Placental Transcriptomic Signatures of Spontaneous Preterm Birth

• Authors: Alison G PAQUETTE, University of Washington; James MACDONALD, University of Washington; Theo BAMMLER, University of Washington; Drew B DAY, Seattle Children’s Research Institute; Christine T LOFTUS, University of Washington; Erin BUTH, University of Washington; W Alex MASON, University of Tennessee Health Science Center; Nicole R BUSH, University of California San Francisco; Kaja Z LEWINN, University of California San Francisco; Carmen Marsit, Emory University; James A LITCH, Global Alliance to Prevent Preterm Birth and Stillbirth (GAPPS); Michael GRAVETT, University of Washington; Daniel A ENQUOBAHRIE, University of Washington; Sheela SATHYANARAYANA, University of Washington
• Journal Title: American Journal of Obstetrics and Gynecology
• Volume: Volume 228, Number 1
• Publisher: Elsevier | 2022-07-19, Pages 73.e1-73.e18
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1016/j.ajog.2022.07.015
• Subjects: Health Sciences, Obstetrics and Gynecology; Biology, Molecular
• Keywords: Transcriptomics; Placenta; Spontaneous Preterm Birth; IL1B; GABRP; ALPL; chemokine signaling; placental metabolism; signal transduction

Abstract

Background: Spontaneous preterm birth accounts for the majority of preterm births and results in significant morbidity in the newborn and childhood period. This subtype of preterm birth represents an increasing proportion of all preterm births compared to medically indicated preterm birth, yet 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 leading to spontaneous preterm birth. Objective: This analysis aimed to identify genes whose placental expression was associated with spontaneous preterm birth (including early preterm and late preterm birth). Study Design: The ECHO PATHWAYS Consortium extracted RNA from placental samples collected from the Conditions Affecting Neurocognitive Development and Learning in Early childhood (CANDLE) and Global Alliance to Prevent Prematurity and Stillbirth (GAPPS) 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 length 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, multi-fetal gestation, 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 FDR adjusted P<0.05. Results: In total we identified 1,728 genes whose placental expression was associated with sPTB with more differences in expression in early preterm samples than late preterm samples compared to full term samples. 9 genes were significantly decreased in both early and late spontaneous preterm birth, and 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. Conclusions: This study provides a comprehensive assessment of differences in the placental transcriptome associated with spontaneous preterm birth to date with robust adjustment for confounding. Results of this study are in alignment with known etiology of spontaneous preterm birth, as we identified multiple genes and pathways whose placental and chorioamniotic membrane expression was previously associated with prematurity, including IL1B. We identified decreased expression in key signaling pathways which are essential to placental growth and function, which may be related to the etiology of sPTB. 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 pathological changes in premature placentas, which can inform and improve clinical obstetrics practice.