Background
A short cervix is a risk factor for preterm birth. The molecular drivers of a short
cervix remain elusive. Metabolites may function as mediators of pathologic processes.
Objective
We sought to determine if a distinct cervicovaginal metabolomic profile is associated
with a short cervix (<25 mm) to unveil the potential mechanisms by which premature
cervical remodeling leads to a short cervix.
Study Design
This was a secondary analysis of a completed prospective pregnancy cohort. Cervicovaginal
fluid was obtained between 20 and 24 weeks’ gestation. The participants selected for
metabolomic profiling were frequency-matched by birth outcome and cervicovaginal microbiota
profile. This analysis included 222 participants with cervical length measured. A
short cervix was defined as one having length <25 mm, as measured by transvaginal
ultrasound. Unpaired t-tests were performed with a Bonferroni correction for multiple
comparisons.
Results
There were 27 participants with a short cervix, and 195 with normal cervical length.
Of the 637 metabolites detected, 26 differed between those with a short cervix and
those with normal cervical lengths; 22 were decreased, of which 21 belonged to the
lipid metabolism pathway (all P<.000079). Diethanolamine, erythritol, progesterone, and mannitol or sorbitol were
increased in the cases of short cervix. Among participants with Lactobacillus-deficient microbiota, only diethanolamine and mannitol or sorbitol differed between
short cervix (n=17) and normal cervical length (n=75), both increased.
Conclusion
A short cervix is associated with decreased cervicovaginal lipid metabolites, particularly
sphingolipids. This class of lipids stabilizes cell membranes and protects against
environmental exposures. Increased diethanolamine—an immunostimulatory xenobiotic—is
associated with a short cervix. These observations begin to identify the potential
mechanisms by which modifiable environmental factors may invoke cell damage in the
setting of biological vulnerability, thus promoting premature cervical remodeling
in spontaneous preterm birth.
Key words
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References
- Cervicovaginal microbial communities deficient in Lactobacillus species are associated with second trimester short cervix.Am J Obstet Gynecol. 2020; 222: 491.e1-491.e8
- Cervicovaginal microbiota and local immune response modulate the risk of spontaneous preterm delivery.Nat Commun. 2019; 10: 1305
- Temporal and spatial variation of the human microbiota during pregnancy.Proc Natl Acad Sci U S A. 2015; 112: 11060-11065
- Early pregnancy vaginal microbiome trends and preterm birth.Am J Obstet Gynecol. 2017; 217: 356.e1-356.e18
- Replication and refinement of a vaginal microbial signature of preterm birth in two racially distinct cohorts of US women.Proc Natl Acad Sci U S A. 2017; 114: 9966-9971
- The vaginal microbiome and preterm birth.Nat Med. 2019; 25: 1012-1021
- Prospective observational study of vaginal microbiota pre- and post-rescue cervical cerclage.BJOG. 2019; 126: 916-925
- Vaginal dysbiosis increases risk of preterm fetal membrane rupture, neonatal sepsis and is exacerbated by erythromycin.BMC Med. 2018; 16: 9
- The interaction between vaginal microbiota, cervical length, and vaginal progesterone treatment for preterm birth risk.Microbiome. 2017; 5: 6
- Relationship between vaginal microbial dysbiosis, inflammation, and pregnancy outcomes in cervical cerclage.Sci Transl Med. 2016; 8 (350ra102)
- The vaginal microbiome during pregnancy and the postpartum period in a European population.Sci Rep. 2015; 5: 8988
- Manipulation of epithelial integrity and mucosal immunity by host and microbiota-derived metabolites.Eur J Immunol. 2020; 50: 921-931
- Metabolome–microbiome crosstalk and human disease.Metabolites. 2020; 10: 181
- Inflammatory and microbiota-related regulation of the intestinal epithelial barrier.Front Nutr. 2021; 8: 718356
- Impact of bacterial metabolites on gut barrier function and host immunity: a focus on bacterial metabolism and its relevance for intestinal inflammation.Front Immunol. 2021; 12: 658354
- Inflammation promotes a cytokine response and disrupts the cervical epithelial barrier: a possible mechanism of premature cervical remodeling and preterm birth.Am J Obstet Gynecol. 2012; 206: 208.e1-208.e7
- MIR-143 and miR-145 disrupt the cervical epithelial barrier through dysregulation of cell adhesion, apoptosis and proliferation.Sci Rep. 2017; 7: 3020
- Common cervicovaginal microbial supernatants alter cervical epithelial function: mechanisms by which Lactobacillus crispatus contributes to cervical health.Front Microbiol. 2018; 9: 2181
- 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; 61: 102127
- Women with preterm birth have a distinct cervicovaginal metabolome.Am J Obstet Gynecol. 2015; 212: 776.e1-776.e12
- Women with symptomatic preterm birth have a distinct cervicovaginal metabolome.Am J Perinatol. 2017; 34: 1078-1083
- Cervicovaginal microbiome composition is associated with metabolic profiles in healthy pregnancy.mBio. 2020; 11 (e01851–20)
- Identification of potential biomarkers in the cervicovaginal fluid by metabolic profiling for preterm birth.Metabolites. 2020; 10: 349
- Cervicovaginal microbiota and metabolome predict preterm birth risk in an ethnically diverse cohort.JCI Insight. 2021; 6e149257
- New insights into vaginal environment During pregnancy.Front Mol Biosci. 2021; 8: 656844
- Exploratory and confirmatory analysis to investigate the presence of vaginal metabolome expression of microbial invasion of the amniotic cavity in women with preterm labor using high-performance liquid chromatography.Am J ObstetGynecol. 2021; 224: 90.e1-90.e9
- Direct on-swab metabolic profiling of vaginal microbiome host interactions during pregnancy and preterm birth.Nat Commun. 2021; 12: 5967
- A non-optimal cervicovaginal microbiota in pregnancy is associated with a distinct metabolomic signature among non-Hispanic Black individuals.Sci Rep. 2021; 11: 22794
- Vaginal microbiome of reproductive-age women.Proc Natl Acad Sci U S A. 2011; 108: 4680-4687
- Integrated, nontargeted ultrahigh performance liquid chromatography/electrospray ionization tandem mass spectrometry platform for the identification and relative quantification of the small-molecule complement of biological systems.Anal Chem. 2009; 81: 6656-6667
- High resolution mass spectrometry improves data quantity and quality as compared to unit mass resolution mass spectrometry in high- throughput profiling metabolomics.Metabolomics. 2014; 4
- Precision of a clinical metabolomics profiling platform for use in the identification of inborn errors of metabolism.J Appl Lab Med. 2020; 5: 342-356
- Organization of GC/MS and LC/MS metabolomics data into chemical libraries.J Cheminform. 2010; 2: 9
- MetaboLights: a resource evolving in response to the needs of its scientific community.Nucleic Acids Res. 2020; 48: D440-D444
- Estimation of average concentration in the presence of nondetectable values.Appl Occup Environ Hyg. 1990; 5: 46-51
Team RC. R: a language and environment Fr statistical computing Vienna, Austria. 2021, Philadelphia, PA. Available at: https://www.R-project.org/. Accessed October 1, 2021.
- Sphingolipids and their metabolism in physiology and disease.Nat Rev Mol Cell Biol. 2018; 19: 175-191
- Changes in membrane sphingolipid composition modulate dynamics and adhesion of integrin nanoclusters.Sci Rep. 2016; 6: 20693
- Epidermal sphingolipids: metabolism, function, and roles in skin disorders.FEBS Lett. 2006; 580: 5456-5466
- Lipid depletion enables permeation of Staphylococcus aureus bacteria through human stratum corneum.Tissue Barriers. 2020; 81754706
- Vaginal lipidomics of women with vulvovaginal candidiasis and cytolytic vaginosis: a non-targeted LC-MS pilot study.PLoS One. 2018; 13e0202401
- Metabolic signatures of bacterial vaginosis.mBio. 2015; 6: e00204-e00215
- Anti- inflammatory effect of surfactant lipid in the vaginal mucosa: a pilot study.J Low Genit Tract Dis. 2019; 23: 71-74
- Deciphering the complex interplay between microbiota, HPV, inflammation and cancer through cervicovaginal metabolic profiling.EBiomedicine. 2019; 44: 675-690
- NTP toxicology and carcinogenesis studies of diethanolamine (CAS No. 111-42–2) in F344/N rats and B6C3F1 mice (dermal studies).Natl Toxicol Program Tech Rep Ser. 1999; 478: 1-212
- NTP toxicology and carcinogenesis studies of lauric acid diethanolamine condensate (CAS NO. 120-40–1) in F344/N rats and B6C3F1 mice (dermal studies).Natl Toxicol Program Tech Rep Ser. 1999; 480: 1-200
- Lauramide diethanolamine absorption, metabolism, and disposition in rats and mice after oral, intravenous, and dermal administration.Drug Metab Dispos. 1996; 24: 702-710
- Dose response effects of dermally applied diethanolamine on neurogenesis in fetal mouse hippocampus and potential exposure of humans.Toxicol Sci. 2009; 107: 220-226
- The role of intestinal permeability in gastrointestinal disorders and current methods of evaluation.Front Nutr. 2021; 8: 717925
- Cervical remodeling during pregnancy and parturition.Trends Endocrinol Metab. 2010; 21: 353-361
- Cervical remodeling in term and preterm birth: insights from an animal model.Reproduction. 2012; 143: 429-438
- Immunobiology of cervix ripening.Front Immunol. 2019; 10: 3156
- The interplay between bioactive sphingolipids and steroid hormones.Steroids. 2010; 75: 390-399
Article info
Publication history
Published online: April 22, 2022
Accepted:
April 18,
2022
Received in revised form:
April 10,
2022
Received:
December 10,
2021
Footnotes
M.A.E. receives salary support from the National Institutes of Health (NIH; The National Institute of Nursing Research, National Institute of Allergy and Infectious Disease, and Eunice Kennedy Shriver National Institute of Child Health and Human Development). She is also a consultant for Mirvie. The other authors report no conflict of interest.
Society for Maternal-Fetal Medicine/American Association of Obstetricians and Gynecologists Foundation Award (K.G.); NIH R01NR014784 (M.A.E.). The funding sources had no role in study design; collection, analysis, and interpretation of data; writing of the report; or in the decision to submit the article for publication.
This work was accepted as an oral abstract (#9) in the 42nd annual meeting of the Society for Maternal-Fetal Medicine, Orlando, FL, January 31–February 5, 2022.
Cite this article as: Gerson KD, Yang N, Anton L, et al. Second trimester short cervix is associated with decreased abundance of cervicovaginal lipid metabolites. Am J Obstet Gynecol 2022;227:273.e1-18.
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