Key messages
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Early use of medications that stimulate red blood cell production, such as erythropoietin or darbepoetin, probably results in little to no difference in death; may reduce moderate to severe brain-related (neurodevelopmental) disability; has little to no effect on the occurrence of serious eye diseases; may reduce the need for blood transfusions; and probably reduces serious gut problems and severe brain bleeding.
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Given the benefits of these medications, future research should look at how to use these medications fairly and equitably and in a manner that is acceptable to families and healthcare providers.
Why is low red blood cell count a problem for preterm and low-birthweight babies?
Red blood cells carry oxygen throughout the body and are necessary for good health. Preterm babies (those born before their due date) and babies with low birthweight may have too few red blood cells. As a result, they are more prone to death, serious diseases, and may require blood transfusions (receiving donated blood directly into a vein using a drip). However, babies receiving donated blood may be at risk for infections, serious gut problems, and eye diseases.
What are erythropoiesis-stimulating agents?
Erythropoiesis-stimulating agents (ESAs) are medications that stimulate red blood cell production. Examples of ESAs include erythropoietin and darbepoetin.
What did we want to find out?
We wanted to find out if giving ESAs to preterm babies and babies with low birthweight during the first week of life reduces:
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death;
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the occurrence of brain-related (neurodevelopmental) disability;
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the need for blood transfusions;
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the occurrence of serious eye disease (retinopathy of prematurity);
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the occurrence of serious gut problems (necrotizing enterocolitis); and
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the occurrence of severe brain bleeding (intraventricular hemorrhage).
What did we do?
We searched for studies in preterm (less than 37 weeks' gestation [the time period between conception and birth]) or low-birthweight (less than 2500 grams) babies who were given ESAs during the first week of life. We included studies comparing ESAs to placebo (dummy treatment) or no treatment. We compared and summarized the results of the studies and rated our confidence in the evidence based on study methods and sizes.
What did we find?
We found 37 studies involving a total of 6724 babies. The studies were conducted worldwide; however, most took place in Europe (15 studies). The studies ranged in size from 1258 to 22 babies.
Main results
We found that compared to placebo or no treatment, ESAs:
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probably result in little to no difference in death (24 studies, 5217 babies);
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may reduce moderate to severe brain-related disability (3 studies, 1707 babies);
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may reduce the need for blood transfusions (21 studies, 3507 babies);
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have little to no effect on serious eye diseases (14 studies, 3844 babies);
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probably reduce serious gut problems (20 studies, 5749 babies); and
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probably reduce severe brain bleeding (9 studies, 2458 babies).
What are the limitations of the evidence?
We have high to little confidence in the evidence. In cases where our confidence is limited, this was because healthcare providers may have known which treatment the babies were getting, and we have less information and understanding about the effects of darbepoetin (35 studies used erythropoietin, while only two used darbepoetin). Also, the treatments varied according to age group, and it is unclear how some studies were conducted.
How up-to-date is this evidence?
The evidence is current to March 2025. This review updates our previous 2020 review.
Read the full abstract
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 benefits and harms of early administration of ESAs in preterm or low-birthweight infants.
Search strategy
We searched CENTRAL, MEDLINE, Embase, Scopus, DOAJ, and trial registries to 31 March 2025, and checked the reference lists of studies and systematic reviews for potentially relevant studies.
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 use of ESAs probably results in little to no difference in mortality (moderate-certainty evidence); may reduce moderate to severe NDI at 18 to 26 months’ corrected age (low-certainty evidence); has little to no effect on ROP (high-certainty evidence); may reduce the proportion of infants exposed to one or more RBC transfusions (low-certainty evidence); and probably reduces both NEC and sIVH (moderate-certainty evidence).
Given the benefits of ESAs, future research should focus on cost-effectiveness, equity, feasibility of implementation, and acceptability to different stakeholders of the routine use of erythropoietin or darbepoetin among preterm or low-birthweight infants.
Funding
No funding was received for this review.
Registration
Protocol (and previous versions) available via 10.1002/14651858.CD004863; 10.1002/14651858.CD004863.pub2; 10.1002/14651858.CD004863.pub3; 10.1002/14651858.CD004863.pub4; 10.1002/14651858.cd004863.pub5; 10.1002/14651858.CD004863.pub6.
