concern in earlier versions of this review. Early EPO treatment significantly decreased rates of IVH, PVL, and NEC. Neurodevelopmental outcomes at 18 to 22 months and later varied in published studies. Ongoing research should evaluate current clinical practices that will limit donor exposure. Promising but conflicting results related to the neuro protective effect of early EPO require further study. Very different results from the two largest published trials and high heterogeneity in the analyses indicate that we should wait for the results of two ongoing large trials before drawing firm conclusions. Administration of EPO is not currently recommended because limited benefits have been identified to date. Use of darbepoetin requires further study.

Late erythropoiesis-stimulating agents to prevent red blood cell transfusion in preterm or low birth weight infants.

BACKGROUND: 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. OBJECTIVES: 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. SEARCH METHODS: 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. SELECTION CRITERIA: 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. DATA COLLECTION AND ANALYSIS: 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. MAIN RESULTS: 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. AUTHORS' CONCLUSIONS: 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.

Late erythropoiesis-stimulating agents to prevent red blood cell transfusion in preterm or low birth weight infants.

BACKGROUND: 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. OBJECTIVES: 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. SEARCH METHODS: 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. SELECTION CRITERIA: 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. DATA COLLECTION AND ANALYSIS: 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. MAIN RESULTS: 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. AUTHORS' CONCLUSIONS: 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.

Early erythropoiesis-stimulating agents in preterm or low birth weight infants.

BACKGROUND: 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 and to provide neuro protection and protection against necrotising enterocolitis (NEC). Darbepoetin (Darbe) and EPO are currently available ESAs. OBJECTIVES: To assess the effectiveness and safety of ESAs (erythropoietin (EPO) and/or Darbe) initiated early (before eight days after birth) compared with placebo or no intervention in reducing red blood cell (RBC) transfusions, adverse neurological outcomes, and feeding intolerance including necrotising enterocolitis (NEC) in preterm and/or low birth weight infants. Primary objective for studies that primarily investigate the effectiveness and safety of ESAs administered early in reducing red blood cell transfusions:To assess the effectiveness and safety of ESAs initiated early in reducing red blood cell transfusions in preterm infants. Secondary objectives:Review authors performed subgroup analyses of low (≤ 500 IU/kg/week) and high (> 500 IU/kg/week) doses of EPO and the amount of iron supplementation provided: none, low (≤ 5 mg/kg/d), and high (> 5 mg/kg/d). Primary objective for studies that primarily investigate the neuro protective effectiveness of ESAs:To assess the effectiveness and safety of ESAs initiated early in reducing adverse neurological outcomes in preterm infants. Primary objective for studies that primarily investigate the effectiveness of EPO or Darbe administered early in reducing feeding intolerance:To assess the effectiveness and safety of ESAs administered early in reducing feeding intolerance (and NEC) in preterm infants. Other secondary objectives:To compare the effectiveness of ESAs in reducing the incidence of adverse events and improving long-term neurodevelopmental outcomes. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 2), MEDLINE via PubMed (1966 to 10 March 2017), Embase (1980 to 10 March 2017), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 10 March 2017). We searched clinical trials databases, conference proceedings, and reference lists of retrieved articles for randomised and quasi-randomised controlled trials. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials of early initiation of EAS treatment versus placebo or no intervention in preterm or low birth weight infants. DATA COLLECTION AND ANALYSIS: We used the methods described in the Cochrane Handbook for Systematic Reviews of Interventions and the GRADE approach to assess the quality of evidence. MAIN RESULTS: This updated review includes 34 studies enrolling 3643 infants. All analyses compared ESAs versus a control consisting of placebo or no treatment.Early ESAs reduced the risk of 'use of one or more [red blood cell] RBC transfusions' (typical risk ratio (RR) 0.79, 95% confidence interval (CI) 0.74 to 0.85; typical risk difference (RD) -0.14, 95% CI -0.18 to -0.10; I2 = 69% for RR and 62% for RD (moderate heterogeneity); number needed to treat for an additional beneficial outcome (NNTB) 7, 95% CI 6 to 10; 19 studies, 1750 infants). The quality of the evidence was low.Necrotising enterocolitis was significantly reduced in the ESA group compared with the placebo group (typical RR 0.69, 95% CI 0.52 to 0.91; typical RD -0.03, 95% CI -0.05 to -0.01; I2 = 0% for RR and 22% for RD (low heterogeneity); NNTB 33, 95% CI 20 to 100; 15 studies, 2639 infants). The quality of the evidence was moderate.Data show a reduction in 'Any neurodevelopmental impairment at 18 to 22 months' corrected age in the ESA group (typical RR 0.62, 95% CI 0.48 to 0.80; typical RD -0.08, 95% CI -0.12 to -0.04; NNTB 13, 95% CI 8 to 25. I2 = 76% for RR (high heterogeneity) and 66% for RD (moderate); 4 studies, 1130 infants). The quality of the evidence was low.Results reveal increased scores on the Bayley-II Mental Development Index (MDI) at 18 to 24 months in the ESA group (weighted mean difference (WMD) 8.22, 95% CI 6.52 to 9.92; I2 = 97% (high heterogeneity); 3 studies, 981 children). The quality of the evidence was low.The total volume of RBCs transfused per infant was reduced by 7 mL/kg. The number of RBC transfusions per infant was minimally reduced, but the number of donors to whom infants who were transfused were exposed was not significantly reduced. Data show no significant difference in risk of stage ≥ 3 retinopathy of prematurity (ROP) with early EPO (typical RR 1.24, 95% CI 0.81 to 1.90; typical RD 0.01, 95% CI -0.02 to 0.04; I2 = 0% (no heterogeneity) for RR; I2 = 34% (low heterogeneity) for RD; 8 studies, 1283 infants). Mortality was not affected, but results show significant reductions in the incidence of intraventricular haemorrhage (IVH) and periventricular leukomalacia (PVL). AUTHORS' CONCLUSIONS: Early administration of ESAs reduces the use of red blood cell (RBC) transfusions, the volume of RBCs transfused, and donor exposure after study entry. Small reductions are likely to be of limited clinical importance. Donor exposure probably is not avoided, given that all but one study included infants who had received RBC transfusions before trial entry. This update found no significant difference in the rate of ROP (stage ≥ 3) for studies that initiated EPO treatment at less than eight days of age, which has been a topic of concern in earlier versions of this review. Early EPO treatment significantly decreased rates of IVH, PVL, and NEC. Neurodevelopmental outcomes at 18 to 22 months and later varied in published studies. Ongoing research should evaluate current clinical practices that will limit donor exposure. Promising but conflicting results related to the neuro protective effect of early EPO require further study. Very different results from the two largest published trials and high heterogeneity in the analyses indicate that we should wait for the results of two ongoing large trials before drawing firm conclusions. Administration of EPO is not currently recommended because limited benefits have been identified to date. Use of darepoetin requires further study.

Term babies with delayed cord clamping: an approach in preventing anemia (.).

OBJECTIVE: We investigated the effects of delayed and early clamping of the cord on the hematologic status of the baby at birth and at the end of second month. METHODS: Umbilical cord of 74 babies were clamped in the first 30 s (Group 1) and 76 were clamped at 90-120 s (Group 2). Levels of hemoglobin, hematocrit, iron and ferritin were analyzed from the umbilical cord blood at birth and from the venous samples at the end of second month. RESULTS: Hemoglobin, hematocrit, iron and ferritin levels of cord blood were similar in both groups. However, their levels other than ferritin were higher in Group 2 at the end of second month. Two babies had respiratory distress and twelve neonates received phototherapy in Group 2 whereas only five neonates received phototherapy in Group 1. CONCLUSION: Term babies to whom delayed cord clamping was performed had improved hematological parameters at the end of second month. Therefore, delaying cord clamping in these babies may be a favorible approach in preventing anemia.

What kind of milk can prevent infant's sideropenic anemia--comparative study.

INTRODUCTION: The most common cause of sideropenic anemia in infants, during the period of their fast growth and development, is inadequate nutrition or insufficient intake of food rich in iron. The aim of this paper is to provide the insight into the problem of anemia and to emphasize nutrition as an important etiologic factor in the onset and prevention of anemia in infants. MATERIAL AND METHODS: Two retrospective studies were conducted at the Institute for Child and Youth Healthcare of Vojvodina. Department for Infant and Small Children's Pathology. The first study covered the period of eight years (1988-1995), and it included a total of 507 children, aged 1-24 months. The second study covered the period of two years (2010-2011) and a total of 290 children aged 1-12 months were included. The diagnosis of anemia was made according to clinical examination or after taking routine laboratory tests. According to the criteria of the World Health Organization, all children were divided into those with severe, moderate or mild anemia. RESULTS: Out of 507 children examined in the first study, 333 (65.68%) were breastfed, while 174 (34.32%) had never been breastfed. In the second study, 206 (71.03%) out of 290 children were breastfed, while 56 (19.31%) had never been breastfed. In both studies the highest percentage of children breastfed for the longest period was among children with mild form of anemia, while the children who were breastfed for the shortest period had severe anemia. In addition, the highest percentage of anemic children was supplementary fed with cow's milk in both studies. CONCLUSION: Short natural diet, early introduction of supplementation and choice of milk could be determining factors in the development and manifestation of anemia.

Late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants.

BACKGROUND: Low plasma levels of erythropoietin (EPO) in preterm infants provide a rationale for the use of EPO to prevent or treat anaemia. OBJECTIVES: 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. SEARCH METHODS: 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. SELECTION CRITERIA: 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 ANALYSIS: We performed data collection and analyses in accordance with the methods of the Cochrane Neonatal Review Group. MAIN RESULTS: 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. AUTHORS' CONCLUSIONS: 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.

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

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

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

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

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

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

Late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants.

BACKGROUND: Low plasma levels of erythropoietin (EPO) in preterm infants provide a rationale for the use of EPO to prevent or treat anaemia. OBJECTIVES: 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. SEARCH METHODS: 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). SELECTION CRITERIA: 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 ANALYSIS: Data collection and analyses were performed in accordance with the methods of the Cochrane Neonatal Review Group. MAIN RESULTS: 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. AUTHORS' CONCLUSIONS: 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.

Rethinking placental transfusion and cord clamping issues.

A brief delay in clamping the umbilical cord results in a placental transfusion that supplies the infant with a major source of iron during the first few months of life. Cord circulation continues for several minutes after birth and placental transfusion results in approximately 30% more blood volume. Gravity influences the amount of placental transfusion that an infant receives. Placing the infant skin-to-skin requires a longer delay of cord clamping (DCC) than current recommendations. Uterotonics are not contraindicated with DCC. Cord milking is a safe alternative to DCC when one must cut the cord prematurely. Recent randomized controlled trials demonstrate benefits for term and preterm infants from DCC. The belief that DCC causes hyperbilirubinemia or symptomatic polycythemia is unsupported by the available research. Delay of cord clamping substantively increases iron stores in early infancy. Inadequate iron stores in infancy may have an irreversible impact on the developing brain despite oral iron supplementation. Iron deficiency in infancy can lead to neurologic issues in older children including poor school performance, decreased cognitive abilities, and behavioral problems. The management of the umbilical cord in complex situations is inconsistent between birth settings. A change in practice requires collaboration between all types of providers who attend births.

Effect of delayed versus early umbilical cord clamping on neonatal outcomes and iron status at 4 months: a randomised controlled trial.

OBJECTIVE: To investigate the effects of delayed umbilical cord clamping, compared with early clamping, on infant iron status at 4 months of age in a European setting. DESIGN: Randomised controlled trial. SETTING: Swedish county hospital. PARTICIPANTS: 400 full term infants born after a low risk pregnancy. INTERVENTION: Infants were randomised to delayed umbilical cord clamping (≥ 180 seconds after delivery) or early clamping (≤ 10 seconds after delivery). MAIN OUTCOME MEASURES: Haemoglobin and iron status at 4 months of age with the power estimate based on serum ferritin levels. Secondary outcomes included neonatal anaemia, early respiratory symptoms, polycythaemia, and need for phototherapy. RESULTS: At 4 months of age, infants showed no significant differences in haemoglobin concentration between the groups, but infants subjected to delayed cord clamping had 45% (95% confidence interval 23% to 71%) higher mean ferritin concentration (117 µg/L v 81 µg/L, P < 0.001) and a lower prevalence of iron deficiency (1 (0.6%) v 10 (5.7%), P = 0.01, relative risk reduction 0.90; number needed to treat = 20 (17 to 67)). As for secondary outcomes, the delayed cord clamping group had lower prevalence of neonatal anaemia at 2 days of age (2 (1.2%) v 10 (6.3%), P = 0.02, relative risk reduction 0.80, number needed to treat 20 (15 to 111)). There were no significant differences between groups in postnatal respiratory symptoms, polycythaemia, or hyperbilirubinaemia requiring phototherapy. CONCLUSIONS: Delayed cord clamping, compared with early clamping, resulted in improved iron status and reduced prevalence of iron deficiency at 4 months of age, and reduced prevalence of neonatal anaemia, without demonstrable adverse effects. As iron deficiency in infants even without anaemia has been associated with impaired development, delayed cord clamping seems to benefit full term infants even in regions with a relatively low prevalence of iron deficiency anaemia. Trial registration Clinical Trials NCT01245296.

Effects of early human recombinant erythropoietin therapy on the transfusion in healthy preterm infants.

OBJECTIVE: Early recombinant erythropoietin therapy and iron therapy would decrease the need for red blood cells transfusions and prevents anemia of prematurity. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

The importance of delayed cord clamping for Aboriginal babies: a life-enhancing advantage.

Third stage management has typically focused on women and postpartum haemorrhage. Clamping and cutting the umbilical cord following the birth of the baby has continued to be a routine part of this focus. Active versus physiological management of third stage is generally accepted as an evidence-based plan for women to avoid excessive blood loss. Other considerations around this decision are rarely considered, including the baby's perspective. This paper provides a review of the literature regarding timing of clamping and cutting of the umbilical cord and related issues, and discusses the consequences for babies and in particular *Aboriginal babies. Iron stores in babies are improved (among other important advantages) if the cord is left to stop pulsating for 3 min before being clamped. Such a simple measure of patience and informed practice can make a long lasting difference to a baby's health and for Aboriginal babies this advantage can be critical in the short and the long term for their development and wellbeing. To achieve much needed reductions in infancy anaemia and essential increases in infant survival, delayed cord clamping and cutting is recommended for all Aboriginal babies.

[Effects of recombinant human erythropoietin in preterm newborns with infectious diseases]. / Efeitos da eritropoetina recombinante humana em recém-nascidos pré-termo com doenças infecciosas.

OBJECTIVE: To study the effects of recombinant human erythropoietin (rHuEpo) in preterm newborns (PTNs) with serious infectious diseases. METHODS: A not randomized case-control study was carried out in 34 preterm newborns with diagnosis of serious infectious pathologies, gestational age up to 35 weeks, birth weight less than 1500 g and clinical stability. Newborns selected for treatment with rHuEpo received 400 U/kg erythropoietin ss, subcutaneously twice a week. Oral iron supplementation was initiated when the levels of serum ferritin were lower than 60 mcg/l. The study was continued for six weeks or until the patient was discharged from the hospital. Erythropoiesis, granulopoiesis, thrombocytopoiesis, the need for transfusions and the occurrence of new episodes of infectious disease were analyzed. RESULTS: In the treated group there was a significant increase in the number of reticulocytes, although there was no statistically significant difference between the groups with regard to the number or volume of transfusions. There was no significant difference in neutrophils and platelet values. CONCLUSION: The use of rHuEpo, 800 U/kg/week, in PTNs with infectious diseases was effective in inducing erythropoiesis, without significant changes in the number of neutrophils or platelets. This strategy, and the accurate control of the blood collected for laboratory exams, may be beneficial for prevention of the anemia in PTNs with serious infectious diseases.

Efeitos da eritropoetina recombinante humana em recém-nascidos pré-termo com doenças infecciosas / Effects of recombinant human erythropoietin in preterm newborns with infectious diseases

OBJETIVO: Analisar os efeitos da eritropoetina recombinante humana (rHuEpo) em recém-nascidos pré-termo com doenças infecciosas graves. MÉTODOS: Foi realizado um estudo controlado, não randomizado, em 34 recém-nascidos com diagnóstico de patologias infecciosas graves, peso de nascimento igual ou inferior a 1500 g, idade gestacional inferior a 35 semanas e estabilidade clínica. Os recém-nascidos designados para o tratamento com rHuEpo receberam a eritropoetina ß na dose de 400 UI/kg, duas vezes por semana, por via subcutânea. A suplementação oral com ferro foi iniciada quando os níveis de ferritina sérica foram inferiores a 60 mcg/L. O estudo foi realizado durante seis semanas ou até a alta hospitalar do paciente. Foram avaliados a eritropoese, o número de transfusões, o número de neutrófilos, a contagem de plaquetas e os episódios de novas infecções durante o tratamento com o hormônio. RESULTADOS: Houve aumento significativo do número de reticulócitos no grupo tratado; entretanto, não houve impacto sobre o número ou volume de transfusões. Não foram observadas alterações no número de neutrófilos ou plaquetas. CONCLUSÃO: O uso de rHuEpo em RNPT com doenças infecciosas, na dose de 800 UI/Kg/semana, foi efetivo para induzir eritropoese, sem ocorrerem alterações significativas sobre o número de neutrófilos ou plaquetas. Essa estratégia, associada ao controle rigoroso do volume de sangue retirado para exames, poderá ser benéfica na prevenção da anemia em RNPT com infecção grave.

OBJECTIVE: To study the effects of recombinant human erythropoietin (rHuEpo) in preterm newborns (PTNs) with serious infectious diseases. METHODS: A not randomized case-control study was carried out in 34 preterm newborns with diagnosis of serious infectious pathologies, gestational age up to 35 weeks, birth weight less than 1500 g and clinical stability. Newborns selected for treatment with rHuEpo received 400 U/kg erythropoietin ß, subcutaneously twice a week. Oral iron supplementation was initiated when the levels of serum ferritin were lower than 60 mcg/l. The study was continued for six weeks or until the patient was discharged from the hospital. Erythropoiesis, granulopoiesis, thrombocytopoiesis, the need for transfusions and the occurrence of new episodes of infectious disease were analyzed. RESULTS: In the treated group there was a significant increase in the number of reticulocytes, although there was no statistically significant difference between the groups with regard to the number or volume of transfusions. There was no significant difference in neutrophils and platelet values. CONCLUSION: The use of rHuEpo, 800 U/kg/week, in PTNs with infectious diseases was effective in inducing erythropoiesis, without significant changes in the number of neutrophils or platelets. This strategy, and the accurate control of the blood collected for laboratory exams, may be beneficial for prevention of the anemia in PTNs with serious infectious diseases.