We reviewed the evidence about the effectiveness and safety of late initiation of erythropoietin treatment 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.
The percentage of circulating red blood cells (hematocrit) falls after birth in all infants. This is particularly true in preterm infants due to their poor response to anaemia and to the amount of blood that is drawn for necessary testing. Low plasma levels of erythropoietin (a substance in the blood that stimulates red blood cell production) in preterm infants provide a rationale for the use of erythropoietin to prevent/treat anaemia.
The evidence is current to July, 2013.
To date 1591 infants (between eight and 28 days of age) born preterm have been enrolled in 30 studies of late administration of EPO to reduce the use of red blood cell transfusions and to prevent donor exposure.
Study funding sources
We as reviewers have not received any funding for this review and we have no conflict of interest to declare.
The risk of receiving red blood transfusion is reduced following initiation of EPO treatment. However, the overall benefit of EPO is reduced as many of these infants had been exposed to donor blood prior to entry into the trials. Treatment with late EPO did not have any important effects on death or common complications of preterm birth, except for trends in an increased risk for retinopathy of prematurity. Retinopathy of prematurity is a disease of the eye affecting babies born preterm. It is thought to be caused by disorganized growth of retinal blood vessels, which may result in scarring and retinal detachment. Retinopathy of prematurity can be mild and may resolve spontaneously, but it may lead to blindness in serious cases.
Quality of the evidence
The study quality varied and important information regarding the random sequence generation and whether the allocation was concealed or not was often missing. Sample sizes were small and long-term outcomes (18 to 24 months corrected age) were not reported.
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.
Low plasma levels of erythropoietin (EPO) in preterm infants provide a rationale for the use of EPO to prevent or treat anaemia.
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.
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.
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.
We performed data collection and analyses in accordance with the methods of the Cochrane Neonatal Review Group.
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.