ABSTRACT
BACKGROUND
Preterm birth remains a major public health issue affecting 10% of all pregnancies
and increases risks of neonatal morbidity and mortality. Approximately 50% to 60%
of preterm births are spontaneous, resulting from preterm premature rupture of membranes
or preterm labor. The pathogenesis of spontaneous preterm birth is incompletely understood,
and prediction of preterm birth remains elusive. Accurate prediction of preterm birth
would reduce infant morbidity and mortality through targeted patient referral to hospitals
equipped to care for preterm infants. Two previous studies have analyzed cervical
microRNAs in association with spontaneous preterm birth and the length of gestation,
but the extent to which microRNAs serve as predictive biomarkers remains unknown.
OBJECTIVE
This study aimed to examine associations between cervical microRNA expression and
spontaneous preterm birth, with the specific goal of identifying a subset of microRNAs
that predict spontaneous preterm birth.
STUDY DESIGN
We performed a prospective, nested, case-control study of 25 cases with spontaneous
preterm birth and 49 term controls. Controls were matched to cases in a 2:1 ratio
on the basis of age, parity, and self-identified race. Cervical swabs were collected
at a mean gestational age of 17.1 (4.8) weeks of gestation, and microRNAs were analyzed
using a quantitative polymerase chain reaction array. Normalized microRNA expression
was compared between cases and controls, and a false discovery rate of 0.2 was applied
to account for multiple comparisons. Histopathologic analysis of slides of cervical
swab samples was performed to quantify leukocyte burden for adjustment in conditional
regression models. We explored the use of Relief-based unsupervised identification
of top microRNAs and support vector machines to predict spontaneous preterm birth.
We performed microRNA enrichment analysis to explore potential biologic targets and
pathways in which up-regulated microRNAs might be involved.
RESULTS
Of the 754 microRNAs on the polymerase chain reaction array, 346 were detected in
≥75% of participants’ cervical swabs. Average cervical microRNA expression was significantly
higher in cases of spontaneous preterm birth than in controls (P=.01). There were 95 significantly up-regulated individual microRNAs (>2-fold change)
in cases of subsequent spontaneous preterm birth compared with term controls (P<.05; q<0.2). Notably, miR-143, miR-30e-3p, and miR-199b were all significantly up-regulated,
which is consistent with the 1 previous study of cervical microRNA and spontaneous
preterm birth. A Relief-based, novel variable (feature) selection machine learning
approach had low-to-moderate prediction accuracy, with an area under the receiver
operating curve of 0.71. Enrichment analysis revealed that identified microRNAs may
modulate inflammatory cell signaling.
CONCLUSION
In this prospective nested case-control study of cervical microRNA expression and
spontaneous preterm birth, we identified a global increase in microRNA expression
and up-regulation of 95 distinct microRNAs in association with subsequent spontaneous
preterm birth. Larger and more diverse studies are required to determine the ability
of microRNAs to accurately predict spontaneous preterm birth, and mechanistic work
to facilitate development of novel therapeutic interventions to prevent spontaneous
preterm birth is warranted.
Key words
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to American Journal of Obstetrics & Gynecology MFMAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
World Health Organization. Preterm birth. 2018. Available at: https://www.who.int/en/news-room/fact-sheets/detail/preterm-birth. Accessed February 3, 2021.
- Association between temporal changes in neonatal mortality and spontaneous and clinician-initiated deliveries in the United States, 2006-2013.JAMA Pediatr. 2018; 172: 949-957
- The role of routine cervical length screening in selected high- and low-risk women for preterm birth prevention.Am J Obstet Gynecol. 2016; 215 (Society for Maternal-Fetal Medicine (SMFM). Electronic address: [email protected]): B2-B7
- Cervical etiology of spontaneous preterm birth.Semin Fetal Neonatal Med. 2016; 21: 106-112
- Overview of microRNA biogenesis, mechanisms of actions, and circulation.Front Endocrinol. 2018; 9: 402
- Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases.Cell Res. 2008; 18: 997-1006
- Circulating microRNAs as stable blood-based markers for cancer detection.Proc Natl Acad Sci U S A. 2008; 105: 10513-10518
- microRNA expression in the cervix during pregnancy is associated with length of gestation.Epigenetics. 2015; 10: 221-228
- Distinct cervical microRNA profiles are present in women destined to have a preterm birth.Am J Obstet Gynecol. 2014; 210 (e1-11): 221
- American College of Obstetricians and Gynecologists’ Committee on Obstetric Practice, Society for Maternal-Fetal Medicine. Medically indicated late-preterm and early-term deliveries: ACOG Committee Opinion.Obstet Gynecol. 2021; 138: e35-e39
- Pregnancy-associated changes in cervical noncoding RNA.Epigenomics. 2020; 12: 1013-1025
- Altered miRNA expression in the cervix during pregnancy associated with lead and mercury exposure.Epigenomics. 2015; 7: 885-896
- Bacterial and cytokine mixtures predict the length of gestation and are associated with miRNA expression in the cervix.Epigenomics. 2017; 9: 33-45
- Benchmarking relief-based feature selection methods for bioinformatics data mining.J Biomed Inform. 2018; 85: 168-188
- Relief-based feature selection: introduction and review.J Biomed Inform. 2018; 85: 189-203
- miEAA: microRNA enrichment analysis and annotation.Nucleic Acids Res. 2016; 44 (W110-6)
- miEAA 2.0: integrating multi-species microRNA enrichment analysis and workflow management systems.Nucleic Acids Res. 2020; 48: W521-W528
- An overview of microRNAs: biology, functions, therapeutics, and analysis methods.J Cell Physiol. 2019; 234: 5451-5465
- Colonization of the cervicovaginal space with vaginalis leads to local inflammation and cervical remodeling in pregnant mice.PLoS One. 2018; 13e0191524
- Insight into the ecology of vaginal bacteria through integrative analyses of metagenomic and metatranscriptomic data.Genome Biol. 2022; 23: 66
- Comparative meta-RNA-seq of the vaginal microbiota and differential expression by Lactobacillus iners in health and dysbiosis.Microbiome. 2013; 1: 12
- Human cervicovaginal fluid biomarkers to predict term and preterm labor.Front Physiol. 2015; 6: 151
- Cervicovaginal fluid proteomic analysis to identify potential biomarkers for preterm birth.Am J Obstet Gynecol. 2020; 222 (e1-13): 493
- Gene expression. MicroRNA control of protein expression noise.Science. 2015; 348: 128-132
- MiRNAs confer phenotypic robustness to gene networks by suppressing biological noise.Nat Commun. 2013; 4: 2364
- Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells.Nat Cell Biol. 2007; 9: 654-659
- Atheroprotective communication between endothelial cells and smooth muscle cells through miRNAs.Nat Cell Biol. 2012; 14: 249-256
- Adipose-derived circulating miRNAs regulate gene expression in other tissues.Nature. 2017; 542: 450-455
- Molecular pathways: microRNAs, cancer cells, and microenvironment.Clin Cancer Res. 2014; 20: 6247-6253
- MicroRNA control of signal transduction.Nat Rev Mol Cell Biol. 2010; 11: 252-263
- MicroRNAs in cancer: biomarkers, functions and therapy.Trends Mol Med. 2014; 20: 460-469
- MicroRNA as biomarkers and diagnostics.J Cell Physiol. 2016; 231: 25-30
- MicroRNAs: biomarkers, diagnostics, and therapeutics.Methods Mol Biol. 2017; 1617: 57-67
- MicroRNA responses to cellular stress.Cancer Res. 2006; 66: 10843-10848
- Increased microRNA activity in human cancers.PLoS One. 2009; 4: e6045
- A guide to miRNAs in inflammation and innate immune responses.FEBS Journal. 2018; 285: 3695-3716
- Inflammatory proteins in the amniotic fluid, plasma, and cervicovaginal fluid for the prediction of intra-amniotic infection/inflammation and imminent preterm birth in preterm labor.Am J Perinatol. 2022; 39: 766-775
- Proteomic analysis of human cervicovaginal fluid collected before preterm premature rupture of the fetal membranes.Reproduction. 2013; 145: 137-147
- Predicting risk of spontaneous preterm delivery in women with a singleton pregnancy.Paediatr Perinat Epidemiol. 2014; 28: 11-22
- PredictPTB: an interpretable preterm birth prediction model using attention-based recurrent neural networks.BioData Min. 2022; 15: 6
- miR-143 and miR-145 disrupt the cervical epithelial barrier through dysregulation of cell adhesion, apoptosis and proliferation.Sci Rep. 2017; 7: 3020
- Microbial supernatants from Mobiluncus mulieris, a bacteria strongly associated with spontaneous preterm birth, disrupts the cervical epithelial barrier through inflammatory and miRNA mediated mechanisms.Anaerobe. 2020; 61102127
- The random subspace method for constructing decision forests.IEEE Trans Pattern Anal Mach Intell. 1998; 20: 832-844
- XGBoost: A scalable tree boosting system.(presented)in: at: Proceedings of the 22nd ACM SIGKDD International Conference on Knowledge Discovery and Data Mining. San Francisco, CA2016
Article info
Publication history
Published online: October 21, 2022
Accepted:
October 18,
2022
Received:
October 14,
2022
Footnotes
H.H.B and K.D.G. share first authorship.
The authors report no conflict of interest.
The Spontaneous Prematurity and Epigenetics of the Cervix study was funded by the Charles H. Hood Foundation with additional support from the Chrissy and Jesse Brown Family. This work was conducted with support from Harvard Catalyst/Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 TR002541) and financial contributions from Harvard University and its affiliated academic healthcare centers. H.H.B. was supported by NIH K23 ES022242. A.Y.C. was supported by the Reproductive Scientist Development Program from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Burroughs Wellcome Fund (HD000849).
Cite this article as: Burris HH, Gerson KD, Woodward A, et al. Cervical microRNA expression and spontaneous preterm birth. Am J Obstet Gynecol MFM 2022;XX:x.ex-x.ex.
Identification
Copyright
© 2022 Elsevier Inc. All rights reserved.
