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中国循证儿科杂志

中国循证儿科杂志 ›› 2022, Vol. 17 ›› Issue (2): 90-97.

• 论著 • 上一篇    下一篇

轻度新生儿缺氧缺血性脑病神经系统发育结局的系统评价/Meta分析

王颖雯1a,王睁2,程国强1b,王来栓1b,周文浩1bc,张崇凡1d   

  1. 1 复旦大学附属儿科医院上海，201102，a 护理部，b 新生儿科，c 国家卫健委新生儿重点实验室，d 复旦大学GRADE中心；2 上海交通大学医学院附属上海市第一人民医院儿科上海，200080
  • 收稿日期:2022-03-31 修回日期:2022-03-28 出版日期:2022-04-25 发布日期:2022-04-25
  • 通讯作者: 周文浩，张崇凡

Neurodevelopmental outcome in mild neonatal hypoxic-ischemic encephalopathy: A systematic review and meta-analysis

WANG Yinwen1a, WANG Zheng2, CHENG Guoqiang1b, WANG Laishuan1b, ZHOU Wenhao1bc, ZHANG Chongfan1d   

  1. 1 Children's Hospital of Fudan University, Shanghai, 201102, a. Nursing Department; b. Department of Neonatology; c Key Laboratory for Neonates of National Health Comission; d GRADE Center of Fudan University;2 Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200080
  • Received:2022-03-31 Revised:2022-03-28 Online:2022-04-25 Published:2022-04-25
  • Contact: ZHOU Wenhao, email: zhouwenhao@fudan.edu.cn; ZHANG Chongfan, email: chongfan_zhang@fudan.edu.cn

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摘要： 背景：既往认为轻度新生儿却氧缺血性脑病（HIE）具有良好的长期结局，但近年来有证据表明轻度新生儿HIE较正常儿童存在不良神经发育结局。 目的：探讨轻度新生儿HIE是否受益于亚低温治疗。 设计：系统评价/Meta分析。 方法：检索Pubmed、Embase、Cochrane、CINAHL和中国生物医学文献服务系统（SinoMed）。中英文文献检索截止时间分别为2021年11月12日和2021年12月6日。阅读文题和摘要初筛，之后阅读全文进行再筛。再筛排除标准（满足以下条件之一）：①轻度新生儿HIE诊断不符合（改良）Sarnat标准；②新生儿合并有先天畸形；③不能提取新生儿轻度HIE的结局数据；④随访时间＜12月。采用Revman 5.4和R语言对提取的数据进行Meta整合。异质性采用I2检验，I2＞50%选用随机效应模型，I2≤50%选用固定效应模型。使用GRADE评价证据体质量，证据体中文献数量≥10篇进行发表偏倚分析。 主要结局指标：≥12月龄新生儿HIE死亡率和神经系统伤残联合发生率。 结果：中英文数据库共检索到1 839 篇,再筛113篇,最终24篇文献进入本文 Meta 分析。其中RCT 4篇，队列研究7篇，病例系列报告13篇。21篇文献以二分类变量报告神经系统伤残，3篇文献以连续变量报告神经系统伤残。随访时间在12个月至3岁16篇，＞3岁9篇（1篇文献分别在随访至24月和7岁时报告了神经系统伤残事件）。24篇文献在观察期间均未报告死亡事件。21篇以二分类变量报告的文献中，轻度新生儿HIE总样本量为369例，神经系统伤残发生率为21%（95%CI：14%~29%＝，I2=80%，Egger检验提示存在发表偏倚（t=4.68，P<0.01）；亚低温治疗亚组和非亚低温治疗亚组神经系统伤残发生率分别为11%（95%CI：0~23%）和21%（95%CI：13%~29%)。4篇RCT比较接受亚低温治疗和非亚低温治疗的轻度新生儿HIE患儿神经系统伤残发生率，差异无统计学意义（OR=0.78，95%CI：0.27~2.31，I2=0，P=0.62）；4篇队列研究将接受非亚低温治疗轻度新生儿HIE患儿与正常对照儿童相比，神经系统伤残发生率增加19倍（OR=19.06，95%CI：7.01~51.85，I2=42%，P=0.16）。随访12月龄至3岁亚组和＞3岁亚组神经系统伤残发生率分别为20%（95%CI：11%~29%）和24%（95%CI：11%~36%）。 结论：轻度新生儿HIE随访到3岁潜在的神经系统联合伤残风险增加至24%，对症支持治疗基础上予以亚低温治疗利大于弊。

关键词: 新生儿, 轻度, 缺氧缺血性脑病, 亚低温治疗, 神经系统伤残

Abstract: Background：Mild neonatal hypoxic-ischemic encephalopathy (HIE) has been considered to have better long-term outcomes. In recent years, there was evidence that the long-term outcomes of mild HIE were worse than those of normal children. Objective：To explore whether mild neonatal HIE benefits from hypothermia therapy. Design：Systematic review and meta-analysis. Methods：Literature was searched in databases of PubMed, Embase, Cochrane, CINAHL from the establishment to Dec 6,2021, and in database of SinoMed from the establishment to Nov 12, 2021. Retrieved papers were first screened by titles and abstracts. A second phase of screening was subsequently undertaken to screen papers for exclusion criteria as follows either: a. the diagnosis of mild neonatal HIE failing to meet the modified Sarnat standard; b. neonates with congenital malformations; c. failure to extract the outcome data of neonatal mild HIE; d. the follow-up time <12 months. GRADE methodology was used to rate the quality of evidence body. Publication bias analysis was adopted for more than 10 articles in either evidence body, and extracted data were analyzed using Revman 5.4 and R. The I2 test was used for heterogeneity. If I2≤50%, the fixed effect model should be adopted; if I2>50%, the random effect model should be adopted. Main outcome measures：Rate of death and major neurodevelopmental disabilities at more than 12 months. Results：1,839 articles were identified through database searching. A total of 113 full-text articles were assessed for eligibility and 24 articles were included in this review. The review was conducted for 4 RCTs, 7 cohort studies, and 13 case series reports. A total of 21 literature reported nervous system disability by dichotomous variables, and three literature reported nervous system disability by continuous ones. Follow-up time in 16 articles was from 12 months to 3 years, and 9 articles over 3 years (1 article reported neurological disability at 24 months and 7 years old respectively). No deaths were reported in the 24 articles during the observation period. A total of 369 infants with mild neonatal HIE was reported in 21 articles with dichotomous variables and the results showed that the incidence of major neurodevelopmental disabilities in mild HIE survivors was 21% (95%CI: 0.14-0.29), I2=80%, and there was publication bias (Egger test, t=4.68, P<0.01). The incidence of major neurodevelopmental disabilities was 11% (95%CI: 0.00-0.23) on therapeutic hypothermia (6 articles) and 21 percent (95%CI: 0.13-0.29) on non-therapeutic hypothermia (19 articles). There was no difference (OR=0.78, 95%CI: 0.27-2.31, I2=0) in the incidence of major neurodevelopmental disabilities between mild HIE patients treated with therapeutic hypothermia and those not treated with therapeutic hypothermia (4 RCTs), and patients who received non-therapeutic hypothermia compared with normal children (4 cohort studies) had higher incidence of major neurodevelopmental disabilities (OR=19.06, 95%CI: 7.01-51.85, I2=42%). The incidence of neurological disability was 20 percent (95%CI: 11%-29%) in subgroups whose follow-up time was from 12 months to 3 years and 24 percent (95%CI: 11%-36%) in over 3 years. Conclusion：When patients diagnosed with mild HIE was followed up until the age of 3 years old, the potential incidence of major neurodevelopmental disabilities increased to 24%, and benefits of combining with support treatment of therapeutic hypothermia as auxiliary is greater than the disadvantages.

Key words: Neonate, Mild , Hypoxic ischemic encephalopathy, Therapeutic hypothermia, Nervous system disability