Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA; Department of Pediatrics, University of Washington, Seattle, WA.
Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA.
Am J Obstet Gynecol. 2023 Jan;228(1):73.e1-73.e18. doi: 10.1016/j.ajog.2022.07.015. Epub 2022 Jul 19.
Spontaneous preterm birth accounts for most preterm births and leads to significant morbidity in the newborn and childhood period. This subtype of preterm birth represents an increasing proportion of all preterm births when compared with medically indicated preterm birth, yet it is understudied in omics analyses. The placenta is a key regulator of fetal and newborn health, and the placental transcriptome can provide insight into pathologic changes that lead to spontaneous preterm birth.
This analysis aimed to identify genes for which placental expression was associated with spontaneous preterm birth (including early preterm and late preterm birth).
The ECHO PATHWAYS consortium extracted RNA from placental samples collected from the Conditions Affecting Neurocognitive Development and Learning in Early Childhood and the Global Alliance to Prevent Prematurity and Stillbirth studies. Placental transcriptomic data were obtained by RNA sequencing. Linear models were fit to estimate differences in placental gene expression between term birth and spontaneous preterm birth (including gestational age subgroups defined by the American College of Obstetricians and Gynecologists). Models were adjusted for numerous confounding variables, including labor status, cohort, and RNA sequencing batch. This analysis excluded patients with induced labor, chorioamnionitis, multifetal gestations, or medical indications for preterm birth. Our combined cohort contained gene expression data for 14,023 genes in 48 preterm and 540 term samples. Genes and pathways were considered statistically significantly different at false discovery rate-adjusted P value of <.05.
In total, we identified 1728 genes for which placental expression was associated with spontaneous preterm birth with more differences in expression in early preterm samples than late preterm samples when compared with full-term samples. Of those, 9 genes were significantly decreased in both early and late spontaneous preterm birth, and the strongest associations involved placental expression of IL1B, ALPL, and CRLF1. In early and late preterm samples, we observed decreased expression of genes involved in immune signaling, signal transduction, and endocrine function.
This study provides a comprehensive assessment of the differences in the placental transcriptome associated with spontaneous preterm birth with robust adjustment for confounding. Results of this study are in alignment with the known etiology of spontaneous preterm birth, because we identified multiple genes and pathways for which the placental and chorioamniotic membrane expression was previously associated with prematurity, including IL1B. We identified decreased expression in key signaling pathways that are essential for placental growth and function, which may be related to the etiology of spontaneous preterm birth. We identified increased expression of genes within metabolic pathways associated exclusively with early preterm birth. These signaling and metabolic pathways may provide clinically targetable pathways and biomarkers. The findings presented here can be used to understand underlying pathologic changes in premature placentas, which can inform and improve clinical obstetrics practice.
自发性早产占大多数早产，并导致新生儿和儿童期的显著发病率。与医学指征性早产相比，这种早产亚型在组学分析中研究较少，但在自发性早产中占比越来越大。胎盘是胎儿和新生儿健康的关键调节剂，胎盘转录组可以深入了解导致自发性早产的病理变化。
本分析旨在确定胎盘表达与自发性早产（包括早期早产和晚期早产）相关的基因。
ECHO PATHWAYS 联盟从 Conditions Affecting Neurocognitive Development and Learning in Early Childhood 和 Global Alliance to Prevent Prematurity and Stillbirth 研究中收集的胎盘样本中提取 RNA。通过 RNA 测序获得胎盘转录组数据。拟合线性模型估计足月分娩和自发性早产（包括美国妇产科医师学会定义的妊娠期亚组）之间胎盘基因表达的差异。模型调整了许多混杂变量，包括劳动状态、队列和 RNA 测序批次。该分析排除了诱导分娩、绒毛膜羊膜炎、多胎妊娠或医学指征性早产的患者。我们的合并队列包含了 48 例早产和 540 例足月样本中 14023 个基因的基因表达数据。基因和途径的假发现率调整 P 值<.05 时被认为具有统计学显著性差异。
总共确定了 1728 个胎盘表达与自发性早产相关的基因，与足月样本相比，早期早产样本中的表达差异更大，晚期早产样本中的表达差异较小。其中，9 个基因在早期和晚期自发性早产中均显著降低，最强的关联涉及 IL1B、ALPL 和 CRLF1 的胎盘表达。在早期和晚期早产样本中，我们观察到与免疫信号、信号转导和内分泌功能相关的基因表达降低。
本研究全面评估了与自发性早产相关的胎盘转录组的差异，并对混杂因素进行了稳健调整。本研究结果与自发性早产的已知病因一致，因为我们发现了多个与早产相关的基因和途径，包括 IL1B。我们发现与胎盘和绒毛膜羊膜炎生长和功能相关的关键信号通路的表达降低，这可能与自发性早产的病因有关。我们发现与仅与早期早产相关的代谢途径相关的基因表达增加。这些信号和代谢途径可能提供临床上可靶向的途径和生物标志物。这里提出的发现可用于了解早产儿中潜在的病理变化，这可以为临床产科实践提供信息和改进。
