Ohlsson Arne, Aher Sanjay M
Departments of Paediatrics, Obstetrics and Gynaecology and Institute of Health Policy, Management and Evaluation, University ofToronto, Toronto, Canada.
Cochrane Database Syst Rev. 2012 Sep 12(9):CD004863. doi: 10.1002/14651858.CD004863.pub3.
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 early initiation of EPO in reducing red blood cell (RBC) transfusions in preterm and/or low birth weight infants.
The Cochrane Central Register of Controlled Trials (The Cochrane Library), MEDLINE, EMBASE, CINAHL, abstracts from scientific meetings published in Pediatric Research and reference lists of identified trials and reviews were searched through July 2009. Searches were repeated in March 2012 including searches of Pediatric Academic Societies Annual meetings 2000 to 2012 (Abstracts2View(TM)) and clinical trials registries (clinicaltrials.gov; controlled-trials.com; and who.int/ictrp).
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 neonates.
Data collection and analysis were accomplished using the methods of the Neonatal Cochrane Review Group.
The May 2012 update did not identify any new studies for inclusion. A number of randomised controlled trials were excluded as they compared one EPO dosing regimen with another, did not provide the numbers of infants randomised to the EPO and the placebo group, or the dose of EPO was not stated. The update includes 27 studies that enrolled 2293 preterm infants. Early EPO reduced the risk of the "use of one or more RBC transfusions" [typical risk ratio (RR); 0.80 (95% confidence interval (CI) 0.75 to 0.86); typical risk difference (RD) -0.13, (95% CI -0.17 to -0.09); number needed to benefit (NNTB) = eight, (95% CI 6 to 11); 16 studies, 1,825 infants].There was moderate heterogeneity for this outcome [RR (P = 0.004; I(2) = 56.7%); RD (P = 0.003; I(2) = 56.0%)].A total of six studies enrolling 515 infants reported on the total volume of red blood cells transfused per infant. The significant typical mean difference (MD) was a reduction of 6 mL/kg of blood transfused (mL/kg) per infant (95% CI -11 to - 1). There was moderate heterogeneity for this outcome (P = 0.02; I(2) = 63.0%). The results from 14 studies enrolling 1131 infants reported on the number of red blood cell transfusions per infant. The significant typical MD for number of red blood cell transfusions per infant was -0.33, (95% CI -0.48 to -0.18). There was high heterogeneity for this outcome (P = 0.00001, I(2) = 78%). Two studies enrolling 188 infants reported on the number of donors to whom the infant was exposed; the MD was significantly reduced -0.63, (-1.07 to -0.19). There was no heterogeneity for this outcome (P = 0.59; I(2) = 0%).There was a significant increase in the risk of stage ≥ 3 retinopathy of prematurity (ROP) in the early EPO group [typical RR; 1.65, (95% CI 1.12 to 2.43); typical RD; 0.05 (95% CI 0.01 to 0.08); number needed to harm (NNTH); 20, (95% CI 13 to 100); eight studies, 984 infants]. There was no heterogeneity for this outcome for RR (P = 0.87; I(2) = 0%), but there was moderate heterogeneity for RD (P = 0.006; I(2) = 65%). The rates for mortality and other neonatal morbidities were not significantly changed by early EPO treatment nor were neurodevelopmental outcomes at 18 to 22 months in the small number of infants tested to-date.
AUTHORS' CONCLUSIONS: Early administration of EPO reduces the use of RBC transfusions and the volume of RBCs transfused. These small reductions are of limited clinical importance. Donor exposure is probably not avoided since most studies included infants who had received RBC transfusions prior to trial entry. There was a significant increase in the rate of ROP (stage ≥ 3). Early EPO does not significantly decrease or increase any of the other important adverse outcomes. Ongoing research should deal with the issue of ROP and evaluate the current clinical practice that will limit donor exposure. Due to the limited benefits and the increased risk of ROP, early administration of EPO is not recommended. Evidence is lacking for the possible neuro protective role of EPO in preterm infants. This topic will be reviewed in separate Cochrane reviews for preterm and term and late preterm infants.
早产儿血浆促红细胞生成素（EPO）水平较低，这为使用EPO预防或治疗贫血提供了理论依据。
评估早期使用EPO减少早产和/或低出生体重儿红细胞（RBC）输血的有效性和安全性。
检索了Cochrane对照试验中心注册库（Cochrane图书馆）、MEDLINE、EMBASE、CINAHL、发表于《儿科学研究》的科学会议摘要以及已识别试验和综述的参考文献列表，检索截至2009年7月。2012年3月重复检索，包括检索2000年至2012年儿科学术协会年会（Abstracts2View™）以及临床试验注册库（clinicaltrials.gov；controlled-trials.com；who.int/ictrp）。
对早产和/或低出生体重新生儿进行早期（<8日龄）开始EPO治疗与安慰剂或不干预的随机或半随机对照试验。
采用新生儿Cochrane综述组的方法进行数据收集和分析。
2012年5月的更新未识别出任何新的纳入研究。一些随机对照试验被排除，因为它们比较的是一种EPO给药方案与另一种方案，未提供随机分配至EPO组和安慰剂组的婴儿数量，或者未说明EPO的剂量。该更新纳入了27项研究，共2293名早产儿。早期EPO降低了“接受一次或多次RBC输血”的风险[典型风险比（RR）；0.80（95%置信区间（CI）0.75至0.86）；典型风险差（RD）-0.13，（95%CI -0.17至-0.09）；需治疗人数（NNTB）=8，（95%CI 6至11）；16项研究，1825名婴儿]。该结果存在中度异质性[RR（P = 0.004；I² = 56.7%）；RD（P = 0.003；I² = 56.0%）]。共有6项研究，515名婴儿，报告了每名婴儿输注的红细胞总量。显著的典型平均差（MD）为每名婴儿输注的红细胞量减少6 mL/kg（mL/kg）（95%CI -11至-1）。该结果存在中度异质性（P = 0.02；I² = 63.0%）。14项研究，1131名婴儿，报告了每名婴儿的红细胞输血次数。每名婴儿红细胞输血次数的显著典型MD为-0.33，（95%CI -0.48至-0.18）。该结果存在高度异质性（P = 0.00001，I² = 78%）。两项研究，188名婴儿，报告了婴儿接触的供血者数量；MD显著降低-0.63，（-1.07至-0.19）。该结果无异质性（P = 0.59；I² = 0%）。早期EPO组≥3期早产儿视网膜病变（ROP）的风险显著增加[典型RR；1.65，（95%CI 1.12至2.43）；典型RD；0.05（95%CI 0.01至0.08）；需治疗有害人数（NNTH）；20，（95%CI 13至100）；8项研究，984名婴儿]。该结果RR无异质性（P = 0.87；I² = 0%），但RD存在中度异质性（P = 0.006；I² = 65%）。早期EPO治疗未显著改变死亡率和其他新生儿疾病的发生率，在少数迄今为止接受测试的婴儿中，18至22个月时的神经发育结局也未改变。
早期给予EPO可减少RBC输血的使用和RBC输注量。这些小幅度的减少在临床重要性方面有限。由于大多数研究纳入的婴儿在试验入组前已接受过RBC输血，因此可能无法避免供血者接触。ROP（≥3期）的发生率显著增加。早期EPO未显著降低或增加任何其他重要不良结局。正在进行的研究应解决ROP问题，并评估当前可限制供血者接触的临床实践。由于益处有限且ROP风险增加，不建议早期给予EPO。缺乏EPO对早产儿可能的神经保护作用的证据。该主题将在针对早产儿、足月儿和晚期早产儿的单独Cochrane综述中进行评价。
