Arne Ohlsson1, Sanjay M Aher. 1. Departments of Paediatrics, Obstetrics and Gynaecology and Institute of Health Policy, Management and Evaluation, University ofToronto, Toronto, Canada. aohlsson@mtsinai.on.ca.
Abstract
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 early initiation of EPO in reducing red blood cell (RBC) transfusions in preterm and/or low birth weight infants. SEARCH METHODS: 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). SELECTION CRITERIA: 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: Data collection and analysis were accomplished using the methods of the Neonatal Cochrane Review Group. MAIN RESULTS: 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. AUTHORS' CONCLUSIONS: 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.
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 early initiation of EPO in reducing red blood cell (RBC) transfusions in preterm and/or low birth weight infants. SEARCH METHODS: 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). SELECTION CRITERIA: 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: Data collection and analysis were accomplished using the methods of the Neonatal Cochrane Review Group. MAIN RESULTS: 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. AUTHORS' CONCLUSIONS: 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.