Aher Sanjay M, Ohlsson Arne
Neocare Hospital, Neonatal Intensive Care Unit, Mumbai Naka, Nashik, Maharashtra, India, 422002.
University of Toronto, Departments of Paediatrics, Obstetrics and Gynaecology and Institute of Health Policy, Management and Evaluation, Toronto, Canada.
Cochrane Database Syst Rev. 2020 Jan 28;1(1):CD004868. doi: 10.1002/14651858.CD004868.pub6.
Preterm infants have low plasma levels of erythropoietin (EPO), providing a rationale for the use of erythropoiesis-stimulating agents (ESAs) to prevent or treat anaemia. Darbepoetin (Darbe) and EPO are currently available ESAs.
To assess the effectiveness and safety of late initiation of ESAs, between eight and 28 days after birth, in reducing the use of red blood cell (RBC) transfusions in preterm or low birth weight infants.
We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2018, Issue 5), MEDLINE via PubMed (1966 to 5 June 2018), Embase (1980 to 5 June 2018), and CINAHL (1982 to 5 June 2018). We searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials.
Randomised or quasi-randomised controlled trials of late initiation of EPO treatment (started at ≥ eight days of age) versus placebo or no intervention in preterm (< 37 weeks) or low birth weight (< 2500 grams) neonates.
We performed data collection and analyses in accordance with the methods of the Cochrane Neonatal Review Group. We used the GRADE approach to assess the quality of the evidence.
We include 31 studies (32 comparisons) randomising 1651 preterm infants. Literature searches in 2018 identified one new study for inclusion. No new on-going trials were identified and no studies used darbepoetin. Most included trials were of small sample size. The meta-analysis showed a significant effect on the use of one or more RBC transfusions (21 studies (n = 1202); typical risk ratio (RR) 0.72, 95% confidence interval (CI) 0.65 to 0.79; typical risk difference (RD) -0.17, 95% CI -0.22 to -0.12; typical number needed to treat for an additional beneficial outcome (NNTB) 6, 95% CI 5 to 8). There was moderate heterogeneity for this outcome (RR I² = 66%; RD I² = 58%). The quality of the evidence was very low. We obtained similar results in secondary analyses based on different combinations of high/low doses of EPO and iron supplementation. There was no significant reduction in the total volume (mL/kg) of blood transfused per infant (typical mean difference (MD) -1.6 mL/kg, 95% CI -5.8 to 2.6); 5 studies, 197 infants). There was high heterogeneity for this outcome (I² = 92%). There was a significant reduction in the number of transfusions per infant (11 studies enrolling 817 infants; typical MD -0.22, 95% CI -0.38 to -0.06). There was high heterogeneity for this outcome (I² = 94%). Three studies including 404 infants reported on retinopathy of prematurity (ROP) (all stages or stage not reported), with a typical RR 1.27 (95% CI 0.99 to 1.64) and a typical RD of 0.09 (95% CI -0.00 to 0.18). There was high heterogeneity for this outcome for both RR (I² = 83%) and RD (I² = 82%). The quality of the evidence was very low.Three trials enrolling 442 infants reported on ROP (stage ≥ 3). The typical RR was 1.73 (95% CI 0.92 to 3.24) and the typical RD was 0.05 (95% CI -0.01 to 0.10). There was no heterogeneity for this outcome for RR (I² = 18%) but high heterogeneity for RD (I² = 79%). The quality of the evidence was very low.There were no significant differences in other clinical outcomes including mortality and necrotising enterocolitis. For the outcomes of mortality and necrotising enterocolitis, the quality of the evidence was moderate. Long-term neurodevelopmental outcomes were not reported.
AUTHORS' CONCLUSIONS: Late administration of EPO reduces the use of one or more RBC transfusions, the number of RBC transfusions per infant (< 1 transfusion per infant) but not the total volume (mL/kg) of RBCs transfused per infant. Any donor exposure is likely not avoided as most studies included infants who had received RBC transfusions prior to trial entry. Late EPO does not significantly reduce or increase any clinically important adverse outcomes except for a trend in increased risk for ROP. Further research of the use of late EPO treatment, to prevent donor exposure, is not indicated. Research efforts should focus on limiting donor exposure during the first few days of life in sick neonates, when RBC requirements are most likely to be required and cannot be prevented by late EPO treatment. The use of satellite packs (dividing one unit of donor blood into many smaller aliquots) may reduce donor exposure.
早产儿血浆促红细胞生成素（EPO）水平较低，这为使用促红细胞生成剂（ESAs）预防或治疗贫血提供了理论依据。目前可用的ESAs有 darbepoetin（Darbe）和EPO。
评估出生后8至28天开始使用ESAs在减少早产或低出生体重婴儿红细胞（RBC）输血使用方面的有效性和安全性。
我们采用Cochrane新生儿组的标准检索策略，检索Cochrane对照试验中心注册库（CENTRAL 2018年第5期）、通过PubMed检索MEDLINE（1966年至2018年6月5日）、Embase（1980年至2018年6月5日）和CINAHL（1982年至2018年6月5日）。我们检索了临床试验数据库、会议论文集以及检索到的文章的参考文献列表，以查找随机对照试验和半随机试验。
EPO治疗延迟启动（≥8日龄开始）与安慰剂或对早产（<37周）或低出生体重（<2500克）新生儿不进行干预的随机或半随机对照试验。
我们按照Cochrane新生儿综述组的方法进行数据收集和分析。我们采用GRADE方法评估证据质量。
我们纳入了31项研究（32项比较），对1651名早产儿进行了随机分组。2018年的文献检索确定了一项新的纳入研究。未发现新的正在进行的试验，且没有研究使用darbepoetin。大多数纳入试验样本量较小。荟萃分析显示，对使用一次或多次RBC输血有显著影响（21项研究（n = 1202）；典型风险比（RR）0.72，95%置信区间（CI）0.65至0.79；典型风险差（RD）-0.17，95%CI -0.22至-0.12；为获得额外有益结果所需治疗的典型人数（NNTB）6，95%CI 5至8）。该结果存在中度异质性（RR I² = 66%；RD I² = 58%）。证据质量非常低。我们在基于不同高/低剂量EPO和铁补充剂组合的二次分析中获得了类似结果。每名婴儿输血的总体积（mL/kg）没有显著减少（典型平均差（MD）-1.6 mL/kg，95%CI -5.8至2.6）；5项研究，197名婴儿）。该结果存在高度异质性（I² = 92%）。每名婴儿的输血次数显著减少（11项研究，纳入817名婴儿；典型MD -0.22，95%CI -0.38至-0.06）。该结果存在高度异质性（I² = 94%）。三项纳入404名婴儿的研究报告了早产儿视网膜病变（ROP）（所有阶段或未报告阶段），典型RR为1.27（95%CI 0.99至1.64），典型RD为0.09（95%CI -0.00至0.18）。该结果在RR（I² = 83%）和RD（I² = 82%）方面均存在高度异质性。证据质量非常低。三项纳入442名婴儿的试验报告了ROP（≥3期）。典型RR为1.73（95%CI 0.92至3.24），典型RD为0.05（95%CI -0.01至0.10）。该结果在RR方面不存在异质性（I² = 18%），但在RD方面存在高度异质性（I² = 79%）。证据质量非常低。在包括死亡率和坏死性小肠结肠炎在内的其他临床结局方面没有显著差异。对于死亡率和坏死性小肠结肠炎结局，证据质量为中等。未报告长期神经发育结局。
延迟给予EPO可减少一次或多次RBC输血的使用、每名婴儿的RBC输血次数（每名婴儿<1次输血），但不能减少每名婴儿RBC输血的总体积（mL/kg）。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，因此可能无法避免任何供体暴露。延迟给予EPO除了有ROP风险增加的趋势外，不会显著降低或增加任何临床上重要的不良结局。不建议进一步研究延迟给予EPO治疗以预防供体暴露。研究工作应集中在限制患病新生儿出生后头几天的供体暴露，此时最有可能需要RBC且延迟给予EPO治疗无法预防。使用卫星包装（将一个单位的供体血液分成许多较小的等分份）可能会减少供体暴露。
