Bierer Ryann, Peceny M Connie, Hartenberger Carol H, Ohls Robin K
Department of Pediatrics, University of Arizona, Tucson, Arizona, USA.
Pediatrics. 2006 Sep;118(3):e635-40. doi: 10.1542/peds.2005-3186. Epub 2006 Aug 14.
Erythropoietin therapy is effective in decreasing transfusions to varying degrees in preterm infants. Recent animal studies using erythropoietin doses to achieve serum concentrations > 1000 mU/mL report neuroprotective effects. We evaluated the relationship between erythropoietin concentrations and neurodevelopmental outcome in extremely low birth weight infants.
Preterm infants who weighed < or = 1000 g at birth were randomly assigned to erythropoietin (400 U/kg 3 times per week) or placebo/control. Therapy was initiated by 4 days after birth and continued through the 35th postmenstrual week. All infants received supplemental parenteral and enteral iron. Peak serum erythropoietin concentrations were obtained every 2 weeks. Follow-up evaluation included anthropometric measurements, Bayley scales of mental and psychomotor development, neurologic examination, and determination of overall neurodevelopmental impairment. Data were collected at 18 to 22 months' corrected age by certified examiners who were masked to the treatment group. Analyses were performed to identify correlations between erythropoietin concentrations and outcomes.
Sixteen extremely low birth weight infants were enrolled; 1 infant died at 2 weeks (placebo/control), and 15 had erythropoietin concentrations measured (7 erythropoietin, 8 placebo/control). Peak erythropoietin concentrations were significantly different between groups during the study (erythropoietin: 2027 +/- 1464 mU/mL; placebo/control: 26 +/- 11 mU/mL). Before follow-up, 3 infants died (1 erythropoietin, 2 placebo/control), and 12 were available for follow-up (6 erythropoietin, 6 placebo/control). At 18 to 22 months' follow-up, none of the erythropoietin recipients and 2 of the placebo/control infants had Mental Development Index scores < 70. Erythropoietin recipients had Mental Development Index scores of 96 +/- 11, and placebo/control infants had Mental Development Index scores of 78 +/- 7. Psychomotor Development Index scores were similar between groups (87 +/- 13 vs 80 +/- 7). There were no differences between groups with respect to anthropometric measurements. Two of 6 infants in the erythropoietin group and 4 of 6 infants in the placebo/control group had some form of neurodevelopmental impairment. Posthoc analysis showed that infants with erythropoietin concentrations > or = 500 mU/mL had higher Mental Development Index scores than infants with erythropoietin concentrations < 500 mU/mL.
Erythropoietin concentrations did not correlate with Psychomotor Development Index or overall incidence of neurodevelopmental impairment; however, infants with elevated erythropoietin concentrations had higher Mental Development Index scores than those with lower erythropoietin concentrations. Close follow-up of infants who are enrolled in large, multicenter, high-dose erythropoietin studies is required to determine whether a correlation exists between elevated erythropoietin concentrations and improved neurodevelopmental outcome.
促红细胞生成素疗法在不同程度上有效减少早产儿输血。近期使用促红细胞生成素剂量使血清浓度>1000 mU/mL的动物研究报告了神经保护作用。我们评估了极低出生体重儿促红细胞生成素浓度与神经发育结局之间的关系。
出生体重≤1000 g的早产儿被随机分配至促红细胞生成素组（400 U/kg，每周3次）或安慰剂/对照组。治疗在出生后4天内开始，并持续至孕龄35周。所有婴儿均接受肠外和肠内铁补充剂。每2周测定一次血清促红细胞生成素峰值浓度。随访评估包括人体测量、贝利智力和心理运动发育量表、神经学检查以及总体神经发育障碍的判定。由对治疗组情况不知情的认证检查人员在矫正年龄18至22个月时收集数据。进行分析以确定促红细胞生成素浓度与结局之间的相关性。
纳入16例极低出生体重儿；1例婴儿在2周时死亡（安慰剂/对照组），15例测定了促红细胞生成素浓度（7例促红细胞生成素组，8例安慰剂/对照组）。研究期间两组的促红细胞生成素峰值浓度存在显著差异（促红细胞生成素组：2027±1464 mU/mL；安慰剂/对照组：26±11 mU/mL）。随访前，3例婴儿死亡（1例促红细胞生成素组，2例安慰剂/对照组），12例可进行随访（6例促红细胞生成素组，6例安慰剂/对照组）。在18至22个月的随访中，促红细胞生成素组的婴儿均无智力发育指数评分<70，安慰剂/对照组有2例婴儿智力发育指数评分<70。促红细胞生成素组婴儿的智力发育指数评分为96±11，安慰剂/对照组婴儿的智力发育指数评分为78±7。两组间心理运动发育指数评分相似（87±13 vs 80±7）。两组在人体测量方面无差异。促红细胞生成素组6例婴儿中有2例、安慰剂/对照组6例婴儿中有4例存在某种形式的神经发育障碍。事后分析显示，促红细胞生成素浓度≥500 mU/mL的婴儿比促红细胞生成素浓度<500 mU/mL的婴儿有更高的智力发育指数评分。
促红细胞生成素浓度与心理运动发育指数或神经发育障碍的总体发生率无关；然而，促红细胞生成素浓度升高的婴儿比浓度较低的婴儿有更高的智力发育指数评分。需要对参与大型、多中心、高剂量促红细胞生成素研究的婴儿进行密切随访，以确定促红细胞生成素浓度升高与改善神经发育结局之间是否存在相关性。
