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CX3CL1/Fractalkine as a biomarker for early pregnancy prediction of preterm premature rupture of membranes

  • Samy Kahouadji ORCID logo , Yves Giguère , Salomé Lambert , Jean-Claude Forest , Nathalie Bernard , Loïc Blanchon , Geoffroy Marceau , Julie Durif , Bruno Pereira , Denis Gallot , Vincent Sapin and Damien Bouvier EMAIL logo
Published/Copyright: January 26, 2024
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Clinical Chemistry and Laboratory Medicine (CCLM)
From the journal Clinical Chemistry and Laboratory Medicine (CCLM) Volume 62 Issue 6

Abstract

Objectives

The objective of our study was to evaluate serum CX3CL1/Fractalkine, a monocyte/macrophage chemoattractant expressed in cytotrophoblasts and decidual cells, as a predictive biomarker for the occurrence of preterm premature rupture of membranes (PPROM).

Methods

A case-control study of 438 pregnancies including 82 PPROM cases and 64 preterm labor with intact membranes cases with blood samples collected at first trimester, second trimester and delivery was conducted. The predictive ability of CX3CL1 and maternal risk factors for the occurrence of PPROM was assessed by receiver operating characteristic curve analysis. A second, independent cohort was prospectively constituted to confirm the case-control study results.

Results

First trimester CX3CL1 was significantly increased in PPROM cases when compared to matched controls. Multivariate regression analysis highlighted a significant difference for CX3CL1 measured during the first trimester (p<0.001). Alone, CX3CL1 predicts PPROM with a 90 % sensitivity and a specificity around 40 %. The area under the receiver operating characteristic curve for PPROM prediction were 0.64 (95% confidence interval: 0.57–0.71) for first trimester CX3CL1, and 0.61 (95% confidence interval: 0.54–0.68) for maternal risk factors (body mass index<18.5 kg/m2, nulliparity, tobacco use and the absence of high school diploma). The combination of CX3CL1 and maternal risk factors significantly improved the area under the curve: 0.72 (95% confidence interval: 0.66–0.79) (p<0.001). The results were confirmed on a second independent cohort.

Conclusions

CX3CL1 is a promising blood biomarker in the early (first trimester) prediction of PPROM.

Keywords: CX3CL1; fractalkine; prediction; inflammation; PPROM; pregnancy
Corresponding author: Pr. Damien Bouvier, Service de Biochimie et Génétique Moléculaire, Centre de Biologie, CHU Gabriel Montpied, 58 Rue Montalembert, 63000 Clermont-Ferrand, France; Biochemistry and Molecular Genetic Department, CHU Clermont-Ferrand, Clermont-Ferrand, France; and Faculty of Medicine, CNRS 6293, INSERM 1103, GReD, Université Clermont Auvergne, Clermont-Ferrand, France, Phone: +33473754882, Fax: +33473751855, E-mail:

Funding source: Institute of Human Development, Child and Youth Health

Award Identifier / Grant number: NRFHPG-78880

Funding source: Région Auvergne-Rhône-Alpes

Award Identifier / Grant number: SCUSI2017

  1. Research ethics: This research complied with the tenets of the Helsinki Declaration. The first study was approved by the CHU de Québec Ethics Review Board (initial approval date: 9 November 2004, Project 5-04-10-01 [95.05.17l SC12-01-159]). The confirmation study was approved by local Ethics Committee (IRB00013412, “CHU de Clermont Ferrand IRB #1”, IRB number 2022-CF72) with compliance to the French policy of individual data protection.

  2. Informed consent: For the case-control study, all participants provided written informed consent. For the confirmation study, patients were informed of their right to express their disagreement regarding the use of their clinical information and serum for research purposes.

  3. Author contributions: Samy Kahouadji: investigation, writing – original draft, data curation. Yves Giguère: conceptualization, writing – review & editing, supervision, validation. Salomé Lambert: investigation, data curation. Jean-claude Forest: conceptualization, writing – review & editing, supervision, validation. Nathalie Bernard: resources, supervision, data curation. Loïc Blanchon: conceptualization, writing – review & editing. Geoffroy Marceau: resources, supervision. Julie Durif: investigation, resources, data curation. Bruno Pereira: methodology, formal analysis. Denis Gallot: writing – review & editing, supervision, validation. Vincent Sapin: conceptualization, writing – review & editing, validation. Damien Bouvier: conceptualization, writing – review & editing, supervision, funding acquisition, validation. The authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  4. Competing interests: The authors state no conflict of interest.

  5. Research funding: This work was supported by the Canadian Institutes of Health Research (CIHR, Healthy Pregnancy Initiative from the Institute for Human Development, Child and Youth Health, Grant No: NRFHPG-78880). This work was also funded by the Auvergne Rhône-Alpes region as part of the support program for international academic and scientific cooperation between the two French and Canadian teams (SCUSI 2017).

  6. Data availability: Data are available from the CHU de Québec-Université Laval Ethics Review Board (e-mail: or ) for researchers who meet the criteria for access to confidential data. Data is confidential and cannot be shared publicly.

References

1. Glover, AV, Manuck, TA. Screening for spontaneous preterm birth and resultant therapies to reduce neonatal morbidity and mortality: a review. Semin Fetal Neonatal Med 2018;23:126–32. https://doi.org/10.1016/j.siny.2017.11.007.Search in Google Scholar PubMed PubMed Central

2. Menon, R, Richardson, LS. Preterm prelabor rupture of the membranes: a disease of the fetal membranes. Semin Perinatol 2017;41:409–19. https://doi.org/10.1053/j.semperi.2017.07.012.Search in Google Scholar PubMed PubMed Central

3. American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins—Obstetrics. Prediction and prevention of spontaneous preterm birth: ACOG practice bulletin, number 234. Obstet Gynecol 2021;138:e65–90.10.1097/AOG.0000000000004479Search in Google Scholar PubMed

4. Andrikopoulou, M, Purisch, SE, Handal-Orefice, R, Gyamfi-Bannerman, C. Low-dose aspirin is associated with reduced spontaneous preterm birth in nulliparous women. Am J Obstet Gynecol 2018;219:399.e1–6. https://doi.org/10.1016/j.ajog.2018.06.011.Search in Google Scholar PubMed

5. Duley, L, Meher, S, Hunter, KE, Seidler, AL, Askie, LM. Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev 2019;2019:CD004659. https://doi.org/10.1002/14651858.cd004659.pub3.Search in Google Scholar PubMed PubMed Central

6. Hoffman, MK, Goudar, SS, Kodkany, BS, Metgud, M, Somannavar, M, Okitawutshu, J, et al.. Low-dose aspirin for the prevention of preterm delivery in nulliparous women with a singleton pregnancy (ASPIRIN): a randomised, double-blind, placebo-controlled trial. Lancet 2020;395:285–93. https://doi.org/10.1016/s0140-6736(19)32973-3.Search in Google Scholar

7. Medicine FWG on GCP in MF. Good clinical practice advice: prediction of preterm labor and preterm premature rupture of membranes. Int J Gynecol Obstet 2019;144:340–6. https://doi.org/10.1002/ijgo.12744.Search in Google Scholar PubMed

8. Bouvier, D, Forest, JC, Blanchon, L, Bujold, E, Pereira, B, Bernard, N, et al.. Risk factors and outcomes of preterm premature rupture of membranes in a cohort of 6968 pregnant women prospectively recruited. J Clin Med 2019;8:1987. https://doi.org/10.3390/jcm8111987.Search in Google Scholar PubMed PubMed Central

9. Lorthe, E. Epidemiology, risk factors and child prognosis: CNGOF preterm premature rupture of membranes guidelines. Gynecol Obstet Fertil Senol 2018;46:1004–21. https://doi.org/10.1016/j.gofs.2018.10.019.Search in Google Scholar PubMed

10. Menon, R, Fortunato, SJ. Infection and the role of inflammation in preterm premature rupture of the membranes. Best Pract Res Clin Obstet Gynaecol 2007;21:467–78. https://doi.org/10.1016/j.bpobgyn.2007.01.008.Search in Google Scholar PubMed

11. Dutta, EH, Behnia, F, Boldogh, I, Saade, GR, Taylor, BD, Kacerovský, M, et al.. Oxidative stress damage-associated molecular signaling pathways differentiate spontaneous preterm birth and preterm premature rupture of the membranes. Mol Hum Reprod 2016;22:143–57. https://doi.org/10.1093/molehr/gav074.Search in Google Scholar PubMed

12. Brown, MB, von Chamier, M, Allam, AB, Reyes, L. M1/M2 macrophage polarity in normal and complicated pregnancy. Front Immunol 2014;5:606. https://doi.org/10.3389/fimmu.2014.00606.Search in Google Scholar PubMed PubMed Central

13. Mollica Poeta, V, Massara, M, Capucetti, A, Bonecchi, R. Chemokines and chemokine receptors: new targets for cancer immunotherapy. Front Immunol 2019;10:379. https://doi.org/10.3389/fimmu.2019.00379.Search in Google Scholar PubMed PubMed Central

14. Ullah, A, Zhao, J, Singla, RK, Shen, B. Pathophysiological impact of CXC and CX3CL1 chemokines in preeclampsia and gestational diabetes mellitus. Front Cell Dev Biol 2023;11:1272536. https://doi.org/10.3389/fcell.2023.1272536.Search in Google Scholar PubMed PubMed Central

15. Ullah, A, Zhao, J, Li, J, Singla, RK, Shen, B. Involvement of CXC chemokines (CXCL1–CXCL17) in gastric cancer: prognosis and therapeutic molecules. Life Sci 2024;336:122277. https://doi.org/10.1016/j.lfs.2023.122277.Search in Google Scholar PubMed

16. Santoni, A, Carlino, C, Stabile, H, Gismondi, A. Mechanisms underlying recruitment and accumulation of decidual NK cells in uterus during pregnancy. Am J Reprod Immunol 2008;59:417–24. https://doi.org/10.1111/j.1600-0897.2008.00598.x.Search in Google Scholar PubMed

17. Julia, V, Staumont-Salle, D, Dombrowicz, D. Role of fractalkine/CX3CL1 and its receptor CX3CR1 in allergic diseases. Med Sci 2016;32:260–6. https://doi.org/10.1051/medsci/20163203010.Search in Google Scholar PubMed

18. Huang, SJ, Chen, CP, Buchwalder, L, Yu, YC, Piao, L, Huang, CY, et al.. Regulation of CX3CL1 expression in human first-trimester decidual cells: implications for preeclampsia. Reprod Sci 2019;26:1256–65. https://doi.org/10.1177/1933719118815592.Search in Google Scholar PubMed PubMed Central

19. Mizoguchi, M, Ishida, Y, Nosaka, M, Kimura, A, Kuninaka, Y, Yahata, T, et al.. Prevention of lipopolysaccharide-induced preterm labor by the lack of CX3CL1-CX3CR1 interaction in mice. PLoS One 2018;13:e0207085. https://doi.org/10.1371/journal.pone.0207085.Search in Google Scholar PubMed PubMed Central

20. Nonn, O, Güttler, J, Forstner, D, Maninger, S, Zadora, J, Balogh, A, et al.. Placental CX3CL1 is deregulated by angiotensin II and contributes to a pro-inflammatory trophoblast-monocyte interaction. Int J Mol Sci 2019;20:E641. https://doi.org/10.3390/ijms20030641.Search in Google Scholar PubMed PubMed Central

21. Forest, JC, Thériault, S, Massé, J, Bujold, E, Giguère, Y. Soluble Fms-like tyrosine kinase-1 to placental growth factor ratio in mid-pregnancy as a predictor of preterm preeclampsia in asymptomatic pregnant women. Clin Chem Lab Med 2014;52:1169–78. https://doi.org/10.1515/cclm-2013-0955.Search in Google Scholar PubMed

22. Cohen, DK. Educational technology, policy, and practice. Educ Eval Pol Anal 1987;9:153–70. https://doi.org/10.3102/01623737009002153.Search in Google Scholar

23. Kervancioglu Demirci, E, Salamonsen, LA, Gauster, M. The role of CX3CL1 in fetal-maternal interaction during human gestation. Cell Adhes Migrat 2016;10:189–96. https://doi.org/10.1080/19336918.2015.1089378.Search in Google Scholar PubMed PubMed Central

24. Szukiewicz, D, Kochanowski, J, Pyzlak, M, Szewczyk, G, Stangret, A, Mittal, TK. Fractalkine (CX3CL1) and its receptor CX3CR1 may contribute to increased angiogenesis in diabetic placenta. Mediat Inflamm 2013;2013:437576. https://doi.org/10.1155/2013/437576.Search in Google Scholar PubMed PubMed Central

25. Agbadjé, TT, Menear, M, Gagnon, MP, Légaré, F. Theory-based approach to developing an implementation plan to support the adoption of a patient decision aid for Down syndrome prenatal screening. Implement Sci 2021;16:56. https://doi.org/10.1186/s13012-021-01103-5.Search in Google Scholar PubMed PubMed Central

26. Chiu, CPH, Feng, Q, Chaemsaithong, P, Sahota, DS, Lau, YY, Yeung, YK, et al.. Prediction of spontaneous preterm birth and preterm prelabor rupture of membranes using maternal factors, obstetric history and biomarkers of placental function at 11–13 weeks. Ultrasound Obstet Gynecol 2022;60:192–9. https://doi.org/10.1002/uog.24917.Search in Google Scholar PubMed

27. Menon, R, Fortunato, SJ. The role of matrix degrading enzymes and apoptosis in rupture of membranes. J Soc Gynecol Invest 2004;11:427–37. https://doi.org/10.1016/j.jsgi.2004.04.001.Search in Google Scholar PubMed

28. Menon, R, Boldogh, I, Hawkins, HK, Woodson, M, Polettini, J, Syed, TA, et al.. Histological evidence of oxidative stress and premature senescence in preterm premature rupture of the human fetal membranes recapitulated in vitro. Am J Pathol 2014;184:1740–51. https://doi.org/10.1016/j.ajpath.2014.02.011.Search in Google Scholar PubMed

29. Lannon, SMR, Vanderhoeven, JP, Eschenbach, DA, Gravett, MG, Adams Waldorf, KM. Synergy and interactions among biological pathways leading to preterm premature rupture of membranes. Reprod Sci 2014;21:1215–27. https://doi.org/10.1177/1933719114534535.Search in Google Scholar PubMed PubMed Central

30. Jones, BA, Riegsecker, S, Rahman, A, Beamer, M, Aboualaiwi, W, Khuder, SA, et al.. Role of ADAM-17, p38 MAPK, cathepsins, and the proteasome pathway in the synthesis and shedding of fractalkine/CX3 CL1 in rheumatoid arthritis. Arthritis Rheum 2013;65:2814–25. https://doi.org/10.1002/art.38095.Search in Google Scholar PubMed

Supplementary Material

This article contains supplementary material (https://doi.org/10.1515/cclm-2023-1202).

Received: 2023-10-25
Accepted: 2024-01-13
Published Online: 2024-01-26
Published in Print: 2024-05-27

© 2024 Walter de Gruyter GmbH, Berlin/Boston

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https://doi.org/10.1515/cclm-2023-1202
Keywords for this article
CX3CL1; fractalkine; prediction; inflammation; PPROM; pregnancy

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. SARS-CoV-2 is here to stay: do not lower our guard
  4. Reviews
  5. SARS-CoV-2 subgenomic RNA: formation process and rapid molecular diagnostic methods
  6. Prognostic value of anti-SARS-CoV-2 antibodies: a systematic review
  7. Presence of SARS-CoV-2 RNA in COVID-19 survivors with post-COVID symptoms: a systematic review of the literature
  8. Opinion Papers
  9. Harmonizing the post-analytical phase: focus on the laboratory report
  10. Blood-based biomarkers in Alzheimer’s disease – moving towards a new era of diagnostics
  11. A comprehensive review on PFAS including survey results from the EFLM Member Societies
  12. General Clinical Chemistry and Laboratory Medicine
  13. Report from the HarmoSter study: different LC-MS/MS androstenedione, DHEAS and testosterone methods compare well; however, unifying calibration is a double-edged sword
  14. An LC–MS/MS method for serum cystatin C quantification and its comparison with two commercial immunoassays
  15. CX3CL1/Fractalkine as a biomarker for early pregnancy prediction of preterm premature rupture of membranes
  16. Elevated S100B urine levels predict seizures in infants complicated by perinatal asphyxia and undergoing therapeutic hypothermia
  17. The correlation of urea and creatinine concentrations in sweat and saliva with plasma during hemodialysis: an observational cohort study
  18. Tubular phosphate transport: a comparison between different methods of urine sample collection in FGF23-dependent hypophosphatemic syndromes
  19. Reference Values and Biological Variations
  20. Monocyte distribution width (MDW): study of reference values in blood donors
  21. Data mining of reference intervals for serum creatinine: an improvement in glomerular filtration rate estimating equations based on Q-values
  22. Hematology and Coagulation
  23. MALDI-MS in first-line screening of newborns for sickle cell disease: results from a prospective study in comparison to HPLC
  24. Cardiovascular Diseases
  25. To rule-in, or not to falsely rule-out, that is the question: evaluation of hs-cTnT EQA performance in light of the ESC-2020 guideline
  26. Temporal biomarker concentration patterns during the early course of acute coronary syndrome
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  28. Proteomic analysis of diabetic retinopathy identifies potential plasma-protein biomarkers for diagnosis and prognosis
  29. Infectious Diseases
  30. Serum biomarkers of inflammation and vascular damage upon SARS-Cov-2 mRNA vaccine in patients with thymic epithelial tumors
  31. A high throughput immuno-affinity mass spectrometry method for detection and quantitation of SARS-CoV-2 nucleoprotein in human saliva and its comparison with RT-PCR, RT-LAMP, and lateral flow rapid antigen test
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