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Meta-Analysis
. 2020 Feb 11;2(2):CD004863.
doi: 10.1002/14651858.CD004863.pub6.

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

Arne Ohlsson  1 , Sanjay M Aher  2
Affiliations
Meta-Analysis

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

Arne Ohlsson et al. Cochrane Database Syst Rev. .

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 darbepoetin requires further study.

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Conflict of interest statement

None.

Figures

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

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    1. Lauterbach R, Kachlik P, Pawlik D, Bajorek I. Evaluation of treatment results for anemia of prematurity treated with various doses of human recombinant erythropoietin. Pediatria Polska 1995;70(9):739‐44. [PUBMED: 8657506] - PubMed
Lima‐Rogel 1998 {published data only}
    1. Lima‐Rogel V, Torres‐Montes A, Espinosa Griesse S, Villegas Alvarez C, Hernandez‐Sierra F, Bissett Mandeville P, et al. Efficacy of early erythropoietin use in critically ill very‐low‐birth‐weight premature newborn infants: controlled clinical trial [Eficacia del uso precoz de eritropoyetina en recien nacidos pretermino de muy bajo peso, criticamente enfermos: ensayo clinico controlado]. Sangre 1998;43(3):191‐5. [PUBMED: 9741224] - PubMed
Maier 1994 {published data only}
    1. Maier RF, Obladen M, Scigalla P, Linderkamp O, Duc G, Hieronimi G, et al. The effect of epoetin beta (recombinant human erythropoietin) on the need for transfusion in very‐low‐birth‐weight infants. European Multicentre Erythropoietin Study Group. New England Journal of Medicine 1994;330(17):1173‐8. [DOI: 10.1056/NEJM199404283301701; PUBMED: 8139627] - DOI - PubMed
Maier 2002 {published and unpublished data}
    1. Maier RF, Obladen M, Muller‐Hansen I, Kattner E, Merz U, Arlettaz R, et al. European Multicenter Erythropoietin Beta Study Group. Early treatment with erythropoietin beta ameliorates anemia and reduces transfusion requirements in infants with birth weights below 1000 g. Journal of Pediatrics 2002;141(1):8‐15. [DOI: 10.1067/mpd.2002.124309; PUBMED: 12091844] - DOI - PubMed
Meister 1997 {published data only}
    1. Meister B, Maurer H, Simma B, Kern H, Ulmer H, Hittmair A, et al. The effect of recombinant human erythropoietin on circulating hematopoietic progenitor cells in anemic premature infants. Stem Cells 1997;15(5):359‐63. [DOI: 10.1002/stem.150359; PUBMED: 9323798] - DOI - PubMed
Meyer 2003 {published data only}
    1. Meyer MP, Sharma E, Carsons M. Recombinant erythropoietin and blood transfusion in selected infants. Archives of Disease in Childhood. Fetal and Neonatal Edition 2003;88(1):F41‐5. [PUBMED: 12496225] - PMC - PubMed
Obladen 1991 {published data only}
    1. Obladen M, Maier R, Segerer H, Grauel EL, Holland BM, Stewart G, et al. Efficacy and safety of recombinant human erythropoietin to prevent the anaemias of prematurity. European randomized multicenter trial. Contributions to Nephrology 1991;88:314‐26. [PUBMED: 2040194] - PubMed
Ohls 1995 {published data only}
    1. Ohls RK, Osborne KA, Christensen RD. Efficacy and cost analysis of treating very low birth weight infants with erythropoietin during their first two weeks of life: a randomized, placebo‐controlled trial. Journal of Pediatrics 1995;126(3):421‐6. [PUBMED: 7869205] - PubMed
Ohls 1997 {published data only}
    1. Ohls RK, Harcum J, Schibler KR, Christensen RD. The effect of erythropoietin on the transfusion requirements of preterm infants weighing 750 grams or less: a randomized, double blind, placebo‐controlled study. Journal of Pediatrics 1997;131(5):661‐5. [PUBMED: 9403642] - PubMed
Ohls 2001A {published data only}
    1. Ehrenkranz RA, Ohls RK, Das A, Vohr BR. Neurodevelopmental outcome and growth at 18‐22 months in extremely low birth weight infants treated with early erythropoietin. Pediatric Research 2002;51:291A. - PubMed
    1. Ohls RK, Ehrenkranz RA, Das A, Dusick AM, Yolton K, Romano E, et al. Neurodevelopmental outcome and growth at 18 to 22 months' corrected age in extremely low birth weight infants treated with early erythropoietin and iron. Pediatrics 2004;114(5):1287‐91. - PubMed
    1. Ohls RK, Ehrenkranz RA, Das A, Dusick AM, Yolton K, Romano E, et al. National Institute of Child Health and Human Development Neonatal Research Network. Neurodevelopmental outcome and growth at 18 to 22 months' corrected age in extremely low birth weight infants treated with early erythropoietin and iron. Pediatrics 2004;114(5):1287‐91. [DOI: 10.1542/peds.2003-1129-L; PUBMED: 15520109] - DOI - PubMed
    1. Ohls RK, Ehrenkranz RA, Lemons JA, Korones SB, Stoll BJ, Stark AR, et al. A multicenter randomized double‐masked placebo‐controlled trial of early erythropoietin and iron administration to preterm infants. Pediatric Research 1999;45:216A. - PubMed
    1. Ohls RK, Ehrenkranz RA, Wright LL, Lemons JA, Korones SB, Stoll BJ, et al. Effects of early erythropoietin therapy on the transfusion requirements of preterm infants below 1250 grams birth weight: a multicenter, randomized, controlled trial. Pediatrics 2001;108(4):934‐42. [PUBMED: 11581447] - PubMed
Ohls 2001B {published data only}
    1. Ohls RK, Ehrenkranz RA, Wright LL, Lemons JA, Korones SB, Stoll BJ, et al. Effects of early erythropoietin therapy on the transfusion requirements of preterm infants below 1250 grams birth weight: a multicenter, randomized, controlled trial. Pediatrics 2001;108(4):934‐42. [PUBMED: 11581447] - PubMed
Ohls 2013 {published data only}
    1. Lowe JR, Rieger RE, Moss NC, Yeo RA, Winter S, Patel S, et al. Impact of erythropoiesis‐stimulating agents on behavioral measures in children born preterm. Journal of Pediatrics 2017;184:75‐80.e1. [DOI: 10.1016/j.jpeds.2017.01.020; PUBMED: 28185625] - DOI - PMC - PubMed
    1. Ohls RK, Cannon DC, Phillips J, Caprihan A, Patel S, Winter S, et al. Preschool assessment of preterm infants treated with darbepoetin and erythropoietin. Pediatrics 2016;137(3):e20153859. [DOI: 10.1542/peds.2015-3859; PUBMED: 26908704] - DOI - PMC - PubMed
    1. Ohls RK, Christensen RD, Kamath‐Rayne BD, Rosenberg A, Wiedmeier SE, Roohi M, et al. A randomized, masked, placebo‐controlled study of darbepoetin alfa in preterm infants. Pediatrics 2013;132(1):e119‐27. [DOI: 10.1542/peds.2013-0143; PUBMED: 23776118] - DOI - PMC - PubMed
    1. Ohls RK, Kamath‐Rayne BD, Christensen RD, Wiedmeier SE, Rosenberg A, Fuller J, et al. Cognitive outcomes of preterm infants randomized to darbepoetin, erythropoietin, or placebo. Pediatrics 2014;133(6):1023‐30. [PUBMED: 24819566] - PMC - PubMed
    1. Ohls RK, Kamath‐Rayne BD, Christensen RD, Wiedmeier SE, Rosenberg A, Schrader R, et al. Neurocognitive outcomes at 18‐22 months corrected age are improved in preterm infants administered darbepoetin or erythropoietin. Pediatric Academic Societies' Annual meeting 2013. 2013:E‐PAS2013:1165.5.
Peltoniemi 2017 {published data only}
    1. Peltoniemi OM, Anttila E, Kaukola T, Buonocore G, Hallman M. Randomized trial of early erythropoietin supplementation after preterm birth: iron metabolism and outcome. Early Human Development 2017;109:44‐9. [DOI: 10.1016/j.earlhumdev.2017.04.001; PUBMED: 28433798] - DOI - PubMed
Qiao 2017 {published data only}
    1. Qiao L, Tang Q, Zhu W, Zhang H, Zhu Y, Wang H. Effect of early parenteral iron combined erythropoietin in preterm infants. Medicine 2017;96(9):e5795. [DOI: 10.1097/MD.0000000000005795; PUBMED: 28248850] - DOI - PMC - PubMed
Salvado 2000 {published data only}
    1. Salvado A, Ramolfo P, Escobar M, Nunez A, Aguayo I, Standen J, et al. Early erythropoietin use for the prevention of anemia in infant premature [Uso precoz de la eritropoyetina en la prevencion de la anemia del prematuro]. Revista Medica de Chile 2000;128(12):1313‐7. [PUBMED: 11227239] - PubMed
Song 2016 {published data only}
    1. Song J, Sun H, Xu F, Kang W, Gao L, Guo J. Recombinant human erythropoietin improves neurological outcomes in very preterm infants. Annals of Neurology 2016;80(1):24‐34. [DOI: 10.1002/ana.24677; PUBMED: 27130143] - DOI - PMC - PubMed
Soubasi 1993 {published data only}
    1. Soubasi V, Kremenopoulos G, Diamandi E, Tsantali C, Tsakiris D. In which neonates does early recombinant human erythropoietin treatment prevent anemia of prematurity? Results of a randomized, controlled study. Pediatric Research 1993;34(5):675‐9. [DOI: 10.1203/00006450-199311000-00022; PUBMED: 8284109] - DOI - PubMed
Soubasi 1995 {published data only}
    1. Soubasi V, Kremenopoulos G, Diamanti E, Tsantali C, Sarafidis K, Tsakiris D. Follow‐up of very low birth weight infants after erythropoietin treatment to prevent anemia of prematurity. Journal of Pediatrics 1995;127(2):291‐7. [PUBMED: 7636658] - PubMed
Soubasi 2000 {published data only}
    1. Soubasi V, Kremenopoulos G, Tsantali C, Savopoulou P, Mussafiris C, Dimitrou M. Use of erythropoietin and its effects on blood lactate and 2,3‐diphosphoglycerate in premature neonates. Biology of the Neonate 2000;78(4):281‐7. [DOI: ; PUBMED: 11093007] - PubMed
Yasmeen 2012 {published data only}
    1. Yasmeen BHN, Chowdhury MA, Hoque MM, Hossain MM, Jahan R, Aktar S. Effect of short term recombinant human erythropoietin therapy in the prevention of anemia of prematurity in very low birth weight infants. Bangladesh Medical Research Council Bulletin 2012;38(3):119‐23. [PUBMED: 23540189] - PubMed
Yeo 2001 {published data only}
    1. Yeo CL, Choo S, Ho LY. Effect of recombinant human erythropoietin on transfusion needs in preterm infants. Journal of Paediatrics and Child Health 2001;37(4):352‐8. [PUBMED: 11532054] - PubMed

References to studies excluded from this review

Al Mofada 1994 {published data only}
    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]
Amin 2002 {published data only}
    1. Amin AA, Alzahrani DM. Efficacy of erythropoietin in premature infants. Saudi Medical Journal 2002;23(3):287‐90. [PUBMED: 11938417] - PubMed
Basiri 2015 {published data only}
    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]
Bierer 2006 {published data only}
    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
Brown 1999 {published data only}
    1. Brown MS, Keith JF 3rd. Comparison between two and five doses a week of recombinant erythropoietin for anemia of prematurity: a randomized trial. Pediatrics 1999;104(2 Pt 1):210‐5. [PUBMED: 10428996] - PubMed
Costa 2013 {published data only}
    1. Costa S, Romagnoli C, Zuppa AA, Cota F, Socorrano A, Gallini F, et al. How to administrate erythropoietin, intravenous or subcutaneous?. Acta Paediatrica 2013;102(6):579‐83. [DOI: 10.1111/apa.12193; PUBMED: 23414120] - DOI - PubMed
Fearing 2002 {published data only}
    1. Fearing MK, Eades B, Martinez B, Wood N, Accardo L, Browning CA, et al. Cost effective use of recombinant erythropoietin (HuEPO) in very low birth weight (VLBW) infants for improved clinical outcomes. Pediatric Research 2002;51:310A.
Haiden 2006a {published data only}
    1. Haiden N, Schwindt J, Cardona F, Berger A, Klebermass K, Wald M, et al. Effects of a combined therapy of erythropoietin, iron, folate, and vitamin B12 on the transfusion requirements of extremely low birth weight infants. Pediatrics 2006;118(5):2004‐13. [DOI: 10.1542/peds.2006-1113; PUBMED: 17079573] - DOI - PubMed
Haiden 2006b {published data only}
    1. Haiden N, Klebermass K, Cardona F, Schwindt J, Berger A, Kohlhauser‐Vollmuth C, et al. A randomized, controlled trial of the effects of adding vitamin B12 and folate to erythropoietin for the treatment of anemia of prematurity. Pediatrics 2006;118(1):180‐8. [DOI: 10.1542/peds.2005-2475; PUBMED: 16818564] - DOI - PubMed
Juul 2008 {published data only}
    1. Juul SE, McPherson RJ, Bauer LA, Ledbetter KJ, Gleason CA, Mayock DE. A phase I/II trial of high‐dose erythropoietin in extremely low birth weight infants: pharmacokinetics and safety. Pediatrics 2008;122(2):383‐91. [DOI: 10.1542/peds.2007-2711; PUBMED: 18676557] - DOI - PubMed
Klipp 2007 {published data only}
    1. Klipp M, Holzwarth AU, Poeschl JM, Nelle M, Linderkamp O. Effects of erythropoietin on erythrocyte deformability in non‐transfused preterm infants. Acta Paediatrica 2007;96(2):253‐6. [PUBMED: 17429915] - PubMed
Krallis 1999 {published data only}
    1. Krallis N, Cholevas V, Mavridis A, Georgiou I, Bourantas K, Andronikou S. Effect of recombinant human erythropoietin in preterm infants. European Journal of Haematology 1999;63(2):71‐6. [PUBMED: 10480285] - PubMed
López‐Catzín 2015 {published data only}
    1. López‐Catzín JF, Bolado‐García PB, Gamboa‐López GJ, Medina‐Escobedo CE, Cambranes‐Catzima LR. Decreased transfusions in preterm infants with anemia treated with erythropoietin [Disminución de transfusiones en prematuros con anemia tratados con eritropoyetina]. Revista Medica del Instituto Mexicano del Seguro Social 2016;54(5):576‐80. [PUBMED: 27428338] - PubMed
Maggio 2007 {published data only}
    1. Maggio L, Scorrano A, Cota F, Gallini F, Romagnoli C, Zuppa AA. Randomized controlled trial on the effectiveness of early recombinant erythropoietin administered to preterm infants by continuous intravenous versus subcutaneous route. Pediatric Academic Societies' Annual Meeting 2007. 2007:E‐PAS2007:616315.9.
Maier 1998 {published data only}
    1. Maier RF, Obladen M, Kattner E, Natzschka J, Messer J, Regazzoni BM, et al. High‐versus low‐dose erythropoietin in extremely low birth weight infants. Journal of Pediatrics 1998;132(5):866‐70. [PUBMED: 9602202] - PubMed
Ohls 1996 {published data only}
    1. Ohls RK, Veerman MW, Christensen RD. Pharmacokinetics and effectiveness of recombinant erythropoietin administered to preterm infants by continuous infusion in total parenteral nutrition solution. Journal of Pediatrics 1996;128(4):518‐23. [PUBMED: 8618186] - PubMed
Saeidi 2012 {published data only}
    1. Saeidi R, Banihashem A, Hammoud M, Gholami M. Comparison of oral recombinant erythropoietin and subcutaneous recombinant erythropoietin in prevention of anemia of prematurity. Iranian Red Crescent Medical Journal 2012;14(3):178‐81. [PUBMED: 22737576] - PMC - PubMed
Soubasi 2005 {published data only}
    1. Soubasi V, Pouliou T, Tsantali C, Lithoxopoulou M, Drossou V, Kremenopoulos G. Is erythropoietin (EPO) a multifunctional tissue protective cytokine? Follow‐up of rHuEPO treated prematures. Pediatric Academic Societies' Annual Meeting 2005. 2005:PAS 2005;57:164.
Soubasi 2009 {published data only}
    1. Soubasi V, Petridou S, Sarafidis K, Agathi T, Griva M, Drossou V. High dose of erythropoietin in premature neonates: short‐term outcomes. Pediatric Academic Societies' Annual Meeting 2009. 2009:E‐PAS 2009;5506:105.
Turker 2005 {published data only}
    1. Turker G, Sarper N, Gokalp S, Usluer H. The effect of early recombinant erythropoietin and enteral iron supplementation on blood transfusion in preterm infants. American Journal of Perinatology 2005;22(8):449‐55. [DOI: 10.1055/s-2005-918888; PUBMED: 16283605] - DOI - PubMed
Vázquez López 2011 {published data only}
    1. Vázquez López MÁ, Llamas MÁ, Galera R, Sanchez AR, Lendinez F, Gonzalez‐Ripoll M, et al. Comparison between one and three doses a week of recombinant erythropoietin in very low birth weight infants. Journal of Perinatology 2011;31(2):118‐24. [DOI: 10.1038/jp.2010.80; PUBMED: 20689518] - DOI - PubMed
Zhu 2009 {published data only}
    1. Zhu C, Kang W, Xu F, Cheng X, Zhang Z, Jia L, et al. Erythropoietin improved neurologic outcomes in newborns with hypoxic‐ischemic encephalopathy. Pediatrics 2009;124(2):e218‐26. [DOI: 10.1542/peds.2008-3553; PUBMED: 19651565] - DOI - PubMed

References to ongoing studies

NCT01378273 {published data only}
    1. NCT01378273. Preterm Erythropoietin Neuroprotection Trial (PENUT Trial). clinicaltrials.gov/show/NCT01378273 (first received 20 June 2011).
NCT02550054 {published data only}
    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).

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References to other published versions of this review

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