Spontaneous preterm birth has enormous consequences for newborns, children, and families. Intra-amniotic inflammation (IAI) is the leading cause of spontaneous preterm delivery, mainly at earlier gestational ages. Amniocentesis is the only method used to identify IAI in clinical practice. Although it is an invasive procedure with a very low risk of complications, many women and physicians are hesitant about amniocentesis on this indication. This has been an incentive to explore IAI and the intra-amniotic environment through noninvasive techniques, such as sampling cervical mucus, vaginal fluid, or maternal blood. With this overview, we aim to provide a concise update on the state of the art of the noninvasive sampling of the intrauterine environment in women with preterm labor and intact membranes. So far, it is unknown whether this screening helps improve our knowledge about the impact of IAI on the neonatal and long-term outcome, but we believe it merits this review.

1.
Rodriguez-Trujillo A, Cobo T, Vives I, Bosch J, Kacerovsky M, et al: Gestational age is more important for short-term neonatal outcome than microbial invasion of the amniotic cavity or intra-amniotic inflammation in preterm prelabor rupture of membranes. Acta Obstet Gynecol Scand 2016;95:926-933.
2.
Combs CA, Gravett M, Garite TJ, Hickok DE, Lapidus J, et al: Amniotic fluid infection, inflammation, and colonization in preterm labor with intact membranes. Am J Obstet Gynecol 2014;210:125.e1-125.e15.
3.
Shim SS, Romero R, Hong JS, Park CW, Jun JK, et al: Clinical significance of intra-amniotic inflammation in patients with preterm premature rupture of membranes. Am J Obstet Gynecol 2004;191:1339-1345.
4.
Yoon BH, Romero R, Moon JB, Shim SS, Kim M, et al: Clinical significance of intra-amniotic inflammation in patients with preterm labor and intact membranes. Am J Obstet Gynecol 2001;185:1130-1136.
5.
Jacobsson B, Mattsby-Baltzer I, Andersch B, Bokstrom H, Holst RM, et al: Microbial invasion and cytokine response in amniotic fluid in a Swedish population of women in preterm labor. Acta Obstet Gynecol Scand 2003;82:120-128.
6.
Cobo T, Palacio M, Navarro-Sastre A, Ribes A, Bosch J, et al: Predictive value of combined amniotic fluid proteomic biomarkers and interleukin-6 in preterm labor with intact membranes. Am J Obstet Gynecol 2009;200:499.e1-6.
7.
Romero R, Yoon BH, Mazor M, Gomez R, Diamond MP, et al: The diagnostic and prognostic value of amniotic fluid white blood cell count, glucose, interleukin-6, and gram stain in patients with preterm labor and intact membranes. Am J Obstet Gynecol 1993;169:805-816.
8.
Romero R, Chaiworapongsa T, Alpay Savasan Z, Xu Y, Hussein Y, et al: Damage-associated molecular patterns (DAMPs) in preterm labor with intact membranes and preterm PROM: a study of the alarmin HMGB1. J Matern Fetal Neonatal Med 2011;24:1444-1455.
9.
Romero R, Miranda J, Chaiworapongsa T, Korzeniewski SJ, Chaemsaithong P, et al: Prevalence and clinical significance of sterile intra-amniotic inflammation in patients with preterm labor and intact membranes. Am J Reprod Immunol 2014;72:458-474.
10.
Triunfo S, Parra-Saavedra M, Rodriguez-Sureda V, Crovetto F, Dominguez C, et al: Angiogenic factors and Doppler evaluation in normally growing fetuses at routine third-trimester scan: prediction of subsequent low birth weight. Fetal Diagn Ther 2016;40:13-20.
11.
Kim SY, Kim HJ, Park SY, Han YJ, Choi JS, et al: Early prediction of hypertensive disorders of pregnancy using cell-free fetal DNA, cell-free total DNA, and biochemical markers. Fetal Diagn Ther 2016;40:255-262.
12.
Yefet E, Kuzmin O, Schwartz N, Basson F, Nachum Z: Predictive value of second-trimester biomarkers and maternal features for adverse pregnancy outcomes. Fetal Diagn Ther 2017, Epub ahead of print.
13.
Becher N, Adams Waldorf K, Hein M, Uldbjerg N: The cervical mucus plug: structured review of the literature. Acta Obstet Gynecol Scand 2009;88:502-513.
14.
Anderson DJ, Marathe J, Pudney J: The structure of the human vaginal stratum corneum and its role in immune defense. Am J Reprod Immunol 2014;71:618-623.
15.
Santolaya-Forgas J, Townsend R, Santolaya JL, Patel P, Herrera-Garcia G, et al: The microbiota and transgenomic networks: potential implications for maternal-fetal medicine. Fetal Diagn Ther 2016;39:1-3.
16.
Aagaard K, Riehle K, Ma J, Segata N, Mistretta TA, et al: A metagenomic approach to characterization of the vaginal microbiome signature in pregnancy. PLoS One 2012;7:e36466.
17.
Hernandez-Rodriguez C, Romero-Gonzalez R, Albani-Campanario M, Figueroa-Damian R, Meraz-Cruz N, et al: Vaginal microbiota of healthy pregnant Mexican women is constituted by four Lactobacillus species and several vaginosis-associated bacteria. Infect Dis Obstet Gynecol 2011;2011:851485.
18.
Hyman RW, Fukushima M, Jiang H, Fung E, Rand L, et al: Diversity of the vaginal microbiome correlates with preterm birth. Reprod Sci 2014;21:32-40.
19.
Romero R, Hassan SS, Gajer P, Tarca AL, Fadrosh DW, et al: The composition and stability of the vaginal microbiota of normal pregnant women is different from that of non-pregnant women. Microbiome 2014;2:4.
20.
Verstraelen H, Verhelst R, Claeys G, De Backer E, Temmerman M, et al: Longitudinal analysis of the vaginal microflora in pregnancy suggests that L. crispatus promotes the stability of the normal vaginal microflora and that L. gasseri and/or L. iners are more conducive to the occurrence of abnormal vaginal microflora. BMC Microbiol 2009;9:116.
21.
Orfanelli T, Jayaram A, Doulaveris G, Forney LJ, Ledger WJ, et al: Human epididymis protein 4 and secretory leukocyte protease inhibitor in vaginal fluid: relation to vaginal components and bacterial composition. Reprod Sci 2014;21:538-542.
22.
Kyongo JK, Jespers V, Goovaerts O, Michiels J, Menten J, et al: Searching for lower female genital tract soluble and cellular biomarkers: defining levels and predictors in a cohort of healthy Caucasian women. PLoS One 2012;7:e43951.
23.
Sakai M, Ishiyama A, Tabata M, Sasaki Y, Yoneda S, et al: Relationship between cervical mucus interleukin-8 concentrations and vaginal bacteria in pregnancy. Am J Reprod Immunol 2004;52:106-112.
24.
Nikolaitchouk N, Andersch B, Falsen E, Strombeck L, Mattsby-Baltzer I: The lower genital tract microbiota in relation to cytokine-, SLPI- and endotoxin levels: application of checkerboard DNA-DNA hybridization (CDH). APMIS 2008;116:263-277.
25.
Mitchell C, Marrazzo J: Bacterial vaginosis and the cervicovaginal immune response. Am J Reprod Immunol 2014;71:555-563.
26.
Balkus J, Agnew K, Lawler R, Mitchell C, Hitti J: Effects of pregnancy and bacterial vaginosis on proinflammatory cytokine and secretory leukocyte protease inhibitor concentrations in vaginal secretions. J Pregnancy 2010;2010:385981.
27.
Beigi RH, Yudin MH, Cosentino L, Meyn LA, Hillier SL: Cytokines, pregnancy, and bacterial vaginosis: comparison of levels of cervical cytokines in pregnant and nonpregnant women with bacterial vaginosis. J Infect Dis 2007;196:1355-1360.
28.
Marconi C, Donders GG, Parada CM, Giraldo PC, da Silva MG: Do Atopobium vaginae, Megasphaera sp. and Leptotrichia sp. change the local innate immune response and sialidase activity in bacterial vaginosis? Sex Transm Infect 2013;89:167-173.
29.
Musilova I, Kutova R, Pliskova L, Stepan M, Menon R, et al: Intraamniotic inflammation in women with preterm prelabor rupture of membranes. PLoS One 2015;10:e0133929.
30.
Romero R, Miranda J, Chaemsaithong P, Chaiworapongsa T, Kusanovic JP, et al: Sterile and microbial-associated intra-amniotic inflammation in preterm prelabor rupture of membranes. J Matern Fetal Neonatal Med 2015;28:1394-1409.
31.
Jacobsson B, Mattsby-Baltzer I, Hagberg H: Interleukin-6 and interleukin-8 in cervical and amniotic fluid: relationship to microbial invasion of the chorioamniotic membranes. BJOG 2005;112:719-724.
32.
Holst RM, Mattsby-Baltzer I, Wennerholm UB, Hagberg H, Jacobsson B: Interleukin-6 and interleukin-8 in cervical fluid in a population of Swedish women in preterm labor: relationship to microbial invasion of the amniotic fluid, intra-amniotic inflammation, and preterm delivery. Acta Obstet Gynecol Scand 2005;84:551-557.
33.
Holst RM, Jacobsson B, Hagberg H, Wennerholm UB: Cervical length in women in preterm labor with intact membranes: relationship to intra-amniotic inflammation/microbial invasion, cervical inflammation and preterm delivery. Ultrasound Obstet Gynecol 2006;28:768-774.
34.
Rizzo G, Capponi A, Rinaldo D, Tedeschi D, Arduini D, et al: Interleukin-6 concentrations in cervical secretions identify microbial invasion of the amniotic cavity in patients with preterm labor and intact membranes. Am J Obstet Gynecol 1996;175:812-817.
35.
Jacobsson B, Holst RM, Mattsby-Baltzer I, Nikolaitchouk N, Wennerholm UB, et al: Interleukin-18 in cervical mucus and amniotic fluid: relationship to microbial invasion of the amniotic fluid, intra-amniotic inflammation and preterm delivery. BJOG 2003;110:598-603.
36.
Jacobsson B, Holst RM, Wennerholm UB, Andersson B, Lilja H, et al: Monocyte chemotactic protein-1 in cervical and amniotic fluid: relationship to microbial invasion of the amniotic cavity, intra-amniotic inflammation, and preterm delivery. Am J Obstet Gynecol 2003;189:1161-1167.
37.
Rizzo G, Capponi A, Vlachopoulou A, Angelini E, Grassi C, et al: The diagnostic value of interleukin-8 and fetal fibronectin concentrations in cervical secretions in patients with preterm labor and intact membranes. J Perinat Med 1997;25:461-468.
38.
Rizzo G, Capponi A, Vlachopoulou A, Angelini E, Grassi C, et al: Ultrasonographic assessment of the uterine cervix and interleukin-8 concentrations in cervical secretions predict intrauterine infection in patients with preterm labor and intact membranes. Ultrasound Obstet Gynecol 1998;12:86-92.
39.
Gravett MG, Thomas A, Schneider KA, Reddy AP, Dasari S, Jacob T, Lu X, Rodland M, Pereira L, Sadowsky DW, Roberts CT Jr, Novy MJ, Nagalla SR: Proteomic analysis of cervical-vaginal fluid: identification of novel biomarkers for detection of intra-amniotic infection. J Proteome Res. 2007;6:89-96.
40.
Holst RM, Hagberg H, Wennerholm UB, Skogstrand K, Thorsen P, et al: Prediction of microbial invasion of the amniotic cavity in women with preterm labour: analysis of multiple proteins in amniotic and cervical fluids. BJOG 2011;118:240-249.
41.
Hitti J, Hillier SL, Agnew KJ, Krohn MA, Reisner DP, et al: Vaginal indicators of amniotic fluid infection in preterm labor. Obstet Gynecol 2001;97:211-219.
42.
Park JW, Park KH, Lee SY: Noninvasive prediction of intra-amniotic infection and/or inflammation in women with preterm labor: various cytokines in cervicovaginal fluid. Reprod Sci 2013;20:262-268.
43.
Combs CA, Garite TJ, Lapidus JA, Lapointe JP, Gravett M, et al: Detection of microbial invasion of the amniotic cavity by analysis of cervicovaginal proteins in women with preterm labor and intact membranes. Am J Obstet Gynecol 2015;212:482.e1-482.e12.
44.
Hitti J, Lapidus JA, Lu X, Reddy AP, Jacob T, et al: Noninvasive diagnosis of intraamniotic infection: proteomic biomarkers in vaginal fluid. Am J Obstet Gynecol 2010;203:32.e1-8.
45.
Dulay AT, Buhimschi IA, Zhao G, Bahtiyar MO, Thung SF, et al: Compartmentalization of acute phase reactants interleukin-6, C-reactive protein and procalcitonin as biomarkers of intra-amniotic infection and chorioamnionitis. Cytokine 2015;76:236-243.
46.
Cobo T, Tsiartas P, Kacerovsky M, Holst RM, Hougaard DM, et al: Maternal inflammatory response to microbial invasion of the amniotic cavity: analyses of multiple proteins in the maternal serum. Acta Obstet Gynecol Scand 2013;92:61-68.
47.
Jacobsson B, Mattsby-Baltzer I, Andersch B, Bokstrom H, Holst RM, et al: Microbial invasion and cytokine response in amniotic fluid in a Swedish population of women with preterm prelabor rupture of membranes. Acta Obstet Gynecol Scand 2003;82:423-431.
48.
Ruetschi U, Rosen A, Karlsson G, Zetterberg H, Rymo L, et al: Proteomic analysis using protein chips to detect biomarkers in cervical and amniotic fluid in women with intra-amniotic inflammation. J Proteome Res 2005;4:2236-2242.
49.
Mazaki-Tovi S, Romero R, Vaisbuch E, Erez O, Mittal P, et al: Dysregulation of maternal serum adiponectin in preterm labor. J Matern Fetal Neonatal Med 2009;22:887-904.
50.
Cruciani L, Romero R, Vaisbuch E, Kusanovic JP, Chaiworapongsa T, et al: Pentraxin 3 in maternal circulation: an association with preterm labor and preterm PROM, but not with intra-amniotic infection/inflammation. J Matern Fetal Neonatal Med 2010;23:1097-1105.
51.
Park CW, Yoon BH, Park JS, Jun JK: An elevated maternal serum C-reactive protein in the context of intra-amniotic inflammation is an indicator that the development of amnionitis, an intense fetal and AF inflammatory response are likely in patients with preterm labor: clinical implications. J Matern Fetal Neonatal Med 2013;26:847-853.
52.
Holst RM, Laurini R, Jacobsson B, Samuelsson E, Savman K, et al: Expression of cytokines and chemokines in cervical and amniotic fluid: relationship to histological chorioamnionitis. J Matern Fetal Neonatal Med 2007;20:885-893.
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