Early erythropoietin for preventing red blood cell transfusion in preterm, low birth weight infants, or preterm infants with low birth weight

In newborn infants, the number of red blood cells in the circulation decreases after birth. In infants born before term this decrease is exaggerated by frequent withdrawal of blood, which may be 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 anaemia. EPO can be given 'early' (before the infant reaches eight days of age) in order to prevent or decrease the use of red blood cell transfusions. A total of 2209 infants born before term have been enrolled in 27 studies that used this approach. Early EPO treatment reduced the number of red blood cell transfusions and donor exposures following its use. 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 with the exception that EPO may increase the risk for retinopathy of prematurity, a serious complication that can cause blindness in babies born before term. Based on our findings EPO is not recommended for routine use in preterm infants.

Authors' conclusions: 

Early administration of EPO reduces the use of RBC transfusions, the volume of RBCs transfused, and donor exposure after study entry. The small reductions are likely to be of limited clinical importance. Donor exposure is probably not avoided since all but one study included infants who had received RBC transfusions prior to trial entry. In this update there was no significant increase in the rate of ROP (stage ≥ 3) for studies that initiated EPO treatment at less than eight days of age. In a post hoc analysis including all studies that reported on ROP stage ≥ 3 regardless of age at initiation of treatment there was an increased risk of ROP. The rates for mortality and morbidities including intraventricular haemorrhage and necrotizing enterocolitis were not significantly changed by early EPO treatment. Neurodevelopmental outcomes at 18 to 22 months vary in the studies published to date. Ongoing research should deal with the issue of ROP and evaluate current clinical practice that will limit donor exposure. Due to the limited benefits and the possibly increased risk of ROP, administration of EPO is not recommended. Darbepoetin requires further study. The possible neuroprotective role of EPO in neonates will be reviewed in separate Cochrane reviews.

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Background: 

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 initiation of EPO or darbepoetin (initiated before eight days after birth) in reducing red blood cell (RBC) transfusions in preterm and/or low birth weight infants.

Search strategy: 

The Cochrane Library, MEDLINE, EMBASE, CINAHL, reference lists of identified trials and reviews, Pediatric Academic Societies Annual meetings 2000 to 2013 (Abstracts2ViewTM) and clinical trials registries (clinicaltrials.gov; controlled-trials.com; and who.int/ictrp) were searched in July 2013.

Selection criteria: 

Randomised or quasi-randomised controlled trials of early (< eight days of age) initiation of EPO treatment versus placebo or no intervention in preterm and/or low birth weight infants.

Data collection and analysis: 

The methods of the Neonatal Cochrane Review Group were used.

Main results: 

The updated review includes 27 studies enrolling 2209 infants. One study enrolling infants at a mean age of > eight days and one duplicate publication were excluded. One new study using darbepoetin was identified.

Early EPO reduced the risk of the 'use of one or more RBC transfusions' (typical risk ratio (RR) 0.79, 95% confidence interval (CI) 0.73 to 0.85; typical risk difference (RD) -0.14, 95% CI -0.18 to -0.10; I2 = 54% for both; number needed to treat to benefit (NNTB) 7, 95% CI 6 to 10; 16 studies, 1661 infants).

The total volume of RBCs transfused per infant was reduced (typical mean difference (MD) 7 mL/kg, 95% CI -12 to - 2; I2 = 63%; 7 studies, 581 infants). The number of RBC transfusions per infant was minimally reduced (typical MD -0.27, 95% CI -0.42 to -0.12; I2 = 64%; 13 studies, 951 infants). The number of donors to whom the infants were exposed was significantly reduced (MD-0.54, 95% CI -0.89 to -0.20; I2 = 0%; 3 studies, 254 infants).

There was a non-significant increase in the risk of stage ≥ 3 retinopathy of prematurity (ROP) with early EPO (typical RR 1.37, 95% CI 0.87 to 2.17; I2 = 0%; typical RD 0.03, 95% CI -0.01 to 0.06; I2 = 29%; 7 studies, 801 infants). A post hoc analysis including all studies that reported on ROP stage ≥ 3, regardless of the age of the infant when EPO treatment was started, showed a significantly increased typical RR of 1.48 (95% CI 1.02 to 2.13; P = 0.04; I2 = 0%) and typical RD of 0.03 (95% CI 0.00 to 0.06; P = 0.03; I2 = 50%; 10 studies, 1303 infants) with a number needed to treat to harm (NNTH) of 33 (95% CI 17 to infinity). In an Italian study in which the authors compared the use of early intravenous EPO with subcutaneous EPO the overall incidence of stage ≥ 3 was 15%, similar to the incidence of 17% in the study by Romagnoli and co-workers.

The rates for mortality and morbidities including intraventricular haemorrhage and necrotizing enterocolitis were not significantly changed by early EPO treatment. Neurodevelopmental outcomes at 18 to 22 months varied.

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