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Meta-Analysis
. 2017 Nov 16;11(11):CD004863.
doi: 10.1002/14651858.CD004863.pub5.

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

Arne Ohlsson  1 , Sanjay M Aher
Affiliations
Meta-Analysis

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

Arne Ohlsson et al. Cochrane Database Syst Rev. .

Update in

Abstract

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.

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Conflict of interest statement

None.

Figures

Figure 1
Figure 1
Study flow diagram: review update.
Figure 2
Figure 2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figure 3
Figure 3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figure 4
Figure 4
Forest plot of comparison: 1 Erythropoietin versus placebo or no treatment, outcome: 1.1 Use of 1 or more red blood cell transfusions (low and high doses of EPO).
Figure 5
Figure 5
Funnel plot of comparison: 1 Erythropoietin versus placebo or no treatment, outcome: 1.1 Use of 1 or more red blood cell transfusions (low and high doses of EPO).
Analysis 1.1
Analysis 1.1
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 1 Use of 1 or more red blood cell transfusions (low and high doses of EPO).
Analysis 1.2
Analysis 1.2
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 2 Use of 1 or more blood transfusions (high dose of EPO).
Analysis 1.3
Analysis 1.3
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 3 Use of 1 or more red blood cell transfusions (low‐dose EPO).
Analysis 1.4
Analysis 1.4
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 4 Total volume (mL/kg) of blood transfused per infant.
Analysis 1.5
Analysis 1.5
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 5 Number of red blood transfusions per infant.
Analysis 1.6
Analysis 1.6
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 6 Number of donors to whom the infant was exposed.
Analysis 1.7
Analysis 1.7
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 7 Mortality during initial hospital stay (all causes of mortality).
Analysis 1.8
Analysis 1.8
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 8 Retinopathy of prematurity (all stages or stage not reported).
Analysis 1.9
Analysis 1.9
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 9 Retinopathy of prematurity (stage ≥ 3).
Analysis 1.10
Analysis 1.10
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 10 Proven sepsis.
Analysis 1.11
Analysis 1.11
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 11 Necrotising enterocolitis (stage not reported).
Analysis 1.12
Analysis 1.12
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 12 Intraventricular haemorrhage (all grades).
Analysis 1.13
Analysis 1.13
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 13 Intraventricular haemorrhage (grades III and IV).
Analysis 1.14
Analysis 1.14
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 14 Periventricular leukomalacia.
Analysis 1.15
Analysis 1.15
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 15 Length of hospital stay (days).
Analysis 1.16
Analysis 1.16
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 16 Bronchopulmonary dysplasia.
Analysis 1.17
Analysis 1.17
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 17 Neutropenia.
Analysis 1.18
Analysis 1.18
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 18 Hypertension.
Analysis 1.19
Analysis 1.19
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 19 Hemangioma.
Analysis 1.20
Analysis 1.20
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 20 Neonatal Behavioral Neurological Assessment at 40 weeks' PMA.
Analysis 1.21
Analysis 1.21
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 21 Infants with white matter injury at term‐corrected PMA.
Analysis 1.22
Analysis 1.22
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 22 Infants with white matter signal abnormality at term‐corrected PMA.
Analysis 1.23
Analysis 1.23
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 23 Infants with periventricular white matter loss at term‐corrected PMA.
Analysis 1.24
Analysis 1.24
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 24 Infants with grey matter injury at term‐corrected PMA.
Analysis 1.25
Analysis 1.25
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 25 Survivors at discharge from hospital without severe IVH, PVL, ROP.
Analysis 1.26
Analysis 1.26
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 26 Bayley‐II MDI < 70 at 18 to 24 months' corrected age.
Analysis 1.27
Analysis 1.27
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 27 Bayley‐II PDI < 70 at 18 to 22 months' corrected age (in children examined).
Analysis 1.28
Analysis 1.28
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 28 Bayley‐II MDI at 18 to 24 months.
Analysis 1.29
Analysis 1.29
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 29 Bayley‐II PDI at 18 to 24 months.
Analysis 1.30
Analysis 1.30
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 30 Cerebral palsy at 18 to 24 months' corrected age.
Analysis 1.31
Analysis 1.31
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 31 Any neurodevelopmental impairment at 18 to 22 months' corrected age (in children examined).
Analysis 1.32
Analysis 1.32
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 32 Visual impairment at 18 to 24 months' corrected age.
Analysis 1.33
Analysis 1.33
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 33 Hearing impairment at 18 to 24 months' corrected age.
Analysis 1.34
Analysis 1.34
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 34 BSID‐III composite cognitive scores at 18 to 22 months.
Analysis 1.35
Analysis 1.35
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 35 BSID‐III composite language score.
Analysis 1.36
Analysis 1.36
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 36 BSID‐III composite social/emotional score.
Analysis 1.37
Analysis 1.37
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 37 BSID‐III object performance (OP) score.
Analysis 1.38
Analysis 1.38
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 38 WPPSI‐III FSIQ at 3.5 to 4 years of age.
Analysis 1.39
Analysis 1.39
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 39 WPPSI‐III VIQ at 3.5 to 4 years of age.
Analysis 1.40
Analysis 1.40
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 40 WPPSI‐III PIQ at 3.5 to 4 years of age.
Analysis 1.41
Analysis 1.41
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 41 WPPSI‐III GLC at 3.5 to 4 years of age.
Analysis 1.42
Analysis 1.42
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 42 Executive function at 3.5 to 4 years of age.
Analysis 1.43
Analysis 1.43
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 43 Working memory at 3.5 to 4 years of age.
Analysis 1.44
Analysis 1.44
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 44 Inhibition at 3.5 to 4 years of age.
Analysis 1.45
Analysis 1.45
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 45 Griffiths Developmental Scale at 2 years of age.
Analysis 1.46
Analysis 1.46
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 46 Survival without major neurological or neurodevelopmental disorders at 2 years of age.
Analysis 1.47
Analysis 1.47
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 47 Death or moderate/severe neurological disability at 18 to 24 months.
Analysis 1.48
Analysis 1.48
Comparison 1 Erythropoietin versus placebo or no treatment, Outcome 48 Moderate/severe neurological disability at 18 to 24 months.
Analysis 2.1
Analysis 2.1
Comparison 2 Darbepoetin alfa versus placebo or no treatment, Outcome 1 Use of 1 or more red blood cell transfusions.
Analysis 2.2
Analysis 2.2
Comparison 2 Darbepoetin alfa versus placebo or no treatment, Outcome 2 Total volume (mL/kg) of blood transfused per infant (all infants).
Analysis 2.3
Analysis 2.3
Comparison 2 Darbepoetin alfa versus placebo or no treatment, Outcome 3 Total volume (mL/kg) of blood transfused in transfused infants only.
Analysis 2.4
Analysis 2.4
Comparison 2 Darbepoetin alfa versus placebo or no treatment, Outcome 4 Number of blood transfusions per infant.
Analysis 2.5
Analysis 2.5
Comparison 2 Darbepoetin alfa versus placebo or no treatment, Outcome 5 Number of donors the infant was exposed to.
Analysis 2.6
Analysis 2.6
Comparison 2 Darbepoetin alfa versus placebo or no treatment, Outcome 6 Mortality during initial hospital stay (all causes of mortality).
Analysis 2.7
Analysis 2.7
Comparison 2 Darbepoetin alfa versus placebo or no treatment, Outcome 7 Retinopathy of prematurity (all stages).
Analysis 2.8
Analysis 2.8
Comparison 2 Darbepoetin alfa versus placebo or no treatment, Outcome 8 Retinopathy of prematurity (stage ≥ 3).
Analysis 2.9
Analysis 2.9
Comparison 2 Darbepoetin alfa versus placebo or no treatment, Outcome 9 Necrotising enterocolitis (> stage 2).
Analysis 2.10
Analysis 2.10
Comparison 2 Darbepoetin alfa versus placebo or no treatment, Outcome 10 Proven sepsis.
Analysis 2.11
Analysis 2.11
Comparison 2 Darbepoetin alfa versus placebo or no treatment, Outcome 11 Intraventricular haemorrhage (grades III and IV).
Analysis 2.12
Analysis 2.12
Comparison 2 Darbepoetin alfa versus placebo or no treatment, Outcome 12 Periventricular leukomalacia.
Analysis 2.13
Analysis 2.13
Comparison 2 Darbepoetin alfa versus placebo or no treatment, Outcome 13 Bronchopulmonary dysplasia (supplemental oxygen at 36 weeks' PMA).
Analysis 2.14
Analysis 2.14
Comparison 2 Darbepoetin alfa versus placebo or no treatment, Outcome 14 Length of hospital stay (days).
Analysis 2.15
Analysis 2.15
Comparison 2 Darbepoetin alfa versus placebo or no treatment, Outcome 15 Neutropenia.
Analysis 2.16
Analysis 2.16
Comparison 2 Darbepoetin alfa versus placebo or no treatment, Outcome 16 Hypertension.
Analysis 2.17
Analysis 2.17
Comparison 2 Darbepoetin alfa versus placebo or no treatment, Outcome 17 Cerebral palsy at 18 to 22 months.
Analysis 2.18
Analysis 2.18
Comparison 2 Darbepoetin alfa versus placebo or no treatment, Outcome 18 NDI (with CP, visual defect, hearing defect, or cognitive score < 85) at 18 to 22 months.
Analysis 2.19
Analysis 2.19
Comparison 2 Darbepoetin alfa versus placebo or no treatment, Outcome 19 BSID‐III composite cognitive score at 18 to 22 months.
Analysis 2.20
Analysis 2.20
Comparison 2 Darbepoetin alfa versus placebo or no treatment, Outcome 20 BSID‐III composite language score at 18 to 22 months.
Analysis 2.21
Analysis 2.21
Comparison 2 Darbepoetin alfa versus placebo or no treatment, Outcome 21 Bayley‐III social/emotional score at 18 to 22 months.
Analysis 2.22
Analysis 2.22
Comparison 2 Darbepoetin alfa versus placebo or no treatment, Outcome 22 OP score at 18 to 22 months.
Analysis 2.23
Analysis 2.23
Comparison 2 Darbepoetin alfa versus placebo or no treatment, Outcome 23 WPPSI‐III FSIQ at 3.5 to 4 years of age.
Analysis 2.24
Analysis 2.24
Comparison 2 Darbepoetin alfa versus placebo or no treatment, Outcome 24 WPPSI‐III VIQ at 3.5 to 4 years of age.
Analysis 2.25
Analysis 2.25
Comparison 2 Darbepoetin alfa versus placebo or no treatment, Outcome 25 WPPSI‐III PIQ at 3.5 to 4 years of age.
Analysis 2.26
Analysis 2.26
Comparison 2 Darbepoetin alfa versus placebo or no treatment, Outcome 26 WPPSI‐III GLC at 3.5 to 4 years of age.
Analysis 2.27
Analysis 2.27
Comparison 2 Darbepoetin alfa versus placebo or no treatment, Outcome 27 Executive function at 3.5 to 4 years of age.
Analysis 2.28
Analysis 2.28
Comparison 2 Darbepoetin alfa versus placebo or no treatment, Outcome 28 Working memory at 3.5 to 4 years of age.
Analysis 2.29
Analysis 2.29
Comparison 2 Darbepoetin alfa versus placebo or no treatment, Outcome 29 Inhibition at 3.5 to 4 years of age.
Analysis 3.1
Analysis 3.1
Comparison 3 Darbepoetin alfa or erythropoietin (erythropoiesis‐stimulating agents ‐ ESAs) versus placebo or no treatment, Outcome 1 BSID‐III composite cognitive score at 18 to 22 months.
Analysis 3.2
Analysis 3.2
Comparison 3 Darbepoetin alfa or erythropoietin (erythropoiesis‐stimulating agents ‐ ESAs) versus placebo or no treatment, Outcome 2 BSID‐III composite language score at 18 to 22 months.
Analysis 3.3
Analysis 3.3
Comparison 3 Darbepoetin alfa or erythropoietin (erythropoiesis‐stimulating agents ‐ ESAs) versus placebo or no treatment, Outcome 3 BSID‐III composite social/emotional score at 18 to 22 months.
Analysis 3.4
Analysis 3.4
Comparison 3 Darbepoetin alfa or erythropoietin (erythropoiesis‐stimulating agents ‐ ESAs) versus placebo or no treatment, Outcome 4 OP score at 18 to 24 months.
Analysis 3.5
Analysis 3.5
Comparison 3 Darbepoetin alfa or erythropoietin (erythropoiesis‐stimulating agents ‐ ESAs) versus placebo or no treatment, Outcome 5 BASC‐2 composite scores at 3.5 to 4 years ‐ adaptive skills.
Analysis 3.6
Analysis 3.6
Comparison 3 Darbepoetin alfa or erythropoietin (erythropoiesis‐stimulating agents ‐ ESAs) versus placebo or no treatment, Outcome 6 BASC‐2 composite scores at 3.5 to 4 years ‐ behaviour symptoms.
Analysis 3.7
Analysis 3.7
Comparison 3 Darbepoetin alfa or erythropoietin (erythropoiesis‐stimulating agents ‐ ESAs) versus placebo or no treatment, Outcome 7 BASC‐2 composite score at 3.5 to 4 years ‐ externalising problems.
Analysis 3.8
Analysis 3.8
Comparison 3 Darbepoetin alfa or erythropoietin (erythropoiesis‐stimulating agents ‐ ESAs) versus placebo or no treatment, Outcome 8 BASC‐2 composite scores at 3.5 to 4 years ‐ internalising problems.
Analysis 3.9
Analysis 3.9
Comparison 3 Darbepoetin alfa or erythropoietin (erythropoiesis‐stimulating agents ‐ ESAs) versus placebo or no treatment, Outcome 9 WPPSI‐III FSIQ at 3.5 to 4 years of age.
Analysis 3.10
Analysis 3.10
Comparison 3 Darbepoetin alfa or erythropoietin (erythropoiesis‐stimulating agents ‐ ESAs) versus placebo or no treatment, Outcome 10 WPPSI‐III VIQ at 3.5 to 4 years of age.
Analysis 3.11
Analysis 3.11
Comparison 3 Darbepoetin alfa or erythropoietin (erythropoiesis‐stimulating agents ‐ ESAs) versus placebo or no treatment, Outcome 11 WPPSI‐III PIQ at 3.5 to 4 years of age.
Analysis 3.12
Analysis 3.12
Comparison 3 Darbepoetin alfa or erythropoietin (erythropoiesis‐stimulating agents ‐ ESAs) versus placebo or no treatment, Outcome 12 WPPSI‐III GLC at 3.5 to 4 years of age.
Analysis 3.13
Analysis 3.13
Comparison 3 Darbepoetin alfa or erythropoietin (erythropoiesis‐stimulating agents ‐ ESAs) versus placebo or no treatment, Outcome 13 Executive function at 3.5 to 4 years.
Analysis 3.14
Analysis 3.14
Comparison 3 Darbepoetin alfa or erythropoietin (erythropoiesis‐stimulating agents ‐ ESAs) versus placebo or no treatment, Outcome 14 Working memory at 3.5 to 4 years.
Analysis 3.15
Analysis 3.15
Comparison 3 Darbepoetin alfa or erythropoietin (erythropoiesis‐stimulating agents ‐ ESAs) versus placebo or no treatment, Outcome 15 Inhibition at 3.5 to 4 years.
Analysis 4.1
Analysis 4.1
Comparison 4 Erythropoietin versus placebo to improve feeding intolerance, Outcome 1 Time to achieve full enteral feeding (days).
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Update of

References

References to studies included in this review

    1. Arif B, Ferhan K. Recombinant human erythropoietin therapy in low‐birthweight preterm infants: a prospective controlled study. Pediatrics International 2005;47(1):67‐71. [DOI: 10.1111/j.1442-200x.2005.02007.x; PUBMED: 15693870] - DOI - PubMed
    1. Avent M, Cory BJ, Galpin J, Ballot DE, Cooper PA, Sherman G, et al. A comparison of high versus low dose recombinant human erythropoietin versus blood transfusion in the management of anaemia of prematurity in a developing country. Journal of Tropical Pediatrics 2002;48(4):227‐33. [PUBMED: 12200985] - PubMed
    1. Carnielli V, Montini G, Riol R, Dall'Amico R, Cantarutti F. Effect of high doses of human recombinant erythropoietin on the need for blood transfusions in preterm infants. Journal of Pediatrics 1992;121(1):98‐102. [PUBMED: 1625101] - PubMed
    1. Carnielli VP, Riol R, Montini G. Iron supplementation enhances response to high doses of recombinant human erythropoietin in preterm infants. Archives of Disease in Childhood. Fetal and Neonatal Edition 1998;79(1):F44‐8. [PUBMED: 9797624] - PMC - PubMed
    1. Chang L, Liu W, Liao C, Zhao X. Preventive effects of different dosages of recombinant human erythropoietin on anemia of premature infants. Journal of Tongji Medical University/Tong Ji Yi Ke da Xue Xue Bao 1998;18(4):239‐42. [PUBMED: 10806855] - PubMed

References to studies excluded from this review

    1. Al Mofada SM. Safety and efficacy of early erythropoietin administration to pre‐term infants: a preliminary report. Medical Science Research 1994;22(10):749‐50. [EMBASE: 1994345936]
    1. Amin AA, Alzahrani DM. Efficacy of erythropoietin in premature infants. Saudi Medical Journal 2002;23(3):287‐90. [PUBMED: 11938417] - PubMed
    1. Basiri B, Shokouhi M, Pezeshki N, Torabian S. Beneficial erythropoietic effects of recombinant human erythropoietin in very low‐birth weight infants: a single‐center randomized double‐blinded placebo‐controlled trial. Journal of Clinical Neonatology 2015;4(2):87‐90. [EMBASE: 2015952409]
    1. Bierer R, Peceney MC, Hartenberger CH, Ohls RK. Erythropoietin concentrations and neurodevelopmental outcome in preterm infants. Pediatrics 2006;118(3):e635‐40. [DOI: 10.1542/peds.2005-3186; PUBMED: 16908620] - DOI - PubMed
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References to ongoing studies

    1. NCT01378273. Preterm Erythropoietin Neuroprotection Trial (PENUT Trial). clinicaltrials.gov/show/NCT01378273 (first received 20 June 2011).
    1. NCT02550054. Erythropoietin in Premature Infants to Prevent Encephalopathy [Erythropoietin in Premature Infants to Prevent Encephalopathy: A Multi‐centre Randomized Blinded Controlled Study of the Efficacy of Erythropoietin in China]. clinicaltrials.gov/show/NCT02550054 (first received 04 September 2015).

Additional references

    1. Aher SM, Ohlsson A. Late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database of Systematic Reviews 2006, Issue 3. [DOI: 10.1002/14651858.CD004868.pub2] - DOI - PubMed
    1. Aher SM, Ohlsson A. Early versus late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database of Systematic Reviews 2006, Issue 3. [DOI: 10.1002/14651858.CD004865.pub2] - DOI - PubMed
    1. Aher SM, Ohlsson A. Late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database of Systematic Reviews 2012, Issue 9. [DOI: 10.1002/14651858.CD004868.pub3] - DOI - PubMed
    1. Aher SM, Ohlsson A. Early versus late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database of Systematic Reviews 2012, Issue 10. [DOI: 10.1002/14651858.CD004865.pub2] - DOI - PubMed
    1. Baer VL, Lambert DK, Henry E, Snow GL, Christensen RD. Red blood cell transfusion of preterm neonates with grade 1 intraventricular hemorrhage is associated with extension to a grade 3 or 4 hemorrhage. Transfusion 2011;51(9):1933‐9. [DOI: 10.1111/j.1537-2995.2011.03081.x; PUBMED: 21382049] - DOI - PubMed

References to other published versions of this review

    1. Ohlsson A, Aher SM. Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database of Systematic Reviews 2006, Issue 3. [DOI: 10.1002/14651858.CD004863.pub2] - DOI - PubMed
    1. Ohlsson A, Aher SM. Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database of Systematic Reviews 2012, Issue 9. [DOI: 10.1002/14651858.CD004863.pub3] - DOI - PubMed
    1. Ohlsson A, Aher SM. Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database of Systematic Reviews 2014, Issue 4. [DOI: 10.1002/14651858.CD004863.pub4] - DOI - PubMed

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