J Korean Med Sci.  2021 Nov;36(44):e279. 10.3346/jkms.2021.36.e279.

Maternal Plasma and Amniotic Fluid LBP, Pentraxin 3, Resistin, and IGFBP-3: Biomarkers of Microbial Invasion of Amniotic Cavity and/or Intra-amniotic Inflammation in Women with Preterm Premature Rupture of Membranes

• Joo E
• Park KH
• Kim YM
• Ahn K
• Hong S

• KMID: 2522359
• DOI: http://doi.org/10.3346/jkms.2021.36.e279

Abstract

Background
We sought to determine whether lipopolysaccharide binding protein (LBP), pentraxin 3, resistin, and insulin-like growth factor binding protein (IGFBP)-3 in plasma and amniotic fluid (AF) can predict microbial invasion of the amniotic cavity (MIAC), intra-amniotic inflammation (IAI), and microbial-associated IAI in women with preterm premature rupture of membranes (PPROM).
Methods
This was a retrospective cohort study involving 168 singleton pregnant women with PPROM. AF obtained via amniocentesis was cultured and assayed for interleukin (IL)-6 to define IAI and for IL-8 to compare with AF biomarkers. Plasma samples were collected at the time of amniocentesis, and C-reactive protein (CRP) levels in serum were compared with plasma biomarkers. The stored plasma and AF samples were assayed for LBP, pentraxin 3 (PTX3), resistin, and IGFBP-3 by ELISA.
Results
Multivariate logistic regression analysis revealed that: 1) elevated plasma and AF levels of LBP were independently associated with increased risks of MIAC, IAI, and microbial-associated IAI; 2) elevated AF, but not plasma, PTX3, and resistin levels were independently associated with increased risks of MIAC, IAI, and microbial-associated IAI; 3) decreased IGFBP-3 levels in the plasma were independently associated with only IAI, whereas those in the AF were associated with only microbial-associated IAI. Among the tested biomarkers, AF PTX3 and resistin had the highest predictive performance for MIAC, IAI, and microbial-associated IAI (area under the curves [AUC] = 0.85–0.95), which is similar to the performance of AF IL-8. The AUCs of the plasma LBP and IGFBP-3 were similar to that of serum CRP with respect to IAI.
Conclusion
Maternal plasma LBP and IGFBP-3 are potential biomarkers for the non-invasive identification of IAI in women with PPROM, with a similar accuracy to the serum CRP level. AF LBP, PTX3, resistin, and IGFBP-3 may be involved in the intra-amniotic inflammatory responses in PPROM complicated by MIAC.

Keyword

Amniotic Fluid; Intra-Amniotic Inflammation; IGFBP-3; Inflammatory Mediators; Microbial Invasion of Amniotic Cavity; Plasma; Preterm Premature Rupture of Membranes

Figure

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  Fig. 1 (A) ROC curves of plasma LBP and AF LBP, PTX3, and resistin for predicting microbial invasion of the amniotic cavity. (B) ROC curves of plasma LBP and IGFBP-3, and AF LBP, PTX3, and resistin for predicting intra-amniotic inflammation. (C) ROC curves of plasma LBP and AF LBP, PTX3, resistin, and IGFBP-3 for predicting microbial-associated IAI.LBP = lipopolysaccharide binding protein, AF = amniotic fluid, PTX3 = pentraxin 3, IGFBP = insulin-like growth factor-binding protein, ROC = receiver-operating characteristic.

Reference

1. Mercer BM. Preterm premature rupture of the membranes. Obstet Gynecol. 2003; 101(1):178–193. PMID: 12517665.

2. Manuck TA, Varner MW. Neonatal and early childhood outcomes following early vs later preterm premature rupture of membranes. Am J Obstet Gynecol. 2014; 211(3):308.e1–308.e6. PMID: 24858202.

3. Menon R, Richardson LS. Preterm prelabor rupture of the membranes: a disease of the fetal membranes. Semin Perinatol. 2017; 41(7):409–419. PMID: 28807394.

4. Sae-Lin P, Wanitpongpan P. Incidence and risk factors of preterm premature rupture of membranes in singleton pregnancies at Siriraj Hospital. J Obstet Gynaecol Res. 2019; 45(3):573–577. PMID: 30537150.

5. Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet. 2008; 371(9606):75–84. PMID: 18177778.

6. Ryu A, Park KH, Oh KJ, Lee SY, Jeong EH, Park JW. Predictive value of combined cervicovaginal cytokines and gestational age at sampling for intra-amniotic infection in preterm premature rupture of membranes. Acta Obstet Gynecol Scand. 2013; 92(5):517–524. PMID: 23324124.

7. Park KH, Kim SN, Oh KJ, Lee SY, Jeong EH, Ryu A. Noninvasive prediction of intra-amniotic infection and/or inflammation in preterm premature rupture of membranes. Reprod Sci. 2012; 19(6):658–665. PMID: 22457430.

8. Hong JS, Park KH, Noh JH, Suh YH. Cervical length and the risk of microbial invasion of the amniotic cavity in women with preterm premature rupture of membranes. J Korean Med Sci. 2007; 22(4):713–717. PMID: 17728515.

9. Jung EY, Park KH, Han BR, Cho SH, Yoo HN, Lee J. Amniotic fluid infection, cytokine levels, and mortality and adverse pulmonary, intestinal, and neurologic outcomes in infants at 32 weeks' gestation or less. J Korean Med Sci. 2017; 32(3):480–487. PMID: 28145652.

10. Gonçalves LF, Chaiworapongsa T, Romero R. Intrauterine infection and prematurity. Ment Retard Dev Disabil Res Rev. 2002; 8(1):3–13. PMID: 11921380.

11. Oh KJ, Park KH, Kim SN, Jeong EH, Lee SY, Yoon HY. Predictive value of intra-amniotic and serum markers for inflammatory lesions of preterm placenta. Placenta. 2011; 32(10):732–736. PMID: 21839511.

12. Lee SM, Park KH, Jung EY, Kook SY, Park H, Jeon SJ. Inflammatory proteins in maternal plasma, cervicovaginal and amniotic fluids as predictors of intra-amniotic infection in preterm premature rupture of membranes. PLoS One. 2018; 13(7):e0200311. PMID: 29979758.

13. Jung EY, Park KH, Han BR, Cho SH, Ryu A. Measurement of interleukin 8 in cervicovaginal fluid in women with preterm premature rupture of membranes: a comparison of amniotic fluid samples. Reprod Sci. 2017; 24(1):142–147. PMID: 27233755.

14. Holmström E, Myntti T, Sorsa T, Kruit H, Juhila J, Paavonen J, et al. Cervical and amniotic fluid matrix metalloproteinase-8 and interleukin-6 concentrations in preterm pregnancies with or without preterm premature rupture of membranes. Fetal Diagn Ther. 2019; 46(2):103–110. PMID: 30308501.

15. Kacerovsky M, Musilova I, Hornychova H, Kutova R, Pliskova L, Kostal M, et al. Bedside assessment of amniotic fluid interleukin-6 in preterm prelabor rupture of membranes. Am J Obstet Gynecol. 2014; 211(4):385.e1–385.e9. PMID: 24705131.

16. Muta T, Takeshige K. Essential roles of CD14 and lipopolysaccharide-binding protein for activation of toll-like receptor (TLR)2 as well as TLR4 Reconstitution of TLR2- and TLR4-activation by distinguishable ligands in LPS preparations. Eur J Biochem. 2001; 268(16):4580–4589. PMID: 11502220.

17. Deban L, Russo RC, Sironi M, Moalli F, Scanziani M, Zambelli V, et al. Regulation of leukocyte recruitment by the long pentraxin PTX3. Nat Immunol. 2010; 11(4):328–334. PMID: 20208538.

18. Acquarone E, Monacelli F, Borghi R, Nencioni A, Odetti P. Resistin: a reappraisal. Mech Ageing Dev. 2019; 178:46–63. PMID: 30650338.

19. Espinoza J, Romero R, Chaiworapongsa T, Kim JC, Yoshimatsu J, Edwin S, et al. Lipopolysaccharide-binding protein in microbial invasion of the amniotic cavity and human parturition. J Matern Fetal Neonatal Med. 2002; 12(5):313–321. PMID: 12607763.

20. Cruciani L, Romero R, Vaisbuch E, Kusanovic JP, Chaiworapongsa T, Mazaki-Tovi S, et al. Pentraxin 3 in amniotic fluid: a novel association with intra-amniotic infection and inflammation. J Perinat Med. 2010; 38(2):161–171. PMID: 19792835.

21. Kusanovic JP, Romero R, Mazaki-Tovi S, Chaiworapongsa T, Mittal P, Gotsch F, et al. Resistin in amniotic fluid and its association with intra-amniotic infection and inflammation. J Matern Fetal Neonatal Med. 2008; 21(12):902–916. PMID: 19065463.

22. Slater T, Haywood NJ, Matthews C, Cheema H, Wheatcroft SB. Insulin-like growth factor binding proteins and angiogenesis: from cancer to cardiovascular disease. Cytokine Growth Factor Rev. 2019; 46:28–35. PMID: 30954375.

23. Aguilar-Cazares D, Chavez-Dominguez R, Carlos-Reyes A, Lopez-Camarillo C, Hernadez de la Cruz ON, Lopez-Gonzalez JS. Contribution of angiogenesis to inflammation and cancer. Front Oncol. 2019; 9:1399. PMID: 31921656.

24. Mor F, Quintana FJ, Cohen IR. Angiogenesis-inflammation cross-talk: vascular endothelial growth factor is secreted by activated T cells and induces Th1 polarization. J Immunol. 2004; 172(7):4618–4623. PMID: 15034080.

25. Lee SY, Park KH, Jeong EH, Oh KJ, Ryu A, Kim A. Intra-amniotic infection/inflammation as a risk factor for subsequent ruptured membranes after clinically indicated amniocentesis in preterm labor. J Korean Med Sci. 2013; 28(8):1226–1232. PMID: 23960452.

26. Lee SY, Park KH, Jeong EH, Oh KJ, Ryu A, Park KU. Relationship between maternal serum C-reactive protein, funisitis and early-onset neonatal sepsis. J Korean Med Sci. 2012; 27(6):674–680. PMID: 22690100.

27. Kim HJ, Park KH, Kim YM, Joo E, Ahn K, Shin S. A protein microarray analysis of amniotic fluid proteins for the prediction of spontaneous preterm delivery in women with preterm premature rupture of membranes at 23 to 30 weeks of gestation. PLoS One. 2020; 15(12):e0244720. PMID: 33382822.

28. Chaemsaithong P, Romero R, Korzeniewski SJ, Martinez-Varea A, Dong Z, Yoon BH, et al. A point of care test for interleukin-6 in amniotic fluid in preterm prelabor rupture of membranes: a step toward the early treatment of acute intra-amniotic inflammation/infection. J Matern Fetal Neonatal Med. 2016; 29(3):360–367. PMID: 25758620.

29. Jung EY, Choi BY, Rhee J, Park J, Cho SH, Park KH. Relation between amniotic fluid infection or cytokine levels and hearing screen failure in infants at 32 wk gestation or less. Pediatr Res. 2017; 81(2):349–355. PMID: 27925622.

30. Gibbs RS, Blanco JD, St Clair PJ, Castaneda YS. Quantitative bacteriology of amniotic fluid from women with clinical intraamniotic infection at term. J Infect Dis. 1982; 145(1):1–8. PMID: 7033397.

31. DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics. 1988; 44(3):837–845. PMID: 3203132.

32. Kacerovsky M, Drahosova M, Hornychova H, Pliskova L, Bolehovska R, Forstl M, et al. Value of amniotic fluid interleukin-8 for the prediction of histological chorioamnionitis in preterm premature rupture of membranes. Neuroendocrinol Lett. 2009; 30(6):733–738. PMID: 20038922.

33. Chen FC, Sarioglu N, Büscher U, Dudenhausen JW. Lipopolysaccharide binding protein in the early diagnosis of intraamniotic infection of pregnant women with premature rupture of the membranes. J Perinat Med. 2009; 37(2):135–139. PMID: 18783308.

34. Park JW, Park KH, Jung EY. Clinical significance of histologic chorioamnionitis with a negative amniotic fluid culture in patients with preterm labor and premature membrane rupture. PLoS One. 2017; 12(3):e0173312. PMID: 28278303.

35. Brockway HM, Kallapur SG, Buhimschi IA, Buhimschi CS, Ackerman WE, Muglia LJ, et al. Unique transcriptomic landscapes identified in idiopathic spontaneous and infection related preterm births compared to normal term births. PLoS One. 2019; 14(11):e0225062. PMID: 31703110.

36. Lynch AM, Wagner BD, Deterding RR, Giclas PC, Gibbs RS, Janoff EN, et al. The relationship of circulating proteins in early pregnancy with preterm birth. Am J Obstet Gynecol. 2016; 214(4):517.e1–517.e8. PMID: 26576488.

37. DeBoer MD, Scharf RJ, Leite AM, Férrer A, Havt A, Pinkerton R, et al. Systemic inflammation, growth factors, and linear growth in the setting of infection and malnutrition. Nutrition. 2017; 33:248–253. PMID: 27712965.

38. Lee MJ, Shin DH, Ko KI, Koo HM, Kim CH, Doh FM, et al. Association between the ratio of insulin-like growth factor-I to insulin-like growth factor binding protein-3 and inflammation in incident automated peritoneal dialysis patients. Growth Horm IGF Res. 2013; 23(5):170–174. PMID: 23850448.

39. Cooley SM, Donnelly JC, Collins C, Geary MP, Rodeck CH, Hindmarsh PC. The relationship between maternal insulin-like growth factors 1 and 2 (IGF-1, IGF-2) and IGFBP-3 to gestational age and preterm delivery. J Perinat Med. 2010; 38(3):255–259. PMID: 20121533.

40. Sproston NR, Ashworth JJ. Role of C-Reactive Protein at Sites of Inflammation and Infection. Front Immunol. 2018; 9:754. PMID: 29706967.

41. Musilova I, Andrys C, Krejsek J, Drahosova M, Zednikova B, Pliskova L, et al. Amniotic fluid pentraxins: Potential early markers for identifying intra-amniotic inflammatory complications in preterm pre-labor rupture of membranes. Am J Reprod Immunol. 2018; 79(5):e12789. PMID: 29193454.

42. Kacerovsky M, Tosner J, Drahosova M, Hornychova H, Andrys C. Pentraxin 3 in amniotic fluid as a marker of intra-amniotic inflammation in women with preterm premature rupture of membranes. Int J Gynaecol Obstet. 2010; 108(3):203–206. PMID: 20022320.

43. Pang SS, Le YY. Role of resistin in inflammation and inflammation-related diseases. Cell Mol Immunol. 2006; 3(1):29–34. PMID: 16549046.

44. Mazaki-Tovi S, Vaisbuch E, Romero R, Kusanovic JP, Chaiworapongsa T, Kim SK, et al. Hyperresistinemia - a novel feature in systemic infection during human pregnancy. Am J Reprod Immunol. 2010; 63(5):358–369. PMID: 20178460.

45. Mantovani A, Garlanda C, Doni A, Bottazzi B. Pentraxins in innate immunity: from C-reactive protein to the long pentraxin PTX3. J Clin Immunol. 2008; 28(1):1–13. PMID: 17828584.

46. DiGiulio DB, Romero R, Kusanovic JP, Gómez R, Kim CJ, Seok KS, et al. Prevalence and diversity of microbes in the amniotic fluid, the fetal inflammatory response, and pregnancy outcome in women with preterm pre-labor rupture of membranes. Am J Reprod Immunol. 2010; 64(1):38–57. PMID: 20331587.

47. Combs CA, Gravett M, Garite TJ, Hickok DE, Lapidus J, Porreco R, et al. Amniotic fluid infection, inflammation, and colonization in preterm labor with intact membranes. Am J Obstet Gynecol. 2014; 210(2):125.e1–125.15. PMID: 24274987.