Aher S M, Ohlsson A
Chelsea and Westminster Hospital, Department of Neonatology, 369 Fulham Road, London, UK SW10 9NH.
Cochrane Database Syst Rev. 2006 Jul 19(3):CD004865. doi: 10.1002/14651858.CD004865.pub2.
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.
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.
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.
Randomized or quasi-randomized controlled trials.
Preterm (< 37 weeks gestational age) or low birth weight infants (< 2500 g) less than eight days of age.
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.
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.
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.
由于生理因素和频繁采血，早产儿出生后血细胞比容会下降。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（出生后8天内）与晚期（出生后8 - 28天）开始使用EPO减少早产和/或低出生体重儿红细胞输血的有效性和安全性。
检索了Cochrane对照试验中心注册库（CENTRAL，Cochrane图书馆，2006年第2期）。2005年11月对MEDLINE、EMBASE和CINAHL进行了电子和手工检索，还检索了个人文件、已识别试验的参考文献以及儿科学术协会和欧洲儿科研究学会会议发表在《儿科研究》上的摘要。
随机或半随机对照试验。
孕周小于37周的早产儿或出生体重小于2500g且出生小于8天的婴儿。
早期开始使用EPO（出生8天内开始）与晚期开始使用EPO（出生8 - 28天开始）。结局指标：报告以下至少一项结局：使用一次或多次红细胞输血；每个婴儿输血的总体积（ml/kg）；每个婴儿的输血次数；婴儿接触的供血者数量；初次住院期间的死亡率（所有原因）；以及与早产相关的常见结局。
作者独立遵循Cochrane新生儿综述小组的标准方法来评估研究质量并报告结局。使用RevMan 4.2.8计算的加权治疗效果包括典型相对危险度（RR）、典型风险差值（RD）、受益所需治疗人数（NNTB）、伤害所需治疗人数（NNTH）和平均差值（MD），均带有95%置信区间（CI）。采用固定效应模型进行荟萃分析。进行了包括I²检验在内的异质性检验，以评估合并数据的适宜性。
确定了两项纳入262例婴儿的高质量随机双盲对照研究（多纳托，2000年；迈尔，2002年）。两项研究对输血的标准定义明确但不完全相同。在纳入研究前，14%至32%的婴儿已接受过输血。早期使用EPO组在“使用一次或多次红细胞输血”方面有非显著性降低[典型RR 0.91（95%CI 0.78，1.06）；典型RD - 0.07（95%CI -0.18，0.04）]。两项研究（n = 262）均报告了“每个婴儿的输血次数”；与晚期使用EPO相比，早期使用EPO导致的降低无统计学意义[典型加权平均差 - 0.32（95%CI -0.92，0.29）]。每个婴儿输血的总体积或婴儿接触的供血者数量均无显著减少。对191例婴儿评估了早产儿视网膜病变（ROP）（所有阶段）。早期使用EPO导致ROP风险显著增加[典型RR 1.40（95%CI 1.05，1.86）；典型RD 0.16（95%CI 0.03，0.29）；NNTH 6（95%CI 3 - 33）]。该结局存在统计学显著异质性。两项研究（n = 191）均报告了ROP > 3期。未观察到风险有统计学显著增加[典型RR 1.56（95%CI 0.71，3.41）；典型RD为0.05（95%CI - 0.04，0.14）]。该结局的RR或RD均无统计学显著异质性。未报告其他重要的有利或不利的新生儿结局或副作用。
与晚期使用EPO相比，早期使用EPO在“使用一次或多次红细胞输血”或“每个婴儿的输血次数”这一主要结局上并未显著降低。目前缺乏证据表明早期使用EPO与晚期使用EPO相比在减少接触供血者血液方面有任何实质性益处，因为这些研究中很大比例（14% - 30%）的婴儿在纳入研究前已接触过供血者血液。早期使用EPO治疗导致ROP（任何级别）风险有统计学显著增加以及ROP > 3期有类似趋势这一发现令人高度关注。无需进一步开展比较早期与晚期使用EPO的研究。
