Bardill James R, Karimpour-Fard Anis, Breckenfelder Courtney C, Sucharov Carmen C, Eason Caitlin R, Gallagher Lauren T, Khailova Ludmila, Wright Clyde J, Gien Jason, Galan Henry L, Derderian Sarkis Christopher
Department of Surgery, University of Colorado School of Medicine, Aurora, CO (Bardill, Breckenfelder, Eason, Gallagher, and Derderian); Department of Surgery, Laboratory for Fetal and Regenerative Biology, University of Colorado Denver School of Medicine, Aurora, CO (Bardill, Breckenfelder, Eason, Khailova, and Derderian).
Department of Biomedical Informatics, University of Colorado School of Medicine, Aurora, CO (Karimpour-Fard).
Am J Obstet Gynecol MFM. 2024 Dec;6(12):101535. doi: 10.1016/j.ajogmf.2024.101535. Epub 2024 Nov 4.
Congenital diaphragmatic hernia (CDH) is characterized by a diaphragmatic defect, leading to herniation of abdominal organs into the chest, lung compression, and impaired lung development, often resulting in pulmonary hypertension and lung hypoplasia. Prenatal imaging techniques like ultrasound and MRI provide anatomical predictors of outcomes, but their limitations necessitate novel biomarkers for better prognostic accuracy.
This study aims to identify unique circulating maternal, fetal, and neonatal microRNAs (miRNAs) that can distinguish CDH pregnancies from healthy controls and assess their potential as markers of disease severity.
We conducted a prospective study involving third-trimester maternal blood, amniotic fluid, cord blood, and neonatal blood samples from pregnancies complicated by CDH and healthy controls. miRNA expression was analyzed using RNA-sequencing, and random forest analysis identified miRNAs distinguishing CDH survivors from nonsurvivors. Pathway enrichment analyses were performed to explore the biological relevance of differentially expressed miRNAs.
Significant miRNA expression differences were observed between CDH and control samples across all sample types. In infant blood, 148 miRNAs were up-regulated, and 36 were down-regulated in CDH cases. Pathway analysis revealed that dysregulated miRNAs in CDH targeted pathways related to protein binding, transcription regulation, and signaling pathways implicated in pulmonary hypertension and lung hypoplasia. Random forest analysis identified miRNAs in maternal blood (miR-7850-5p_L-1R+2, miR-942-3p, and miR-197-3p) that distinguished CDH survivors from nonsurvivors, with an receiver operating characteristic area under the curve of 1.0.
Circulating miRNAs in maternal blood offer promising biomarkers for predicting CDH outcomes. miRNAs from infant blood provide mechanistic insights and potential targets for therapeutic intervention in critical pathways of pulmonary hypertension and lung hypoplasia. Further studies with larger cohorts are needed to validate these findings and explore the clinical application of miRNA biomarkers in CDH management.
先天性膈疝（CDH）的特征是膈肌缺损，导致腹部器官疝入胸腔，压迫肺部，影响肺发育，常导致肺动脉高压和肺发育不全。超声和MRI等产前成像技术可提供预后的解剖学预测指标，但其局限性使得需要新的生物标志物以提高预后准确性。
本研究旨在识别独特的循环母体、胎儿和新生儿微小RNA（miRNA），这些miRNA可区分CDH妊娠与健康对照，并评估其作为疾病严重程度标志物的潜力。
我们进行了一项前瞻性研究，纳入了妊娠晚期患有CDH的孕妇和健康对照的母体血液、羊水、脐带血和新生儿血液样本。使用RNA测序分析miRNA表达，并通过随机森林分析确定区分CDH存活者与非存活者的miRNA。进行通路富集分析以探索差异表达miRNA的生物学相关性。
在所有样本类型中，CDH样本与对照样本之间均观察到显著的miRNA表达差异。在婴儿血液中，CDH病例中有148种miRNA上调，36种miRNA下调。通路分析显示，CDH中失调的miRNA靶向与蛋白质结合、转录调控以及与肺动脉高压和肺发育不全相关的信号通路。随机森林分析确定母体血液中的miRNA（miR-7850-5p_L-1R+2、miR-942-3p和miR-197-3p）可区分CDH存活者与非存活者，受试者工作特征曲线下面积为1.0。
母体血液中的循环miRNA为预测CDH预后提供了有前景的生物标志物。婴儿血液中的miRNA为肺动脉高压和肺发育不全关键通路的治疗干预提供了机制见解和潜在靶点。需要更大样本量的进一步研究来验证这些发现，并探索miRNA生物标志物在CDH管理中的临床应用。
