Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Mid-trimester amniotic fluid pro-inflammatory biomarkers predict the risk of spontaneous preterm delivery in twins: a retrospective cohort study

Abstract

Objective:

To evaluate the association between the concentrations of immune-related proteins in mid-trimester amniotic fluid (AF) and the subsequent risk of spontaneous preterm delivery in twins.

Study Design:

The study population consisted of consecutive women with a twin pregnancy who underwent clinically indicated genetic amniocentesis at 15 to 20 weeks, and had a subsequent spontaneous delivery in the early preterm period (<32 weeks (cases)) or at term (37 to 42 weeks (controls)). AF was analyzed for cytokines (interleukin (IL)-1ß, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13 and IL-15, interferon-γ, tumor necrosis factor-α), matrix metalloproteinases (MMP-1, MMP-2, MMP-3, MMP-8, MMP-9 and MMP-12), and chemokines (complement factor-D/Adipsin, Serpin E1/PAI-1, Adiponectin/Acrp30, C-Reactive Protein, CCL2/MCP-1, Leptin, Resistin) using multiplex immunoassay kits. The association between AF protein levels and subsequent early preterm birth were examined.

Result:

A total of 96 sets of twins were enrolled, including 17 early preterm birth cases and 79 term controls. AF concentrations of IL-6, IL-8, MMP-3, MMP-8 and MMP-9, and CCL2/MCP-1 were significantly higher in cases than controls. Among these analytes, the combination of AF IL-8 and MMP-9 values had the highest predictive value for early preterm birth. The risk was 8% (10/132) for IL-8<1200 pg ml−1 and MMP-9<1000 pg ml−1, 30% (15/50) for IL-8>1200 pg ml−1 or MMP-9>1000 pg ml−1, and 90% (9/10) for IL-8>1200 pg ml−1 and MMP-9>1000 pg ml−1 (P<0.001).

Conclusion:

High concentrations of IL-8 and MMP-9 in mid-trimester AF in twins predicted well the risk of early preterm birth.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Menacker F, Kirmeyer S et al. Births: final data for 2005. Natl Vital Stat Rep 2007; 56: 1–103.

    PubMed  Google Scholar 

  2. Mathews TJ, MacDorman MF . Infant mortality statistics from the 2005 period linked birth/infant death data set. Natl Vital Stat Rep 2008; 57: 1–32.

    CAS  PubMed  Google Scholar 

  3. Yoon BH, Romero R, Park JS, Kim CJ, Kim SH, Choi JH et al. Fetal exposure to an intra-amniotic inflammation and the development of cerebral palsy at the age of three years. Am J Obstet Gynecol 2000; 182: 675–681.

    Article  CAS  PubMed  Google Scholar 

  4. Rovira N, Alarcon A, Iriondo M, Ibanez M, Poo P, Cusi V et al. Impact of histological chorioamnionitis, funisitis and clinical chorioamnionitis on neurodevelopmental outcome of preterm infants. Early Hum Dev 2011; 87: 253–257.

    Article  PubMed  Google Scholar 

  5. Zanardo V, Vedovato S, Suppiej A, Trevisanuto D, Migliore M, Di Venosa B et al. Histological inflammatory responses in the placenta and early neonatal brain injury. Pediatr Dev Pathol 2008; 11: 350–354.

    Article  PubMed  Google Scholar 

  6. Polam S, Koons A, Anwar M, Shen-Schwarz S, Hegyi T . Effect of chorioamnionitis on neurodevelopmental outcome in preterm infants. Arch Pediatr Adolesc Med 2005; 159: 1032–1035.

    Article  PubMed  Google Scholar 

  7. Shim SS, Romero R, Hong JS, Park CW, Jun JK, Kim BI et al. Clinical significance of intra-amniotic inflammation in patients with preterm premature rupture of membranes. Am J Obstet Gynecol 2004; 191: 1339–1345.

    Article  PubMed  Google Scholar 

  8. Spinillo A, Capuzzo E, Stronati M, Ometto A, Orcesi S, Fazzi E . Effect of preterm premature rupture of membranes on neurodevelopmental outcome: follow up at two years of age. Br J Obstet Gynaecol 1995; 102: 882–887.

    Article  CAS  PubMed  Google Scholar 

  9. Yoon BH, Oh SY, Romero R, Shim SS, Han SY, Park JS et al. An elevated amniotic fluid matrix metalloproteinase-8 level at the time of mid-trimester genetic amniocentesis is a risk factor for spontaneous preterm delivery. Am J Obstet Gynecol 2001; 185: 1162–1167.

    Article  CAS  PubMed  Google Scholar 

  10. La Sala GB, Ardizzoni A, Capodanno F, Manca L, Baschieri MC, Soncini E et al. Protein microarrays on midtrimester amniotic fluids: a novel approach for the diagnosis of early intrauterine inflammation related to preterm delivery. Int J Immunopathol Pharmacol 2012; 25: 1029–1040.

    Article  CAS  PubMed  Google Scholar 

  11. Puchner K, Iavazzo C, Gourgiotis D, Boutsikou M, Baka S, Hassiakos D et al. Mid-trimester amniotic fluid interleukins (IL-1beta, IL-10 and IL-18) as possible predictors of preterm delivery. In Vivo 2011; 25: 141–148.

    CAS  PubMed  Google Scholar 

  12. Pressman EK, Thornburg LL, Glantz JC, Earhart A, Wall PD, Ashraf M et al. Inflammatory cytokines and antioxidants in midtrimester amniotic fluid: correlation with pregnancy outcome. Am J Obstet Gynecol 2011; 204 (155): e151–e157.

    Google Scholar 

  13. Bamberg C, Fotopoulou C, Thiem D, Roehr CC, Dudenhausen JW, Kalache KD . Correlation of midtrimester amniotic fluid cytokine concentrations with adverse pregnancy outcome in terms of spontaneous abortion, preterm birth, and preeclampsia. J Matern Fetal Neonatal Med 2012; 25: 812–817.

    Article  CAS  PubMed  Google Scholar 

  14. Malamitsi-Puchner A, Vrachnis N, Samoli E, Baka S, Alexandrakis G, Puchner KP et al. Investigation of midtrimester amniotic fluid factors as potential predictors of term and preterm deliveries. Mediators Inflamm 2006; 2006: 94381.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Romero R, Yoon BH, Mazor M, Gomez R, Gonzalez R, Diamond MP et al. A comparative study of the diagnostic performance of amniotic fluid glucose, white blood cell count, interleukin-6, and gram stain in the detection of microbial invasion in patients with preterm premature rupture of membranes. Am J Obstet Gynecol 1993; 169: 839–851.

    Article  CAS  PubMed  Google Scholar 

  16. Borna S, Mirzaie F, Abdollahi A . Mid-trimester amniotic fluid C-reactive protein, ferritin and lactate dehydrogenase concentrations and subsequent risk of spontaneous preterm labour. Aust NZ J Obstet Gynaecol 2009; 49: 400–403.

    Article  Google Scholar 

  17. Keeler SM, Kiefer DG, Rust OA, Vintzileos A, Atlas RO, Bornstein E et al. Comprehensive amniotic fluid cytokine profile evaluation in women with a short cervix: which cytokine(s) correlates best with outcome? Am J Obstet Gynecol 2009; 201 (276): e271–e276.

    Google Scholar 

  18. Mazaki-Tovi S, Romero R, Vaisbuch E, Kusanovic JP, Erez O, Mittal P et al. Adiponectin in amniotic fluid in normal pregnancy, spontaneous labor at term, and preterm labor: a novel association with intra-amniotic infection/inflammation. J Matern Fetal Neonatal Med 2010; 23: 120–130.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hauguel-de Mouzon S, Guerre-Millo M . The placenta cytokine network and inflammatory signals. Placenta 2006; 27: 794–798.

    Article  CAS  PubMed  Google Scholar 

  20. Zeger SL, Liang KY . Longitudinal data analysis for discrete and continuous outcomes. Biometrics 1986; 42: 121–130.

    Article  CAS  PubMed  Google Scholar 

  21. Perni SC, Vardhana S, Korneeva I, Tuttle SL, Paraskevas LR, Chasen ST et al. Mycoplasma hominis and Ureaplasma urealyticum in midtrimester amniotic fluid: association with amniotic fluid cytokine levels and pregnancy outcome. Am J Obstet Gynecol 2004; 191: 1382–1386.

    Article  CAS  PubMed  Google Scholar 

  22. Nguyen DP, Gerber S, Hohlfeld P, Sandrine G, Witkin SS . Mycoplasma hominis in mid-trimester amniotic fluid: relation to pregnancy outcome. J Perinat Med 2004; 32: 323–326.

    Article  PubMed  Google Scholar 

  23. Gerber S, Vial Y, Hohlfeld P, Witkin SS . Detection of Ureaplasma urealyticum in second-trimester amniotic fluid by polymerase chain reaction correlates with subsequent preterm labor and delivery. J Infect Dis 2003; 187: 518–521.

    Article  PubMed  Google Scholar 

  24. Khairy P, Ouyang DW, Fernandes SM, Lee-Parritz A, Economy KE, Landzberg MJ . Pregnancy outcomes in women with congenital heart disease. Circulation 2006; 113: 517–524.

    Article  PubMed  Google Scholar 

  25. van Nimwegen FA, Penders J, Stobberingh EE, Postma DS, Koppelman GH, Kerkhof M et al. Mode and place of delivery, gastrointestinal microbiota, and their influence on asthma and atopy. J Allergy Clin Immunol 2011; 128 (948-955): e941–e943.

    Google Scholar 

  26. Xu WL, Atti AR, Gatz M, Pedersen NL, Johansson B, Fratiglioni L . Midlife overweight and obesity increase late-life dementia risk: a population-based twin study. Neurology 2011; 76: 1568–1574.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Huang T, Hoffman B, Meschino W, Kingdom J, Okun N . Prediction of adverse pregnancy outcomes by combinations of first and second trimester biochemistry markers used in the routine prenatal screening of Down syndrome. Prenat Diagn 2010; 30: 471–477.

    PubMed  Google Scholar 

  28. Afzali N, Mohajeri M, Malek A, Alamatian A . Cervical gland area: a new sonographic marker in predicting preterm delivery. Arch Gynecol Obstet 2012; 285: 255–258.

    Article  PubMed  Google Scholar 

  29. Crane JM, Hutchens D . Transvaginal sonographic measurement of cervical length to predict preterm birth in asymptomatic women at increased risk: a systematic review. Ultrasound Obstet Gynecol 2008; 31: 579–587.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by a grant of the Korea Health R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI12C00240300) and by a grant of the Seoul National University Hospital Research Fund (03-2012-0160).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to J S Park.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

DISCLAIMER

This study was presented at the 34th Annual Meeting of the Society for Maternal–Fetal Medicine, New Orleans, LA, USA, 3–8 February 2014.

Supplementary Information accompanies the paper on the Journal of Perinatology website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lee, S., Park, J., Norwitz, E. et al. Mid-trimester amniotic fluid pro-inflammatory biomarkers predict the risk of spontaneous preterm delivery in twins: a retrospective cohort study. J Perinatol 35, 542–546 (2015). https://doi.org/10.1038/jp.2015.29

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/jp.2015.29

This article is cited by

Search

Quick links