Department of Obstetrics and Gynecology, 'L. Mangiagalli' Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
Department of Neuroscience, Reproductive Science and Odontostomatology, University of Naples Federico II, Naples, Italy.
Mol Diagn Ther. 2020 Aug;24(4):409-431. doi: 10.1007/s40291-020-00468-5.
A systematic review was carried out to summarize the available evidence to assess whether circulating nucleic acids in maternal plasma and serum (CNAPS) have the potential to serve as extra and independent markers for the prediction and/or progression monitoring of the most common and severe complications of pregnancy, including preeclampsia, intrauterine growth restriction, preterm delivery, morbidly adherent placenta, gestational diabetes, antiphospholipid syndrome, threatened abortion, intrahepatic cholestasis of pregnancy, and hyperemesis gravidarum.
A comprehensive literature search of the MEDLINE (PubMed), EMBASE, and ISI Web of Knowledge databases was conducted to identify relevant studies that included amounts of CNAPS in the abovementioned pregnancy complications.
Eighty-three studies met the eligibility criteria. The vast majority of studies were conducted on the quantity of total circulating cell free DNA (cfDNA) and cell free fetal DNA (cffDNA), and some were conducted on messenger RNA (mRNA) species. A few studies have instead evaluated the cell free DNA fetal fraction (cfDNAff), but only in a limited number of pregnancy complications. Despite the growing interest and the abundance of the papers available, little information is available for other new CNAPS, including microRNA (miRNA), long noncoding RNA (lncRNA), mitochondrial DNA (mtDNA), and circular RNA.
Due to the heterogeneity of the populations enrolled, the scarcity of the studies that adjusted the CNAPS values for possible confounding factors, and the difficulty in interpreting the published data, no conclusion regarding the statistical robustness and clinical relevance of the data can be made at present. If assayed at the third trimester, the CNAPS have, however, shown better performance, and could be used in populations already at risk of developing complications as suggested by the presence of other clinical features. Other CNAPS, including miRNA, are under investigation, especially for the screening of gestational diabetes mellitus, but no data about their clinical utility are available. Circulating DNA (cfDNA, cffDNA, and cfDNAff) and mRNA have not been properly evaluated yet, especially in patients asymptomatic early in pregnancy but who developed complications later, perhaps because of the high cost of these techniques and the availability of other predictors of pregnancy complications (biochemical, biophysical, and ultrasound markers). Therefore, from the analysis of the data, the positive predictive value is not available. As regards the new CNAPS, including miRNA, there are still no sufficient data to understand if they can be promising markers for pregnancy complications monitoring and screening, since CNAPS are statistically weak and expensive. It is reasonable to currently conclude that the use of the CNAPS in clinical practice is not recommended.
系统综述旨在总结现有证据，评估循环核酸（CNAPS）在母体血浆和血清中是否具有作为预测和/或监测妊娠最常见和最严重并发症（包括子痫前期、宫内生长受限、早产、胎盘黏附不良、妊娠期糖尿病、抗磷脂综合征、先兆流产、妊娠肝内胆汁淤积症和妊娠剧吐）的额外独立标志物的潜力。
通过 MEDLINE（PubMed）、EMBASE 和 ISI Web of Knowledge 数据库全面检索相关文献，以确定纳入上述妊娠并发症中 CNAPS 含量的研究。
83 项研究符合入选标准。绝大多数研究集中在循环游离总 DNA（cfDNA）和游离胎儿 DNA（cffDNA）的数量上，一些研究则集中在信使 RNA（mRNA）上。少数研究评估了游离 DNA 胎儿分数（cfDNAff），但仅限于少数妊娠并发症。尽管人们越来越感兴趣，相关文献也越来越多，但关于其他新的 CNAPS（包括 microRNA（miRNA）、长链非编码 RNA（lncRNA）、线粒体 DNA（mtDNA）和环状 RNA）的信息却很少。
由于纳入人群的异质性、调整 CNAPS 值以适应可能存在的混杂因素的研究相对较少以及对已发表数据的解读困难，目前无法对数据的统计学稳健性和临床相关性做出结论。然而，如果在妊娠晚期进行检测，CNAPS 的表现更好，并且可以用于已经存在其他临床特征的并发症风险人群。其他 CNAPS，包括 miRNA，正在研究中，特别是用于筛查妊娠期糖尿病，但目前尚无关于其临床应用的相关数据。循环 DNA（cfDNA、cffDNA 和 cfDNAff）和 mRNA 尚未得到充分评估，尤其是对于妊娠早期无症状但后来出现并发症的患者，这可能是因为这些技术成本高，而且已经有其他预测妊娠并发症的标志物（生化、生物物理和超声标志物）。因此，从数据分析来看，阳性预测值不可用。至于包括 miRNA 在内的新的 CNAPS，由于它们的统计学效力和成本效益，目前尚不清楚它们是否可以作为妊娠并发症监测和筛查的有希望的标志物。因此，目前可以合理地得出结论，不建议在临床实践中使用 CNAPS。
