Integration of Cervical Length, Inflammatory Marker, and Vaginal Biomarkers (PAMG-1 and fFN) in the Diagnosis of Threatened Preterm Labor
,
Abstract
The aim of this research was to evaluate the diagnostic efficacy of integrating cervical length (CL), interleukin-6 (IL-6), placental alpha microglobulin-1 (PAMG-1), and fetal fibronectin (fFN) in predicting preterm birth among pregnant women with threatened preterm labor (TPL).
This study retrospectively analyzed clinical data from 150 pregnant women admitted for TPL between January 2021 and December 2024. Participants were divided into two groups based on pregnancy outcome: full-term delivery (n=85) and preterm birth (n=65). Additionally, 100 healthy pregnant women with no history of adverse pregnancy outcomes who underwent routine prenatal examinations during the same period were selected as the healthy control group. All participants underwent transvaginal ultrasound to measure CL, and venous blood samples were collected to assess serum IL-6 levels. PAMG-1 and fFN levels were measured in vaginal secretions.
There were no significant differences in baseline characteristics among the three groups. However, significant differences in CL, serum IL-6 levels, and positive rates of PAMG-1 and fFN were detected. Pearson correlation analysis showed significant associations between CL, IL-6, PAMG-1, fFN, and preterm birth. ROC curve analysis indicated that the AUC values for CL, IL-6, PAMG-1, and fFN alone were 0.798, 0.803, 0.753, and 0.754, respectively.
The combined application of these markers yielded an AUC of 0.920, significantly higher than any single marker. The combined use of CL, IL-6, PAMG-1, and fFN significantly enhances the diagnostic accuracy of preterm birth in patients with TPL.
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2. Ohuma EO, Moller AB, Bradley E, Chakwera S, Hussain-Alkhateeb L, Lewin A, et al. National, regional, and global estimates of preterm birth in 2020, with trends from 2010: a systematic analysis. Lancet. 2023;402(10409):1261-71.
3. Crump C, Sundquist J, Sundquist K. Preterm or early term birth and risk of autism. Pediatrics. 2021;148(3):e2021051487.
4. Sharma D, Padmavathi IV, Tabatabaii SA, Farahbakhsh N. Late preterm: a new high risk group in neonatology. J Matern Fetal Neonatal Med. 2021;34(16):2717-30.
5. Ophelders D, Gussenhoven R, Klein L, Jellema RK, Westerlaken RJJ, Hütten MC, et al. Preterm brain injury, antenatal triggers, and therapeutics: timing is key. Cells. 2020;9(8):1871.
6. Luechathananon S, Songthamwat M, Chaiyarach S. Uterocervical angle and cervical length as a tool to predict preterm birth in threatened preterm labor. Int J Womens Health. 2021;13:153-9.
7. Melchor Corcóstegui I, Unibaso Rodríguez E, Ruiz Blanco N, Nikolova T, Nikolova N, Burgos San Cristóbal J, et al. Is mid-trimester cervical length screening effective for reduction of threatened preterm labor? Taiwan J Obstet Gynecol. 2023;62(3):412-6.
8. Hassan SS, Romero R, Berry SM, Dang K, Blackwell SC, Treadwell MC, et al. Patients with an ultrasonographic cervical length ≤15 mm have nearly a 50% risk of early spontaneous preterm delivery. Am J Obstet Gynecol. 2000;182(6):1458-67.
9. Rennert KN, Breuking SH, Schuit E, Bekker MN, Woiski M, de Boer MA, et al. Change in cervical length after arrested preterm labor and risk of preterm birth. Ultrasound Obstet Gynecol. 2021;58(5):750-6.
10. Navathe R, Saccone G, Villani M, Knapp J, Cruz Y, Boelig R, et al. Decrease in the incidence of threatened preterm labor after implementation of transvaginal ultrasound cervical length universal screening. J Matern Fetal Neonatal Med. 2019;32(11):1853-8.
11. Berghella V, Saccone G. Cervical assessment by ultrasound for preventing preterm delivery. Cochrane Database Syst Rev. 2019;9:CD007235.
12. Chen J, Gong G, Zheng W, Xu J, Luo X, Zhang Y. Diagnostic accuracy of quantitative fetal fibronectin to predict spontaneous preterm birth: a meta-analysis. Int J Gynaecol Obstet. 2021;153(2):220-7.
13. Ruma MS, Betts M, Dodman S, Neupane B. Predictive value of quantitative fetal fibronectin for spontaneous preterm birth in asymptomatic pregnancies: a systematic literature review and meta-analysis. J Matern Fetal Neonatal Med. 2023;36(2):2279923.
14. Ng VWY, Seto MTY, Lewis H, Cheung KW. A prospective, double-blinded cohort study using quantitative fetal fibronectin testing in symptomatic women for the prediction of spontaneous preterm delivery. BMC Pregnancy Childbirth. 2023;23(1):225.
15. Dochez V, Ducarme G, Gueudry P, Joueidi Y, Boivin M, Boussamet L, et al. Methods of detection and prevention of preterm labour and the PAMG-1 detection test: a review. J Perinat Med. 2021;49(2):119-26.
16. Melchor JC, Khalil A, Wing D, Schleussner E, Surbek D. Prediction of preterm delivery in symptomatic women using PAMG-1, fetal fibronectin and phIGFBP-1 tests: systematic review and meta-analysis. Ultrasound Obstet Gynecol. 2018;52(4):442-51.
17. Prairie E, Côté F, Tsakpinoglou M, Mina M, Quiniou C, Leimert K, et al. The determinant role of IL-6 in the establishment of inflammation leading to spontaneous preterm birth. Cytokine Growth Factor Rev. 2021;59:118-30.
18. Farias-Jofre M, Romero R, Galaz J, Xu Y, Miller D, Garcia-Flores V, et al. Blockade of IL-6R prevents preterm birth and adverse neonatal outcomes. EBioMedicine. 2023;98:104865.
19. Chang Y, Li W, Shen Y, Li S, Chen X. Association between interleukin-6 and preterm birth: a meta-analysis. Ann Med. 2023;55(2):2284384.
20. Kirici P, Cagiran FT, Kali Z. Impact of spontaneous preterm birth on amniotic fluid NF-κB, IL-6, TNF-α and IL-1β levels in singleton pregnancies conceived after IVF/ICSI treatment or natural conception. Eur Rev Med Pharmacol Sci. 2022;26(22):8395-400.
21. Zuo L, Xu Y, Du S, Li X, Zhao T, Zhang Y, et al. Diagnostic value of serum amyloid A, interleukin-6 in gravidas with spontaneous preterm birth. Clin Chim Acta. 2022;534:77-80.
22. Miller FA, Sacco A, David AL, Boyle AK. Interventions for infection and inflammation-induced preterm birth: a preclinical systematic review. Reprod Sci. 2023;30(2):361-79.
23. Prediction and prevention of spontaneous preterm birth: ACOG Practice Bulletin, Number 234. Obstet Gynecol. 2021;138(2):e65-e90.
24. Walter IJ, Klein Haneveld MJ, Lely AT, Bloemenkamp KWM, Limper M, Kooiman J. Pregnancy outcome predictors in antiphospholipid syndrome: a systematic review and meta-analysis. Autoimmun Rev. 2021;20(10):102901.
25. Akar B, Ceylan Y, Kahraman A, Köle E, Çalışkan E. Centile charts of cervical length in singleton and twin pregnancies between 16 and 24 weeks of gestation. J Turk Ger Gynecol Assoc. 2023;24(2):114-9.
26. Guerby P, Fillion A, Pasquier JC, Bujold E. Evaluation of midtrimester cervical length thresholds for the prediction of spontaneous preterm birth. J Gynecol Obstet Hum Reprod. 2022;51(2):102287.
27. Pinton A, Severac F, Meyer N, Akladios CY, Gaudineau A, Favre R, et al. A comparison of vaginal ultrasound and digital examination in predicting preterm delivery in women with threatened preterm labor: a cohort study. Acta Obstet Gynecol Scand. 2017;96(4):447-53.
28. Zlatnik FJ, Yankowitz J, Whitham J, Burmeister LF. Vaginal ultrasound as an adjunct to cervical digital examination in women at risk of early delivery. Gynecol Obstet Invest. 2001;51(1):12-6.
29. Boelig RC, Feltovich H, Spitz JL, Toland G, Berghella V, Iams JD. Assessment of transvaginal ultrasound cervical length image quality. Obstet Gynecol. 2017;129(3):536-41.
30. Dude A, Miller ES. Change in cervical length across pregnancies and preterm delivery. Am J Perinatol. 2020;37(6):598-602.
31. McGee D, Smith A, Poncil S, Patterson A, Bernstein AI, Racicot K. Cervical HSV-2 infection causes cervical remodeling and increases risk for ascending infection and preterm birth. PLoS One. 2017;12(11):e0188645.
32. Bergh EP, Mann LK, Jain RR, Donepudi R, Moise KJ Jr, Johnson A, et al. Effect of intra-amniotic fluid pressure from polyhydramnios on cervical length in patients with twin-twin transfusion syndrome undergoing fetoscopic laser surgery. Ultrasound Obstet Gynecol. 2019;54(6):774-9.
33. Yaniv-Nachmani H, Melcer Y, Weiner I, Bar K, Kovo M, Hershko C, et al. A comparison of Arabin cervical pessary and vaginal progesterone versus vaginal progesterone only in twin pregnancy for the prevention of preterm birth due to short cervix. Harefuah. 2021;160(1):13-8.
34. Pandey M, Awasthi S, Baranwal S. IL-6: an endogenous activator of MMP-9 in preterm birth. J Reprod Immunol. 2020;141:103147.
35. Shaffer Z, Romero R, Tarca AL, Galaz J, Arenas-Hernandez M, Gudicha DW, et al. The vaginal immunoproteome for the prediction of spontaneous preterm birth: a retrospective longitudinal study. eLife. 2024;13:e84623.
36. Li W, Zhao X, Li S, Chen X, Cui H, Chang Y, et al. Upregulation of TNF-α and IL-6 induces preterm premature rupture of membranes by activation of ADAMTS-9 in embryonic membrane cells. Life Sci. 2020;260:118237.
37. Adedeji MO, Olumodeji AM, Fabamwo AO, Oyedele OY. Quantitative cervicovaginal fetal fibronectin as a predictor of cervical ripening and induced labour duration in late-term pregnancy. J Obstet Gynaecol. 2023;43(1):2204975.
38. Watson HA, Shennan AH. The true clinical utility of quantitative fetal fibronectin. J Matern Fetal Neonatal Med. 2020;33(13):2309-14.
39. Warintaksa P, Romero R, Lertrat W, Yuenyongdechawat N, Mongkolsuk P, Chaiyakarn S, et al. Quantitative cervicovaginal fluid fetal fibronectin: a liquid biopsy for intra-amniotic inflammation. Acta Obstet Gynecol Scand. 2024;103(11):2252-63.
40. Marie E, Ducarme G, Boivin M, Badon V, Pelerin H, Le Thuaut A, et al. The value of a vaginal sample for detecting PAMG-1 (Partosure) in women with a threatened preterm delivery (the MAPOSURE Study): protocol for a multicenter prospective study. BMC Pregnancy Childbirth. 2020;20(1):442.
41. Cnota W, Jagielska A, Janowska E, Banas E, Kierach R, Nycz-Reska M, et al. Prediction of preterm birth using PAMG-1 test: a single centre experience - preliminary report. Ginekol Pol. 2022;93(7):574-577.
42. Pirjani R, Moini A, Almasi-Hashiani A, Farid Mojtahedi M, Vesali S, Hosseini L, et al. Placental alpha microglobulin-1 (PartoSure) test for the prediction of preterm birth: a systematic review and meta-analysis. J Matern Fetal Neonatal Med. 2021;34(20):3445-3457.
43. Esin S, Tohma YA, Alay I, Guden M, Colak E, Demirel N, et al. Comparison of placental α microglobulin-1 protein assay (Amnisure) with speculum examination for the diagnosis of premature preterm rupture of membranes: a clinical evaluation. J Obstet Gynaecol. 2021;41(5):703-7.
44. Son M, Miller ES. Predicting preterm birth: cervical length and fetal fibronectin. Semin Perinatol. 2017;41(8):445-51.
45. Banicevic AC, Ceric A, Popovic M, Micic RZ. Correlation of qualitative alpha1-microglobulin, values of interleukin 6, cervicometry and cervical infection in pregnant women with symptoms of preterm birth. Mater Sociomed. 2023;35(2):118-22.
2. Ohuma EO, Moller AB, Bradley E, Chakwera S, Hussain-Alkhateeb L, Lewin A, et al. National, regional, and global estimates of preterm birth in 2020, with trends from 2010: a systematic analysis. Lancet. 2023;402(10409):1261-71.
3. Crump C, Sundquist J, Sundquist K. Preterm or early term birth and risk of autism. Pediatrics. 2021;148(3):e2021051487.
4. Sharma D, Padmavathi IV, Tabatabaii SA, Farahbakhsh N. Late preterm: a new high risk group in neonatology. J Matern Fetal Neonatal Med. 2021;34(16):2717-30.
5. Ophelders D, Gussenhoven R, Klein L, Jellema RK, Westerlaken RJJ, Hütten MC, et al. Preterm brain injury, antenatal triggers, and therapeutics: timing is key. Cells. 2020;9(8):1871.
6. Luechathananon S, Songthamwat M, Chaiyarach S. Uterocervical angle and cervical length as a tool to predict preterm birth in threatened preterm labor. Int J Womens Health. 2021;13:153-9.
7. Melchor Corcóstegui I, Unibaso Rodríguez E, Ruiz Blanco N, Nikolova T, Nikolova N, Burgos San Cristóbal J, et al. Is mid-trimester cervical length screening effective for reduction of threatened preterm labor? Taiwan J Obstet Gynecol. 2023;62(3):412-6.
8. Hassan SS, Romero R, Berry SM, Dang K, Blackwell SC, Treadwell MC, et al. Patients with an ultrasonographic cervical length ≤15 mm have nearly a 50% risk of early spontaneous preterm delivery. Am J Obstet Gynecol. 2000;182(6):1458-67.
9. Rennert KN, Breuking SH, Schuit E, Bekker MN, Woiski M, de Boer MA, et al. Change in cervical length after arrested preterm labor and risk of preterm birth. Ultrasound Obstet Gynecol. 2021;58(5):750-6.
10. Navathe R, Saccone G, Villani M, Knapp J, Cruz Y, Boelig R, et al. Decrease in the incidence of threatened preterm labor after implementation of transvaginal ultrasound cervical length universal screening. J Matern Fetal Neonatal Med. 2019;32(11):1853-8.
11. Berghella V, Saccone G. Cervical assessment by ultrasound for preventing preterm delivery. Cochrane Database Syst Rev. 2019;9:CD007235.
12. Chen J, Gong G, Zheng W, Xu J, Luo X, Zhang Y. Diagnostic accuracy of quantitative fetal fibronectin to predict spontaneous preterm birth: a meta-analysis. Int J Gynaecol Obstet. 2021;153(2):220-7.
13. Ruma MS, Betts M, Dodman S, Neupane B. Predictive value of quantitative fetal fibronectin for spontaneous preterm birth in asymptomatic pregnancies: a systematic literature review and meta-analysis. J Matern Fetal Neonatal Med. 2023;36(2):2279923.
14. Ng VWY, Seto MTY, Lewis H, Cheung KW. A prospective, double-blinded cohort study using quantitative fetal fibronectin testing in symptomatic women for the prediction of spontaneous preterm delivery. BMC Pregnancy Childbirth. 2023;23(1):225.
15. Dochez V, Ducarme G, Gueudry P, Joueidi Y, Boivin M, Boussamet L, et al. Methods of detection and prevention of preterm labour and the PAMG-1 detection test: a review. J Perinat Med. 2021;49(2):119-26.
16. Melchor JC, Khalil A, Wing D, Schleussner E, Surbek D. Prediction of preterm delivery in symptomatic women using PAMG-1, fetal fibronectin and phIGFBP-1 tests: systematic review and meta-analysis. Ultrasound Obstet Gynecol. 2018;52(4):442-51.
17. Prairie E, Côté F, Tsakpinoglou M, Mina M, Quiniou C, Leimert K, et al. The determinant role of IL-6 in the establishment of inflammation leading to spontaneous preterm birth. Cytokine Growth Factor Rev. 2021;59:118-30.
18. Farias-Jofre M, Romero R, Galaz J, Xu Y, Miller D, Garcia-Flores V, et al. Blockade of IL-6R prevents preterm birth and adverse neonatal outcomes. EBioMedicine. 2023;98:104865.
19. Chang Y, Li W, Shen Y, Li S, Chen X. Association between interleukin-6 and preterm birth: a meta-analysis. Ann Med. 2023;55(2):2284384.
20. Kirici P, Cagiran FT, Kali Z. Impact of spontaneous preterm birth on amniotic fluid NF-κB, IL-6, TNF-α and IL-1β levels in singleton pregnancies conceived after IVF/ICSI treatment or natural conception. Eur Rev Med Pharmacol Sci. 2022;26(22):8395-400.
21. Zuo L, Xu Y, Du S, Li X, Zhao T, Zhang Y, et al. Diagnostic value of serum amyloid A, interleukin-6 in gravidas with spontaneous preterm birth. Clin Chim Acta. 2022;534:77-80.
22. Miller FA, Sacco A, David AL, Boyle AK. Interventions for infection and inflammation-induced preterm birth: a preclinical systematic review. Reprod Sci. 2023;30(2):361-79.
23. Prediction and prevention of spontaneous preterm birth: ACOG Practice Bulletin, Number 234. Obstet Gynecol. 2021;138(2):e65-e90.
24. Walter IJ, Klein Haneveld MJ, Lely AT, Bloemenkamp KWM, Limper M, Kooiman J. Pregnancy outcome predictors in antiphospholipid syndrome: a systematic review and meta-analysis. Autoimmun Rev. 2021;20(10):102901.
25. Akar B, Ceylan Y, Kahraman A, Köle E, Çalışkan E. Centile charts of cervical length in singleton and twin pregnancies between 16 and 24 weeks of gestation. J Turk Ger Gynecol Assoc. 2023;24(2):114-9.
26. Guerby P, Fillion A, Pasquier JC, Bujold E. Evaluation of midtrimester cervical length thresholds for the prediction of spontaneous preterm birth. J Gynecol Obstet Hum Reprod. 2022;51(2):102287.
27. Pinton A, Severac F, Meyer N, Akladios CY, Gaudineau A, Favre R, et al. A comparison of vaginal ultrasound and digital examination in predicting preterm delivery in women with threatened preterm labor: a cohort study. Acta Obstet Gynecol Scand. 2017;96(4):447-53.
28. Zlatnik FJ, Yankowitz J, Whitham J, Burmeister LF. Vaginal ultrasound as an adjunct to cervical digital examination in women at risk of early delivery. Gynecol Obstet Invest. 2001;51(1):12-6.
29. Boelig RC, Feltovich H, Spitz JL, Toland G, Berghella V, Iams JD. Assessment of transvaginal ultrasound cervical length image quality. Obstet Gynecol. 2017;129(3):536-41.
30. Dude A, Miller ES. Change in cervical length across pregnancies and preterm delivery. Am J Perinatol. 2020;37(6):598-602.
31. McGee D, Smith A, Poncil S, Patterson A, Bernstein AI, Racicot K. Cervical HSV-2 infection causes cervical remodeling and increases risk for ascending infection and preterm birth. PLoS One. 2017;12(11):e0188645.
32. Bergh EP, Mann LK, Jain RR, Donepudi R, Moise KJ Jr, Johnson A, et al. Effect of intra-amniotic fluid pressure from polyhydramnios on cervical length in patients with twin-twin transfusion syndrome undergoing fetoscopic laser surgery. Ultrasound Obstet Gynecol. 2019;54(6):774-9.
33. Yaniv-Nachmani H, Melcer Y, Weiner I, Bar K, Kovo M, Hershko C, et al. A comparison of Arabin cervical pessary and vaginal progesterone versus vaginal progesterone only in twin pregnancy for the prevention of preterm birth due to short cervix. Harefuah. 2021;160(1):13-8.
34. Pandey M, Awasthi S, Baranwal S. IL-6: an endogenous activator of MMP-9 in preterm birth. J Reprod Immunol. 2020;141:103147.
35. Shaffer Z, Romero R, Tarca AL, Galaz J, Arenas-Hernandez M, Gudicha DW, et al. The vaginal immunoproteome for the prediction of spontaneous preterm birth: a retrospective longitudinal study. eLife. 2024;13:e84623.
36. Li W, Zhao X, Li S, Chen X, Cui H, Chang Y, et al. Upregulation of TNF-α and IL-6 induces preterm premature rupture of membranes by activation of ADAMTS-9 in embryonic membrane cells. Life Sci. 2020;260:118237.
37. Adedeji MO, Olumodeji AM, Fabamwo AO, Oyedele OY. Quantitative cervicovaginal fetal fibronectin as a predictor of cervical ripening and induced labour duration in late-term pregnancy. J Obstet Gynaecol. 2023;43(1):2204975.
38. Watson HA, Shennan AH. The true clinical utility of quantitative fetal fibronectin. J Matern Fetal Neonatal Med. 2020;33(13):2309-14.
39. Warintaksa P, Romero R, Lertrat W, Yuenyongdechawat N, Mongkolsuk P, Chaiyakarn S, et al. Quantitative cervicovaginal fluid fetal fibronectin: a liquid biopsy for intra-amniotic inflammation. Acta Obstet Gynecol Scand. 2024;103(11):2252-63.
40. Marie E, Ducarme G, Boivin M, Badon V, Pelerin H, Le Thuaut A, et al. The value of a vaginal sample for detecting PAMG-1 (Partosure) in women with a threatened preterm delivery (the MAPOSURE Study): protocol for a multicenter prospective study. BMC Pregnancy Childbirth. 2020;20(1):442.
41. Cnota W, Jagielska A, Janowska E, Banas E, Kierach R, Nycz-Reska M, et al. Prediction of preterm birth using PAMG-1 test: a single centre experience - preliminary report. Ginekol Pol. 2022;93(7):574-577.
42. Pirjani R, Moini A, Almasi-Hashiani A, Farid Mojtahedi M, Vesali S, Hosseini L, et al. Placental alpha microglobulin-1 (PartoSure) test for the prediction of preterm birth: a systematic review and meta-analysis. J Matern Fetal Neonatal Med. 2021;34(20):3445-3457.
43. Esin S, Tohma YA, Alay I, Guden M, Colak E, Demirel N, et al. Comparison of placental α microglobulin-1 protein assay (Amnisure) with speculum examination for the diagnosis of premature preterm rupture of membranes: a clinical evaluation. J Obstet Gynaecol. 2021;41(5):703-7.
44. Son M, Miller ES. Predicting preterm birth: cervical length and fetal fibronectin. Semin Perinatol. 2017;41(8):445-51.
45. Banicevic AC, Ceric A, Popovic M, Micic RZ. Correlation of qualitative alpha1-microglobulin, values of interleukin 6, cervicometry and cervical infection in pregnant women with symptoms of preterm birth. Mater Sociomed. 2023;35(2):118-22.
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| Biomarkers Cervical length measurement Human FFN protein Interleukin-6 Placental hormones Premature obstetric | ||
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How to Cite
1.
Lu J, Lu J, Zhang X, Mu L, Luo W. Integration of Cervical Length, Inflammatory Marker, and Vaginal Biomarkers (PAMG-1 and fFN) in the Diagnosis of Threatened Preterm Labor. Iran J Allergy Asthma Immunol. 2025;:1-12.
