Metabolomic profiles of mid-trimester amniotic fluid are not associated with subsequent spontaneous preterm delivery or gestational duration at delivery

Spontaneous preterm delivery (&lt;37 gestational weeks) has a multifactorial etiology with still incompletely identified pathways. Amniotic fluid is a biofluid with great potential for insights into the feto-maternal milieu. It is rich in metabolites, and metabolic consequences of inflammation is yet researched only to a limited extent. Metabolomic profiling provides opportunities to identify potential biomarkers of inflammatory conditioned pregnancy complications such as spontaneous preterm delivery. The aim of this study was to perform metabolomic profiling of amniotic fluid from uncomplicated singleton pregnancies in the mid-trimester to identify potential biomarkers associated with spontaneous preterm delivery and gestational duration at delivery. A secondary aim was to replicate previously reported mid-trimester amniotic fluid metabolic biomarkers of spontaneous preterm delivery in asymptomatic women. A nested case-control study was performed within a larger cohort study of asymptomatic pregnant women undergoing mid-trimester genetic amniocentesis at 14–19 gestational weeks in Gothenburg, Sweden. Medical records were used to obtain clinical data and delivery outcome variables. Amniotic fluid samples from women with a subsequent spontaneous preterm delivery (<i>n</i> = 37) were matched with amniotic fluid samples from women with a subsequent spontaneous delivery at term (<i>n</i> = 37). Amniotic fluid samples underwent untargeted metabolomic analyses using liquid chromatography-mass spectrometry. Multivariate random forest analyses were used for data processing. A secondary targeted analysis was performed, aiming to replicate previously reported mid-trimester amniotic fluid metabolic biomarkers in women with a subsequent spontaneous preterm delivery. Multivariate analysis did not distinguish the samples from women with a subsequent spontaneous preterm delivery from those with a subsequent term delivery. Neither was the metabolic profile associated with gestational duration at delivery. Potential metabolic biomarker candidates were identified from four publications by two different research groups relating mid-trimester amniotic fluid metabolomes to spontaneous PTD, of which fifteen markers were included in the secondary analysis. None of these were replicated. Metabolomic profiles of early mid-trimester amniotic fluid were not associated with spontaneous preterm delivery or gestational duration at delivery in this cohort.

自发性早产（spontaneous preterm delivery，妊娠周数<37周）的病因具有多因素性，其致病通路至今仍未完全阐明。羊水（amniotic fluid）是一种生物体液，在解析母胎微环境（feto-maternal milieu）方面具有巨大潜力；羊水富含代谢物（metabolites），但针对炎症所引发的代谢变化的研究仍较为有限。代谢组学分析（metabolomic profiling）为识别炎症相关性妊娠并发症（inflammatory conditioned pregnancy complications，如自发性早产）的潜在生物标志物提供了契机。本研究旨在对妊娠中期无并发症单胎妊娠（uncomplicated singleton pregnancies）的羊水样本进行代谢组学分析，以识别与自发性早产及分娩孕周相关的潜在生物标志物；次要研究目的为在无症状女性群体中，复现既往报道的、与自发性早产相关的妊娠中期羊水代谢生物标志物。本研究在瑞典哥德堡开展的一项更大规模队列研究（cohort study）内部开展嵌套病例对照研究（nested case-control study），该队列纳入了妊娠14~19周时接受妊娠中期遗传学羊膜穿刺术（genetic amniocentesis）的无症状孕妇。研究通过病历获取临床数据及分娩结局变量，将后续发生自发性早产的孕妇的羊水样本（n=37）与后续足月自然分娩的孕妇的羊水样本（n=37）进行匹配。采用液相色谱-质谱联用（liquid chromatography-mass spectrometry）技术对羊水样本进行非靶向代谢组学分析，使用多变量随机森林（random forest）分析进行数据处理；此外开展了一项次要靶向代谢组学分析，旨在复现既往报道的、与后续发生自发性早产的孕妇相关的妊娠中期羊水代谢生物标志物。多变量分析无法将后续发生自发性早产的孕妇的羊水样本与足月分娩孕妇的样本区分开来，代谢特征亦与分娩孕周无显著关联。研究从两个不同研究团队发表的4篇相关文献中筛选出潜在代谢生物标志物候选物，这些文献均探讨了妊娠中期羊水代谢组与自发性早产的关联，其中15种标志物被纳入本次次要分析，但未复现任何一种标志物。本队列研究结果显示，妊娠早中期羊水的代谢组特征与自发性早产或分娩孕周均无关联。