Cochrane review: Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants

Abstract Background Hematocrit falls after birth in preterm infants due to physiological factors and blood letting. Low plasma levels of erythropoietin (EPO) in preterm infants provide a rationale for the use of EPO to prevent or treat anemia. Objectives Primary objective: To assess the effectiveness and safety of early initiation of EPO (initiated before eight days after birth) in reducing red blood cell transfusions in preterm and/or low birth weight infants. Secondary objectives: Subgroup analyses of low (< 500 IU/kg/week) and high (> 500 IU/kg/week) doses of EPO and, within these subgroups, analyses of the use of low (< 5 mg/kg/day) and high (> 5 mg/kg/day) doses of supplemental iron, in reducing red blood cell transfusions in these infants. Search strategy The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE, EMBASE, CINAHL, abstracts from scientific meetings published in Pediatric Research and reference lists of identified trials and reviews were searched in November 2005. No language restrictions were applied. Selection criteria Randomised or quasi‐randomized controlled trials of early initiation of EPO treatment (started before 8 days of age) vs. placebo or no intervention in preterm (< 37 weeks) and/or low birth weight (< 2500 g) neonates. For inclusion, the studies needed to provide information on at least one outcome of interest. Data collection and analysis Data were abstracted by the two authors on pre‐tested data collection forms. Data were entered by one review author (AO) and checked for accuracy by the other (SA). Data were analysed using RevMan 4.2.8. The statistical methods included ‘typical’ relative risk (RR), risk difference (RD), number needed to treat to benefit (NNTB) and needed to treat to harm (NNTH) for dichotomous outcomes and weighted mean difference (WMD) for continuous outcomes reported with their 95% confidence intervals (CI). A fixed effects model was used for meta‐analyses. Heterogeneity tests, including the I‐squared (I2) statistic, were performed to assess the appropriateness of pooling the data. Main results Twenty‐three studies enrolling 2074 preterm infants in 18 countries were included in the review. All studies except one applied transfusion guidelines. The quality of the trials varied. Most trials were of small sample size. Only one study clearly stated that infants were excluded if they had received red blood cell transfusion prior to study entry (Arif 2005). A total of 16 studies, including 1825 infants reported on the primary outcome of "use of one or more red cell transfusions". The summary estimates were significant [typical RR; 0.80 (95% CI 0.75, 0.86); typical RD; ‐0.13 (95% CI ‐0.17, ‐0.09); typical NNTB; 8 (95% CI 6, 11)]. There was statistically significant heterogeneity [for RR (p< 0.004), I2= 56.7%; for RD (p = 0.003), I2= 56.0%]. Similar results were obtained in secondary analyses based on different combinations of high doses of EPO and high and low iron supplementation. There were insufficient data to draw conclusions for low doses EPO in combination with high or low dose of iron. Two studies (n = 188) reported a significant reduction in the number of donors to whom the infant was exposed [typical WMD; ‐0.63 (95% CI ‐1.07, ‐0.19)]. A significant reduction in the total volume (ml/kg) of blood transfused per infant [typical WMD; ‐6 ml (95% CI ‐1, ‐11)] and in the number of transfusions per infant [typical WMD ‐0.27 (95% CI ‐0.12, ‐0.42 )] was noted. There was a significant increase in the risk of stage > 3 retinopathy of prematurity (ROP) in the EPO group [typical RR; 1.71 (95% CI 1.15, 2.54); typical RD; 0.05 (95% CI 0.01, 0.09); NNTH; 20 (95% CI 11, 100)]. The non‐significant results for ROP (any stage reported) showed a similar trend. The increased risk for ROP may be associated with use of higher doses of supplemental of iron in the EPO group than in the control group. The rates for mortality, sepsis, intraventricular haemorrhage, periventricular leukomalacia, necrotizing enterocolitis, bronchopulmonary dysplasia, neutropenia, hypertension, length of hospital stay or long‐term neurodevelopmental outcomes were not significantly change by the administration of EPO. Authors' conclusions Early administration of EPO reduces the use one or more red blood cell transfusions, the volume of red blood cells transfused, and the number of donors and transfusions the infant is exposed to following study entry. The small reductions are of limited clinical importance. Any donor exposure is likely not avoided as most studies included infants, who had received red cell transfusions prior to trial entry. There was a significant increase in the rate of ROP (stage >3). Animal data and observational studies in humans support a possible association between treatment with EPO and the development of ROP. EPO does not significantly decrease or increase any of the other important neonatal adverse outcomes including mortality. The incidence of ROP should be ascertained in the studies that have already been conducted but did not report on this outcome. Any ongoing research should deal with the issue of ROP and evaluate the current clinical practice that will limit donor exposure through satellite units. Research efforts should focus on limiting donor exposure (to as few donors as possible) during the first few days of life in sick neonates, when red blood cell transfusions are most likely to be required and cannot be prevented by early (or late) EPO treatment. Due to the limited benefits and the increased risk of ROP, early administration of EPO is not recommended. Plain language summary In all newborn infants, the number of red blood cells in the circulation falls after birth. In infants born before term, this is exaggerated by frequent blood letting, which is necessary to monitor the infant's clinical condition. Therefore, infants born before term are likely to require transfusions of red blood cells. Low levels of erythropoietin (EPO) (a substance in the blood that stimulates red blood cell production) in preterm infants provide a rationale for the use of EPO to prevent or treat anemia. EPO can be given "early" (before the infant reaches eight days of age) in order to prevent the use of red blood cell transfusions. More than 2000 infants born before term have been enrolled in 23 studies that used this approach. EPO reduces the risk of receiving red blood transfusion and donor exposure following initiation of EPO treatment. However, the overall benefit of EPO may not be clinically important, as many of these infants had been exposed to red blood cell transfusions prior to entry into the trials. Treatment with early EPO did not have any important effects on mortality or common complications of preterm birth, except that EPO increased the risk for retinopathy of prematurity, a serious complication that may cause blindness in babies born before term. Based on our findings, EPO is not recommended for routine use in preterm infants.

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