重组人红细胞生成素对于早产儿神经发育保护作用的Meta分析

A meta-analysis of the protection of recombinant human erythropoietin for neurodevelopment in preterm infants

目的采用Meta分析方法评价重组人红细胞生成素(rhEPO)对早产儿神经发育的保护作用。方法制定原始文献的纳入标准、排除标准及检索策略,检索PubMed、EMBASE、Cochrane图书馆、中国期刊全文数据库、万方数据库、维普中文科技期刊数据库及中国生物医学文献数据库等,获得rhEPO对早产儿神经发育保护的RCT或半随机对照试验(quasi-RCT)文献。使用Jadad量表对纳入文献进行质量评价,采用RevMan5.0软件进行Meta分析。以智力发育指数(MDI)、神经运动发育指数(PDI)、新生儿行为神经评估(NBNA)评分、严重神经系统后遗症(脑瘫、失明和听力受损)发生率以及严重早产儿视网膜病(ROP,≥3级)、严重脑室内出血(IVH,≥3级)、坏死性小肠结肠炎(NEC)和支气管肺发育不良(BPD)的发生率等作为观察指标,进行综合评估。结果共检索到118篇文献,符合纳入标准的2篇RCT和3篇quasi-RCT文献(n=233)进入Meta分析,其中英文文献2篇,中文文献3篇。文献质量评价A级1篇,B级1篇,C级3篇。各研究间的基线水平有一定差异,出生体重、孕周、rhEPO剂量和治疗持续时间不尽相同。Meta分析结果显示,rhEPO治疗组MDI评分显著高于对照组(WMD=7.73,95%CI:3.45～12.01,P=0.0004);rhEPO治疗组PDI评分显著高于对照组(WMD=3.81,95%CI:0.59～7.02,P=0.02);rhEPO治疗组NBNA评分显著高于对照组(WMD=1.95,95%CI:1.56～2.35,P<0.00001)。两组MDI评分<70发生率(OR=0.70,95%CI:0.31～1.61)、PDI评分<70发生率(OR=2.46,95%CI:0.94～6.45)、脑瘫(OR=1.08,95%CI:0.39～2.99)、失明(OR=0.34,95%CI:0.01～8.56)和听力受损(OR=1.04,95%CI:0.06～17.15)的发生率差异均无统计学意义。两组严重ROP(OR=1.30,95%CI:0.50～3.43)、严重IVH(OR=2.91,95%CI:0.64～13.23)、NEC(OR=0.57,95%CI:0.13～2.54)和BPD(OR=1.06,95%CI:0.50～2.26)发生率的差异均无统计学意义。结论应用rhEPO治疗可能改善早产儿神经系统预后,可能对于早产儿神经系统发育有保护作用,且不增加严重ROP的发生率。

Objective To assess the efficacy and safety of recombinant human erythropoietin（rhEPO） for improving neurodevelopment outcomes in preterm infants.Methods According to the requirements of Cochrane systematic review,a literature search was performed among PubMed,EMBASE,Cochrane library,CNKI,Wanfang data,VIP and CBM from the establishment of the database till 31 December 2009.Quality assessments of clinical trials were carried out.Randomized controlled trials（RCTs） or quasi-RCTs with rhEPO in preterm infants were enrolled and RevMan 5.0 software was used for meta-analysis.Data extraction,quality assessment,and meta-analysis for the results of homogeneous studies were done by two reviewers.The trials were analyzed using weighted mean difference（WMD） for continuous data and relative risk（RR） for dichotomous data,both kinds of data were expressed by 95%CI.For homogenous data（P≥0.10）,fixed effect model was calculated.Results One hundred and eighteen literatures were reviewed.The studies including reviews（n=22）,non-RCTs（n=35）,foundational researches（n=40）,anaemia studies（n=6）,full-term infants RCTs（n=2）,documents not meeting the major results of the meta analysis（n=8） were excluded.Two RCTs and 3 quasi-RCTs including 233 preterm infants（119 of treatment group and 114 of control group）were included in the analysis.The results of quality assessment were that 1 study was A,1 was B,and 3 were C.There was evidence of a significant effect of therapeutic rhEPO on the outcomes of MDI scores（WMD=7.73,95%CI：3.45-12.01,P=0.000 4）,PDI scores（WMD=3.81,95%CI：0.59-7.02,P=0.02） at 18 to 22 months and NBNA scores（WMD=1.95,95%CI：1.56-2.35,P〈0.000 01） at 40 weeks of corrected gestational age.However,rhEPO had no effect on MDI〈70（OR= 0.70,95%CI：0.31-1.61）,PDI〈70（OR=2.46,95%CI：0.94-6.45）,cerebral palsy（OR=1.08,95%CI：0.39-2.99）,blindness（OR=0.34,95%CI：0.01-8.56） and hearing loss（OR=1.04,95%CI：0.06-17.15）.There were no differences between groups with respect to the percentage of preterm infants with severe ROP of stage Ⅲ or above（OR=1.30,95%CI：0.50-3.43）,severe IVH of stage Ⅲ or above（OR=2.91,95%CI：0.64-13.23）,NEC（OR=0.57,95%CI：0.13-2.54） and BPD（OR=1.06,95%CI：0.50-2.26）.Conclusions The rhEPO treatment had beneficial effect on the neurodevelopment outcomes but did not produce severe ROP to preterm infants.