Supplementary Material for: Therapeutic Hypothermia for Neonatal Encephalopathy in Low- and Middle-Income Countries: A Meta-Analysis

Background: Perinatal asphyxia and hypoxic-ischemic encephalopathy (HIE) represent substantial sources of neonatal morbidity and mortality in low- and middle-income countries (LMICs), leading to high rates of adverse long-term neurological outcomes. Methods: A systematic review with meta-analysis of randomized controlled trials in LMICs was conducted. PubMed, Scopus, Web of Science, CENTRAL, ClinicalTrials.gov, and Google Scholar were searched from inception to August 20, 2021. The population of the study consisted of neonates with gestational age ≥34 weeks and HIE. The main endpoints were overall mortality and the composite outcome of death or severe disability. The certainty of evidence was evaluated with the GRADE approach. Results: Ten studies were included comprising 1,293 neonates. Some concerns of bias were raised due to the nonblinded nature of the intervention. The risk of death was similar between the two groups (risk ratio [RR]: 0.78, 95% confidence interval [CI]: 0.52–1.18). No significant differences were observed in the composite outcome of death or severe disability between the two groups (RR: 0.78, 95% CI: 0.56–1.10, very low quality of evidence). Furthermore, no significant differences were observed in the endpoints of sepsis, shock, acute kidney injury, major arrhythmia, and length of hospital stay. Therapeutic hypothermia was associated with significantly higher risk of thrombocytopenia (RR: 2.13, 95% CI: 1.34–3.38) and clinically significant hemorrhage (RR: 1.57, 95% CI: 1.25–1.97). Conclusion: Therapeutic hypothermia probably results in little to no difference in clinical outcomes among neonates with HIE in LMICs. Further large-scale research targeting proper patient selection is needed to elucidate the utility of therapeutic hypothermia in resource-limited settings. Protocol Registration: The protocol of the study has been prospectively registered by Prospero, CRD42021272284.背景：围产期窒息（Perinatal asphyxia）与缺氧缺血性脑病（hypoxic-ischemic encephalopathy, HIE）是中低收入国家（low- and middle-income countries, LMICs）新生儿发病与死亡的重要成因，可导致较高比例的长期不良神经预后结局。 方法：本研究针对中低收入国家的随机对照试验开展系统评价联合荟萃分析。检索数据库包括PubMed、Scopus、Web of Science、CENTRAL、ClinicalTrials.gov及Google Scholar，检索时限为各数据库建库至2021年8月20日。研究对象为胎龄≥34周的缺氧缺血性脑病新生儿。主要结局指标为总死亡率，以及死亡或重度残疾的复合结局。采用GRADE方法（GRADE approach）评估证据确定性。 结果：最终纳入10项研究，共计1293例新生儿。由于干预措施未采用盲法，研究存在偏倚风险相关的潜在担忧。两组新生儿的死亡风险无显著差异（风险比[risk ratio, RR]=0.78，95%置信区间[confidence interval, CI]=0.52~1.18）。两组在死亡或重度残疾的复合结局上亦未观察到显著差异（RR=0.78，95%CI=0.56~1.10，证据质量极低）。此外，两组在脓毒症、休克、急性肾损伤、严重心律失常及住院时长等指标上均无显著差异。治疗性低温（therapeutic hypothermia）与血小板减少症（thrombocytopenia，RR=2.13，95%CI=1.34~3.38）及临床显著性出血（RR=1.57，95%CI=1.25~1.97）的发生风险显著升高相关。 结论：在中低收入国家的缺氧缺血性脑病新生儿中，治疗性低温对其临床结局的影响可能微乎其微，甚至无差异。未来需开展针对合适患者筛选的大规模研究，以阐明治疗性低温在资源受限环境中的应用价值。 方案注册：本研究方案已通过Prospero平台前瞻性注册，注册号为CRD42021272284。