Jiangxi Key Laboratory of Birth Defect Prevention and Control, Jiangxi Maternal and Child Health Hospital, Nanchang, China.
Chinese Academy of Sciences Key Laboratory of Separation Sciences for Analytical Chemistry, National Chromatographic R&A Center, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
Front Endocrinol (Lausanne). 2023 Feb 24;14:1072461. doi: 10.3389/fendo.2023.1072461. eCollection 2023.
More than half of the cases of fetal structural anomalies have no known cause with standard investigations like karyotype testing and chromosomal microarray. The differential metabolic profiles of amniotic fluid (AF) and maternal blood may reveal valuable information about the physiological processes of fetal development, which may provide valuable biomarkers for fetal health diagnostics.
This cohort study of singleton-pregnant women had indications for amniocentesis, including structural anomalies and a positive result from maternal serum screening or non-invasive prenatal testing, but did not have any positive abnormal karyotype or chromosomal microarray analysis results. A total of 1580 participants were enrolled between June 2021 and March 2022. Of the 1580 pregnant women who underwent amniocentesis, 294 were included in the analysis. There were 137 pregnant women in the discovery cohort and 157 in the validation cohort.
High-coverage untargeted metabolomic analysis of AF revealed distinct metabolic signatures with 321 of the 602 metabolites measured (53%) (false discovery rate, q < 0.005), among which amino acids predominantly changed in structural anomalies. Targeted metabolomics identified glutamate and glutamine as novel predictive markers for structural anomalies, their vital role was also confirmed in the validation cohort with great predictive ability, and the area under the receiver operating characteristic curves (AUCs) were 0.862 and 0.894 respectively. And AUCs for glutamine/glutamate were 0.913 and 0.903 among the two cohorts.
Our results suggested that the aberrant glutamine/glutamate metabolism in AF is associated with nonchromosomal modificantions fetal structural anomalies. Based on our findings, a novel screening method could be established for the nonchromosomal modificantions fetal structural anomalies. And the results also indicate that monitoring fetal metabolic conditions (especially glutamine and glutamine metabolism) may be helpful for antenatal diagnosis and therapy.
超过一半的胎儿结构异常病例在进行标准检查（如核型检测和染色体微阵列）后仍无法找到明确病因。羊水（amniotic fluid，AF）和母体血液的差异代谢谱可能揭示有关胎儿发育生理过程的有价值信息，这可能为胎儿健康诊断提供有价值的生物标志物。
这项对单胎孕妇的队列研究纳入了行羊膜腔穿刺术的指征为结构异常和母体血清筛查或非侵入性产前检测阳性但无异常核型或染色体微阵列分析结果的患者。共有 1580 名孕妇于 2021 年 6 月至 2022 年 3 月入组。在接受羊膜腔穿刺术的 1580 名孕妇中，有 294 名纳入分析。发现队列中有 137 名孕妇，验证队列中有 157 名孕妇。
对羊水进行高覆盖度非靶向代谢组学分析揭示了具有 321 种（占 602 种测量代谢物的 53%）（错误发现率 q<0.005）代谢物的独特代谢特征，其中氨基酸在结构异常中主要发生变化。靶向代谢组学鉴定出谷氨酸和谷氨酰胺是结构异常的新型预测标志物，其在验证队列中的重要作用也得到了证实，其接受者操作特征曲线（receiver operating characteristic curve，ROC）下面积（area under the receiver operating characteristic curve，AUC）分别为 0.862 和 0.894。在两个队列中，谷氨酰胺/谷氨酸的 AUC 分别为 0.913 和 0.903。
我们的结果表明，羊水异常谷氨酰胺/谷氨酸代谢与非染色体修饰的胎儿结构异常有关。基于我们的发现，可能可以建立一种新的非染色体修饰的胎儿结构异常筛查方法。此外，研究结果还表明，监测胎儿代谢状况（尤其是谷氨酰胺和谷氨酰胺代谢）可能有助于产前诊断和治疗。
