Skip to main content

Advertisement

Log in

Immune biomarkers in maternal plasma to identify histologic chorioamnionitis in women with preterm labor

  • Maternal-Fetal Medicine
  • Published:
Archives of Gynecology and Obstetrics Aims and scope Submit manuscript

Abstract

Purpose

To determine whether various selected immune-related proteins in maternal plasma, alone or in combination, can predict histologic chorioamnionitis (HCA) in women with preterm labor, and to compare the predictive abilities of these biomarkers with that of serum C-reactive protein (CRP).

Methods

This retrospective cohort study included 74 consecutive women with preterm labor (23–34 gestational weeks) who delivered within 96 h of blood sampling. Their serum CRP levels were also measured. The stored maternal plasma was assayed for interleukin (IL)-6, matrix metalloproteinase (MMP)-9, tissue inhibitor of metalloproteinases (TIMP)-1, angiopoietin-2, S100 A8/A9, CXCL14, APRIL, and insulin-like growth factor-binding protein-2 (IGFBP-2), using ELISA kits. The primary outcome measure was HCA.

Results

HCA was detected in 59.4% (44/74) of women. Women with HCA had a significantly lower median gestational age at sampling and plasma IGFBP-2 level, and higher median plasma IL-6 and S100 A8/A9 levels than those without HCA. In multivariable analysis, high plasma IL-6 and low plasma IGFBP-2 levels were independently associated with the occurrence of HCA. However, the sensitivities, specificities, and areas under the curve of plasma IL-6, S100 A8/A9, and IGFBP-2, alone or in combination, were similar to or lower than those of serum CRP, for detecting HCA.

Conclusions

Our data suggest that plasma IL-6, S100 A8/A9, and IGFBP-2 could be potential novel biomarkers for predicting HCA in women with PTL; however, elevated plasma levels of these biomarkers, alone or in combination, do not predict HCA better than serum CRP.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Goncalves LF, Chaiworapongsa T, Romero R (2002) Intrauterine infection and prematurity. Ment Retard Dev Disabil Res Rev 8(1):3–13

    Article  PubMed  Google Scholar 

  2. Greig PC, Ernest JM, Teot L, Erikson M, Talley R (1993) Amniotic fluid interleukin-6 levels correlate with histologic chorioamnionitis and amniotic fluid cultures in patients in premature labor with intact membranes. Am J Obstet Gynecol 169 (4):1035–1044

  3. Mueller-Heubach E, Rubinstein DN, Schwarz SS (1990) Histologic chorioamnionitis and preterm delivery in different patient populations. Obstet Gynecol 75(4):622–626

    CAS  PubMed  Google Scholar 

  4. Wu YW, Colford JM Jr (2000) Chorioamnionitis as a risk factor for cerebral palsy: a meta-analysis. JAMA 284(11):1417–1424

    Article  CAS  PubMed  Google Scholar 

  5. Yoon BH, Romero R, Kim CJ, Jun JK, Gomez R, Choi JH et al (1995) Amniotic fluid interleukin-6: a sensitive test for antenatal diagnosis of acute inflammatory lesions of preterm placenta and prediction of perinatal morbidity. Am J Obstet Gynecol 172(3):960–970

    Article  CAS  PubMed  Google Scholar 

  6. Oh KJ, Park KH, Kim SN, Jeong EH, Lee SY, Yoon HY (2011) Predictive value of intra-amniotic and serum markers for inflammatory lesions of preterm placenta. Placenta 32(10):732–736

    Article  CAS  PubMed  Google Scholar 

  7. Kim SA, Park KH, Lee SM (2016) Non-invasive prediction of histologic chorioamnionitis in women with preterm premature rupture of membranes. Yonsei Med J 57(2):461–468

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Miyazaki K, Furuhashi M, Ishikawa K, Tamakoshi K, Hayashi K, Kai A et al (2016) Impact of chorioamnionitis on short- and long-term outcomes in very low birth weight preterm infants: the Neonatal Research Network Japan. J Matern Fetal Neonatal Med 29(2):331–337

    Article  PubMed  Google Scholar 

  9. Odibo AO, Rodis JF, Sanders MM, Borgida AF, Wilson M, Egan JF et al (1999) Relationship of amniotic fluid markers of intra-amniotic infection with histopathology in cases of preterm labor with intact membranes. J Perinatol 19 (6 Pt 1):407-412

  10. Hillier SL, Witkin SS, Krohn MA, Watts DH, Kiviat NB, Eschenbach DA (1993) The relationship of amniotic fluid cytokines and preterm delivery, amniotic fluid infection, histologic chorioamnionitis, and chorioamnion infection. Obstet Gynecol 81(6):941–948

    CAS  PubMed  Google Scholar 

  11. McNamara MF, Wallis T, Qureshi F, Jacques SM, Gonik B (1997) Determining the maternal and fetal cellular immunologic contributions in preterm deliveries with clinical or subclinical chorioamnionitis. Infect Dis Obstet Gynecol 5(4):273–279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Skrablin S, Lovric H, Banovic V, Kralik S, Dijakovic A, Kalafatic D (2007) Maternal plasma interleukin-6, interleukin-1beta and C-reactive protein as indicators of tocolysis failure and neonatal outcome after preterm delivery. J Matern Fetal Neonatal Med 20(4):335–341

    Article  CAS  PubMed  Google Scholar 

  13. Steinborn A, Sohn C, Scharf A, Geka F, Heger S, Kaufmann M (2000) Serum intercellular adhesion molecule-1 levels and histologic chorioamnionitis. Obstet Gynecol 95(5):671–676

    CAS  PubMed  Google Scholar 

  14. Greig PC, Murtha AP, Jimmerson CJ, Herbert WN, Roitman-Johnson B, Allen J (1997) Maternal serum interleukin-6 during pregnancy and during term and preterm labor. Obstet Gynecol 90(3):465–469

    Article  CAS  PubMed  Google Scholar 

  15. Park H, Park JW, Park KH, Kim YM, Kook SY, Jeon SJ (2017) An antibody microarray analysis of plasma proteins for the prediction of histologic chorioamnionitis in women with the preterm labor and intact membranes [abstract]. In: The 30th congress in Korean society of perinatology (abstract OB-6), 61

  16. Park KH, Yoo H, Kook SY, Park H, Jeon SJ, Kim YM (2017) A comparison of immunoregulatory protein profile in plasma between women with and without histologic chorioamnionitis in preterm premature rupture of membranes. In: The 25th world congress on controversies in obstetrics gynecology and infertility (abstract P100-1095), 135

  17. Lee SY, Park KH, Jeong EH, Oh KJ, Ryu A, Kim A (2013) Intra-amniotic infection/inflammation as a risk factor for subsequent ruptured membranes after clinically indicated amniocentesis in preterm labor. J Korean Med Sci 28(8):1226–1232

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Park JW, Park KH, Jung EY, Cho SH, Jang JA, Yoo HN (2017) Short cervical lengths initially detected in mid-trimester and early in the third trimester in asymptomatic twin gestations: association with histologic chorioamnionitis and preterm birth. PLoS One 12(4):e0175455

    Article  PubMed  PubMed Central  Google Scholar 

  19. Gibbs RS, Blanco JD, St Clair PJ, Castaneda YS (1982) Quantitative bacteriology of amniotic fluid from women with clinical intraamniotic infection at term. J Infect Dis 145(1):1–8

    Article  CAS  PubMed  Google Scholar 

  20. DeLong ER, DeLong DM, Clarke-Pearson DL (1988) Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 44(3):837–845

    Article  CAS  Google Scholar 

  21. Murtha AP, Greig PC, Jimmerson CE, Roitman-Johnson B, Allen J, Herbert WN (1996) Maternal serum interleukin-6 concentrations in patients with preterm premature rupture of membranes and evidence of infection. Am J Obstet Gynecol 175(4 Pt 1):966–969

    Article  CAS  PubMed  Google Scholar 

  22. Sayed Ahmed WA, Ahmed MR, Mohamed ML, Hamdy MA, Kamel Z, Elnahas KM (2016) Maternal serum interleukin-6 in the management of patients with preterm premature rupture of membranes. J Matern Fetal Neonatal Med 29(19):3162–3166

    Article  CAS  PubMed  Google Scholar 

  23. Gulati S, Bhatnagar S, Raghunandan C, Bhattacharjee J (2012) Interleukin-6 as a predictor of subclinical chorioamnionitis in preterm premature rupture of membranes. Am J Reprod Immunol 67(3):235–240

    Article  CAS  PubMed  Google Scholar 

  24. Gargano JW, Holzman C, Senagore P, Thorsen P, Skogstrand K, Hougaard DM et al (2008) Mid-pregnancy circulating cytokine levels, histologic chorioamnionitis and spontaneous preterm birth. J Reprod Immunol 79(1):100–110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Baricevic I, Jones DR, Nikolic JA, Nedic O (2006) Gastrointestinal inflammation and the circulating IGF system in humans. Horm Metab Res 38(1):22–27

    Article  CAS  PubMed  Google Scholar 

  26. Shin M, Kang HS, Park JH, Bae JH, Song DK, Im SS (2017) Recent insights into insulin-like growth factor binding protein 2 transcriptional regulation. Endocrinol Metab (Seoul) 32(1):11–17

    Article  CAS  Google Scholar 

  27. Heald AH, Kaushal K, Siddals KW, Rudenski AS, Anderson SG, Gibson JM (2006) Insulin-like growth factor binding protein-2 (IGFBP-2) is a marker for the metabolic syndrome. Exp Clin Endocrinol Diabetes 114(7):371–376

    Article  CAS  PubMed  Google Scholar 

  28. Han VK, Bassett N, Walton J, Challis JR (1996) The expression of insulin-like growth factor (IGF) and IGF-binding protein (IGFBP) genes in the human placenta and membranes: evidence for IGF-IGFBP interactions at the feto-maternal interface. J Clin Endocrinol Metab 81(7):2680–2693

    CAS  PubMed  Google Scholar 

  29. Hill DJ, Clemmons DR (1992) Similar distribution of insulin-like growth factor binding proteins-1, -2, -3 in human fetal tissues. Growth Factors 6(4):315–326

    Article  CAS  PubMed  Google Scholar 

  30. Ryckman C, Vandal K, Rouleau P, Talbot M, Tessier PA (2003) Proinflammatory activities of S100: proteins S100A8, S100A9, and S100A8/A9 induce neutrophil chemotaxis and adhesion. J Immunol 170(6):3233–3242

    Article  CAS  PubMed  Google Scholar 

  31. Pergialiotis V, Prodromidou A, Pappa E, Vlachos GD, Perrea DN, Papantoniou N (2016) An evaluation of calprotectin as serum marker of preeclampsia: a systematic review of observational studies. Inflamm Res 65(2):95–102

    Article  CAS  PubMed  Google Scholar 

  32. Terrin G, Passariello A, De Curtis M, Paludetto R, Berni Canani R (2012) S100 A8/A9 protein as a marker for early diagnosis of necrotising enterocolitis in neonates. Arch Dis Child 97(12):1102

    Article  PubMed  Google Scholar 

  33. Bealer JF, Colgin M (2010) S100A8/A9: a potential new diagnostic aid for acute appendicitis. Acad Emerg Med 17(3):333–336

    Article  PubMed  Google Scholar 

  34. Terrin G, Passariello A, Manguso F, Salvia G, Rapacciuolo L, Messina F et al (2011) Serum calprotectin: an antimicrobial peptide as a new marker for the diagnosis of sepsis in very low birth weight newborns. Clin Dev Immunol 2011:291085

    Article  PubMed  PubMed Central  Google Scholar 

  35. Athayde N, Romero R, Gomez R, Maymon E, Pacora P, Mazor M et al (1999) Matrix metalloproteinases-9 in preterm and term human parturition. J Matern Fetal Med 8(5):213–219

    CAS  PubMed  Google Scholar 

  36. Stygar D, Wang H, Vladic YS, Ekman G, Eriksson H, Sahlin L (2002) Increased level of matrix metalloproteinases 2 and 9 in the ripening process of the human cervix. Biol Reprod 67(3):889–894

    Article  CAS  PubMed  Google Scholar 

  37. Tu FF, Goldenberg RL, Tamura T, Drews M, Zucker SJ, Voss HF (1998) Prenatal plasma matrix metalloproteinase-9 levels to predict spontaneous preterm birth. Obstet Gynecol 92(3):446–449

    CAS  PubMed  Google Scholar 

  38. Caloone J, Rabilloud M, Boutitie F, Traverse-Glehen A, Allias-Montmayeur F, Denis L et al (2016) Accuracy of several maternal seric markers for predicting histological chorioamnionitis after preterm premature rupture of membranes: a prospective and multicentric study. Eur J Obstet Gynecol Reprod Biol 205:133–140

    Article  PubMed  Google Scholar 

  39. Sorokin Y, Romero R, Mele L, Wapner RJ, Iams JD, Dudley DJ et al (2010) Maternal serum interleukin-6, C-reactive protein, and matrix metalloproteinase-9 concentrations as risk factors for preterm birth < 32 weeks and adverse neonatal outcomes. Am J Perinatol 27(8):631–640

    Article  PubMed  PubMed Central  Google Scholar 

  40. Arpino V, Brock M, Gill SE (2015) The role of TIMPs in regulation of extracellular matrix proteolysis. Matrix Biol 44–46:247–254

    Article  Google Scholar 

  41. Locksmith GJ, Clark P, Duff P, Saade GR, Schultz GS (2001) Amniotic fluid concentrations of matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 during pregnancy and labor. Am J Obstet Gynecol 184(2):159–164

    Article  CAS  PubMed  Google Scholar 

  42. Roy-Lacroix ME, Guerard M, Berthiaume M, Rola-Pleszczynski M, Crous-Tsanaclis AM, Pasquier JC (2013) Time-dependent effect of in utero inflammation: a longitudinal study in rats. J Matern Fetal Neonatal Med 26(8):789–794

    Article  CAS  PubMed  Google Scholar 

  43. Geva E, Ginzinger DG, Zaloudek CJ, Moore DH, Byrne A, Jaffe RB (2002) Human placental vascular development: vasculogenic and angiogenic (branching and nonbranching) transformation is regulated by vascular endothelial growth factor-A, angiopoietin-1, and angiopoietin-2. J Clin Endocrinol Metab 87(9):4213–4224

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by a grant from the Korea Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (Grant no. HI 14C1798).

Author information

Authors and Affiliations

Authors

Contributions

JWP: protocol/project development, data analysis, and manuscript writing/editing. KHP: conceptualization, protocol/project development, supervision, funding acquisition, data analysis, and manuscript writing/editing. SYK: data collection or management and data analysis. YMJ: data collection or management and data analysis. YMK: data collection or management, data analysis, and ELISA assay.

Corresponding author

Correspondence to Kyo Hoon Park.

Ethics declarations

Conflict of interest

The authors report no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Park, J.W., Park, K.H., Kook, S.Y. et al. Immune biomarkers in maternal plasma to identify histologic chorioamnionitis in women with preterm labor. Arch Gynecol Obstet 299, 725–732 (2019). https://doi.org/10.1007/s00404-019-05061-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00404-019-05061-8

Keywords

Navigation