Supplementary Material for: Effect of Early Erythropoietin on Retinopathy of Prematurity: A Stratified Meta-Analysis

<b><i>Background:</i></b> Recombinant human erythropoietin (rhEPO) lost its role in minimizing red blood cell transfusion in very preterm infants after it had been associated with severe retinopathy of prematurity (ROP). Previous systematic reviews did not stratify ROP by gestation and birth weight (BW). <b><i>Objectives:</i></b> The aim of this study was to investigate the effect of early prophylactic rhEPO on ROP in a stratified meta-analysis of randomized controlled trials (RCTs). <b><i>Methods:</i></b> The databases EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Trials were searched in January 2022 and complemented by citation searching. RCTs comparing early rhEPO treatment with no treatment or placebo were selected if they were published in a peer-reviewed journal and reported ROP outcomes. Previously unpublished data were requested from the study authors to allow stratified analyses by gestational age (GA) and BW. Data were extracted and analyzed using the standard methods of the Cochrane Neonatal Review Group. Pre-specified outcomes were “ROP stage ≥3” (primary outcome) and “any ROP.” <b><i>Results:</i></b> Fourteen RCTs, comprising 2,040 infants of &lt;29 weeks of GA, were included for meta-analysis. Data syntheses showed no effects of rhEPO on ROP stage ≥3 or on any ROP, neither in infants of &lt;29 weeks GA, nor in infants of &lt;1,000 g BW, nor in any GA strata. The risk ratio (95% confidence interval) for ROP stage ≥3 in infants of &lt;29 weeks of GA was 1.13 (0.84, 1.53), <i>p</i> = 0.41 (quality of evidence: moderate). <b><i>Conclusions:</i></b> The present meta-analysis detected no effects of early rhEPO on ROP in any comparison, but most stratified analyses were limited by low statistical power.

背景：
重组人促红细胞生成素（recombinant human erythropoietin, rhEPO）原本可用于减少极早产儿的红细胞输注需求，但后续因其与严重早产儿视网膜病（retinopathy of prematurity, ROP）相关，失去了这一临床应用价值。既往发表的系统综述均未按胎龄（gestational age, GA）与出生体重（birth weight, BW）对ROP进行分层分析。
目的：
本研究旨在通过对随机对照试验（randomized controlled trials, RCTs）开展分层Meta分析，探讨早期预防性使用rhEPO对ROP的影响。
方法：
本研究于2022年1月检索了EMBASE、MEDLINE及Cochrane对照试验中心注册库，并辅以引文检索以补充文献来源。纳入经同行评议期刊发表、对比早期rhEPO治疗与未治疗/安慰剂、且报告了ROP结局的随机对照试验。我们向研究作者申请获取未发表的原始数据，以便按胎龄与出生体重开展分层分析。数据提取与分析采用Cochrane新生儿综述组（Cochrane Neonatal Review Group）的标准流程。预先设定的结局指标包括“ROP≥3期”（主要结局）与“任意类型ROP”。
结果：
本项Meta分析共纳入14项随机对照试验，涉及2040名胎龄＜29周的早产儿。数据合成结果显示，无论在胎龄＜29周的早产儿、出生体重＜1000g的早产儿，还是任意胎龄分层亚组中，rhEPO均未对ROP≥3期或任意类型ROP产生显著影响。胎龄＜29周的早产儿中，ROP≥3期的风险比（risk ratio, RR）为1.13，95%置信区间（95% confidence interval, CI）为0.84~1.53，p=0.41（证据质量：中等）。
结论：
本项Meta分析未发现早期rhEPO对ROP存在任何显著影响，但多数分层分析受限于统计效能不足。