Neonatal Research Group, Health Research Institute La Fe, Valencia, Spain.
Division of Neonatology, University & Polytechnic Hospital La Fe, Valencia, Spain.
Pediatr Res. 2022 Feb;91(3):598-605. doi: 10.1038/s41390-021-01553-z. Epub 2021 May 5.
Infants with moderate and severe neonatal encephalopathy (NE) frequently suffer from long-term adverse outcomes. We hypothesize that the urinary metabolome of newborns with NE reflects the evolution of injury patterns observed with magnetic resonance imaging (MRI).
Eligible patients were newborn infants with perinatal asphyxia evolving to NE and qualifying for therapeutic hypothermia (TH) included in the HYPOTOP trial. MRI was employed for characterizing brain injury. Urine samples of 55 infants were collected before, during, and after TH. Metabolic profiles of samples were recorded employing three complementary mass spectrometry-based assays, and the alteration of detected metabolic features between groups was assessed.
The longitudinal assessment revealed significant perturbations of the urinary metabolome. After 24 h of TH, a stable disease pattern evolved characterized by the alterations of 4-8% of metabolic features related to lipid metabolism, metabolism of cofactors and vitamins, glycan biosynthesis and metabolism, amino acid metabolism, and nucleotide metabolism. Characteristic metabolomic fingerprints were observed for different MRI injury patterns.
This study shows the potential of urinary metabolic profiles for the noninvasive monitoring of brain injury of infants with NE during TH.
A comprehensive approach for the study of the urinary metabolome was employed involving a semi-targeted capillary electrophoresis-time-of-flight mass spectrometry (TOFMS) assay, an untargeted ultra-performance liquid chromatography (UPLC)-quadrupole TOFMS assay, and a targeted UPLC-tandem MS-based method for the quantification of amino acids. The longitudinal study of the urinary metabolome identified dynamic metabolic changes between birth and until 96 h after the initiation of TH. The identification of altered metabolic pathways in newborns with pathologic MRI outcomes might offer the possibility of developing noninvasive monitoring approaches for personalized adjustment of the treatment and for supporting early outcome prediction.
中重度新生儿脑病（NE）患儿常伴有长期不良预后。我们假设 NE 患儿的尿代谢组学反映了磁共振成像（MRI）观察到的损伤模式的演变。
入选的患儿为新生儿期窒息进展为 NE 并符合接受治疗性低温（TH）标准的患儿，该研究纳入了 HYPOTOP 试验。采用 MRI 对脑损伤进行特征描述。55 例患儿在 TH 前、TH 中及 TH 后采集尿液样本。采用三种互补的基于质谱的检测方法对样本的代谢谱进行记录，并评估组间检测到的代谢特征的变化。
纵向评估显示尿代谢组发生显著变化。在 TH 开始后 24 小时，出现稳定的疾病模式，与脂质代谢、辅因子和维生素代谢、聚糖生物合成和代谢、氨基酸代谢和核苷酸代谢相关的代谢特征改变了 4-8%。不同 MRI 损伤模式存在特征性代谢组指纹图谱。
本研究表明，在接受 TH 的 NE 患儿中，尿代谢谱可能具有用于监测脑损伤的非侵入性潜力。
采用综合方法研究尿代谢组，涉及半靶向毛细管电泳-飞行时间质谱（TOFMS）分析、非靶向超高效液相色谱（UPLC）-四极杆 TOFMS 分析和靶向 UPLC-串联质谱法用于定量分析氨基酸。对出生至 TH 开始后 96 小时的尿代谢组进行纵向研究，确定了代谢变化的动态变化。病理性 MRI 结局新生儿中改变的代谢途径的识别可能为开发非侵入性监测方法提供可能，从而实现治疗的个性化调整，并支持早期预后预测。
