Background: Hematocrit falls after birth in preterm infants due to physiological factors and frequent blood letting. Low plasma levels of erythropoietin (EPO) in preterm infants provide a rationale for the use of EPO to prevent or treat anaemia.
Objectives: To assess the effectiveness and safety of early (before 8 days after birth) versus late (between 8 - 28 days after birth) initiation of EPO in reducing red blood cell transfusions in preterm and/or low birth weight infants.
Search strategy: The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2006) was searched. Electronic and manual searches were conducted in November 2005 of MEDLINE, EMBASE and CINAHL, personal files, bibliographies of identified trials and abstracts by the Pediatric Academic Societies' and the European Society of Pediatric Research Meetings published in Pediatric Research.
Design: Randomized or quasi-randomized controlled trials.
Population: Preterm (< 37 weeks gestational age) or low birth weight infants (< 2500 g) less than eight days of age.
Intervention: Early initiation of EPO (initiated at < 8 days of age) vs. late initiation of EPO (initiated at 8 - 28 days of age). Outcomes; At least one of the following outcomes were reported: Use of one or more red blood cell transfusions; Total volume (ml/kg) of blood transfused per infant; Number of transfusions per infant; Number of donors to whom the infant was exposed; Mortality during initial hospital stay (all causes); and common outcomes associated with preterm birth.
Data collection and analysis: The standard methods of the Cochrane Neonatal Review Group were followed independently by the authors to assess study quality and report outcomes. Weighted treatment effects, calculated using RevMan 4.2.8 included typical relative risk (RR), typical risk difference (RD), number needed to treat to benefit (NNTB), number needed to treat to harm (NNTH) and mean difference (MD), all with 95% confidence intervals (CI). A fixed effect model was used for meta-analyses. Heterogeneity tests including the I-squared (I(2)) test were performed to assess the appropriateness of pooling the data.
Main results: Two high quality randomized double-blind controlled studies enrolling 262 infants were identified (Donato 2000; Maier 2002). Both studies used well defined, but not identical, criteria for blood transfusions. Between 14 and 32% of the enrolled infants had received blood transfusions prior to study entry. A non-significant reduction in the 'use one or more red blood cell transfusions' [typical RR 0.91 (95% CI 0.78, 1.06); typical RD - 0.07 (95% CI -0.18, 0.04)] favouring early EPO was noted. Both studies (n = 262) reported on "number of transfusions per infant"; early EPO administration resulted in a non-significant reduction compared to late EPO [typical WMD - 0.32 (95% CI -0.92, 0.29)]. There was no significant reduction in total volume of blood transfused per infant or in the number of donors to whom the infant was exposed. Retinopathy of prematurity (ROP) (all stages) was assessed in 191 infants. Early EPO led to a significant increase in the risk of ROP [(typical RR 1.40 (95% CI 1.05, 1.86); typical RD 0.16 (95% CI 0.03, 0.29); NNTH 6 (95% CI 3 -33)]. There was statistically significant heterogeneity for this outcome. Both studies (n = 191) reported on ROP stage > 3. No statistically significant increase in risk was noted [typical RR 1.56 (95% CI 0.71, 3.41); typical RD was 0.05 (95% CI - 0.04, 0.14)]. There was no statistically significant heterogeneity for this outcome for either RR or for RD. No other important favourable or adverse neonatal outcomes or side effects were reported.
Authors' conclusions: The use of early EPO did not significantly reduce the primary outcome of "use of one or more red blood cell transfusions", or "number of transfusions per infant" compared to late EPO administration. Currently there is lack of evidence that early EPO vs. late EPO confers any substantial benefits with regard to any donor blood exposure as a large proportion (14 - 30 %) of infants enrolled in these studies were exposed to donor blood prior to study entry. The finding of a statistically significant increased risk of ROP (any grade) and a similar trend for ROP stage > 3 with early EPO treatment is of great concern. No further studies comparing early vs. late administration of EPO are warranted.