Background We have previously shown in two independent cohorts that circulating first trimester Macrophage Inhibitory Cytokine-1 (MIC-1) levels are lower in women in early pregnancy who are destined to miscarriage. While promising, the diagnostic performance of measuring MIC-1 alone was not sufficient for it to be a useful predictive test for miscarriage. Besides MIC-1, there are other cytokines, as well as chemokines, involved in facilitating early pregnancy. We reasoned that screening these factors in maternal plasma could uncover other predictive markers of miscarriage. Methods This was a nested case control study, of 78 women from a prospective study of 462 attending the Early Pregnancy Assessment Unit in the first trimester (EPAU) with a threatened miscarriage; 34 of these subsequently miscarried (cases) and 44 went on to have a normal delivery (controls) Cytokines IL-1β, IL-6 and IL-10, and the chemokines, CXCL8, CCL2, CCL5, CCL7 and CX3CL1 were measured in plasma from our cohort. Results The cytokines IL-1β, IL-6, IL-10 and the chemokine CXCL8 were not detectable in first trimester plasma. The chemokines CCL2, CCL5, CCL7 and CX3CL1 were detectable in all samples but levels did not vary across 5–12 weeks of gestation among controls. Plasma levels of these chemokines were no different in the miscarriage cohort compared to controls. Conclusion The chemokines CCL2, CCL5, CCL7 and CX3CL1 were detectable in plasma during the first trimester while IL-1β, IL-6, IL-10 and CXCL8 were not. However, none of the cytokines and chemokines screened were different in maternal plasma in cases or controls. These therefore do not appear to have potential for application as predictive biomarkers of miscarriage.
References
[1]
Jauniaux E, Poston L, Burton GJ (2006) Placental-related diseases of pregnancy: Involvement of oxidative stress and implications in human evolution. Hum Reprod Update 12: 747–755. doi: 10.1093/humupd/dml016
[2]
Tong S, Marjono B, Brown DA, Mulvey S, Breit SN, et al. (2004) Serum concentrations of macrophage inhibitory cytokine 1 (MIC 1) as a predictor of miscarriage. Lancet 363: 129–130. doi: 10.1016/s0140-6736(03)15265-8
[3]
Tong S, Ngian GL, Onwude JL, Permezel M, Saglam B, et al. (2012) Diagnostic accuracy of maternal serum macrophage inhibitory cytokine-1 and pregnancy-associated plasma protein-A at 6–10 weeks of gestation to predict miscarriage. Obstet Gynecol 119: 1000–1008. doi: 10.1097/aog.0b013e3182518fd3
[4]
Kaitu’u-Lino TJ, Tuohey L, Tong S (2012) Maternal serum interleukin-33 and soluble ST2 across early pregnancy, and their association with miscarriage. J Reprod Immunol 95: 46–49. doi: 10.1016/j.jri.2012.06.003
[5]
Kaitu’u-Lino TJ, Bambang K, Onwude J, Hiscock R, Konje J, et al. (2013) Plasma MIC-1 and PAPP-A Levels Are Decreased among Women Presenting to an Early Pregnancy Assessment Unit, Have Fetal Viability Confirmed but Later Miscarry. PLoS One 8: e72437. doi: 10.1371/journal.pone.0072437
[6]
Johns J, Muttukrishna S, Lygnos M, Groome N, Jauniaux E (2007) Maternal serum hormone concentrations for prediction of adverse outcome in threatened miscarriage. Reprod Biomed Online 15: 413–421. doi: 10.1016/s1472-6483(10)60367-7
[7]
Marjono AB, Brown DA, Horton KE, Wallace EM, Breit SN, et al. (2003) Macrophage inhibitory cytokine-1 in gestational tissues and maternal serum in normal and pre-eclamptic pregnancy. Placenta 24: 100–106. doi: 10.1053/plac.2002.0881
[8]
Muttukrishna S, Swer M, Suri S, Jamil A, Calleja-Agius J, et al. (2011) Soluble Flt-1 and PlGF: new markers of early pregnancy loss? PLoS One 6: e18041. doi: 10.1371/journal.pone.0018041
[9]
Hannan NJ, Jones RL, Critchley HO, Kovacs GJ, Rogers PA, et al. (2004) Coexpression of fractalkine and its receptor in normal human endometrium and in endometrium from users of progestin-only contraception supports a role for fractalkine in leukocyte recruitment and endometrial remodeling. J Clin Endocrinol Metab 89: 6119–6129. doi: 10.1210/jc.2003-031379
[10]
Jones RL, Hannan NJ, Kaitu’u TJ, Zhang J, Salamonsen LA (2004) Identification of chemokines important for leukocyte recruitment to the human endometrium at the times of embryo implantation and menstruation. J Clin Endocrinol Metab 89: 6155–6167. doi: 10.1210/jc.2004-0507
[11]
Hannan NJ, Jones RL, White CA, Salamonsen LA (2006) The chemokines, CX3CL1, CCL14, and CCL4, promote human trophoblast migration at the feto-maternal interface. Biol Reprod 74: 896–904. doi: 10.1095/biolreprod.105.045518
[12]
Red-Horse K, Drake PM, Gunn MD, Fisher SJ (2001) Chemokine ligand and receptor expression in the pregnant uterus: reciprocal patterns in complementary cell subsets suggest functional roles. Am J Pathol 159: 2199–2213. doi: 10.1016/s0002-9440(10)63071-4
[13]
Hannan NJ, Salamonsen LA (2008) CX3CL1 and CCL14 regulate extracellular matrix and adhesion molecules in the trophoblast: potential roles in human embryo implantation. Biol Reprod 79: 58–65. doi: 10.1095/biolreprod.107.066480
[14]
Chaouat G, Ledee-Bataille N, Dubanchet S, Zourbas S, Sandra O, et al. (2004) TH1/TH2 paradigm in pregnancy: paradigm lost? Cytokines in pregnancy/early abortion: reexamining the TH1/TH2 paradigm. Int Arch Allergy Immunol 134: 93–119. doi: 10.1159/000074300
[15]
Lim KJ, Odukoya OA, Ajjan RA, Li TC, Weetman AP, et al. (2000) The role of T-helper cytokines in human reproduction. Fertil Steril 73: 136–142. doi: 10.1016/s0015-0282(99)00457-4
[16]
Dimitriadis E, Stoikos C, Stafford-Bell M, Clark I, Paiva P, et al. (2006) Interleukin-11, IL-11 receptoralpha and leukemia inhibitory factor are dysregulated in endometrium of infertile women with endometriosis during the implantation window. J Reprod Immunol 69: 53–64. doi: 10.1016/j.jri.2005.07.004
[17]
Jasper MJ, Tremellen KP, Robertson SA (2007) Reduced expression of IL-6 and IL-1alpha mRNAs in secretory phase endometrium of women with recurrent miscarriage. J Reprod Immunol 73: 74–84. doi: 10.1016/j.jri.2006.06.003
[18]
Laird SM, Tuckerman EM, Li TC (2006) Cytokine expression in the endometrium of women with implantation failure and recurrent miscarriage. Reprod Biomed Online 13: 13–23. doi: 10.1016/s1472-6483(10)62011-1
[19]
Salamonsen LA, Hannan NJ, Dimitriadis E (2007) Cytokines and chemokines during human embryo implantation: roles in implantation and early placentation. Semin Reprod Med 25: 437–444. doi: 10.1055/s-2007-991041
[20]
Hampton AL, Rogers PA, Affandi B, Salamonsen LA (2001) Expression of the chemokines, monocyte chemotactic protein (MCP)-1 and MCP-2 in endometrium of normal women and Norplant users, does not support a central role in macrophage infiltration into endometrium. J Reprod Immunol 49: 115–132. doi: 10.1016/s0165-0378(00)00082-6
[21]
Galazios G, Tsoulou S, Zografou C, Tripsianis G, Koutlaki N, et al. (2011) The role of cytokines IL-6 and IL-8 in the pathogenesis of spontaneous abortions. J Matern Fetal Neonatal Med 24: 1283–1285. doi: 10.3109/14767058.2011.575482
[22]
Hefler LA, Tempfer CB, Unfried G, Schneeberger C, Lessl K, et al. (2001) A polymorphism of the interleukin-1beta gene and idiopathic recurrent miscarriage. Fertil Steril 76: 377–379. doi: 10.1016/s0015-0282(01)01914-8
[23]
Calleja-Agius J, Jauniaux E, Muttukrishna S (2012) Inflammatory cytokines in maternal circulation and placenta of chromosomally abnormal first trimester miscarriages. Clin Dev Immunol 2012: 175041. doi: 10.1155/2012/175041
[24]
Coomarasamy A, Truchanowicz EG, Rai R (2011) Does first trimester progesterone prophylaxis increase the live birth rate in women with unexplained recurrent miscarriages BMJ 342: d1914. doi: 10.1136/bmj.d1914
[25]
Rumbold A, Middleton P, Pan N, Crowther CA (2011) Vitamin supplementation for preventing miscarriage. Cochrane Database Syst Rev: CD004073.
[26]
Hannan NJ, Evans J, Salamonsen LA (2011) Alternate roles for immune regulators: establishing endometrial receptivity for implantation. Expert Rev Clin Immunol 7: 789–802. doi: 10.1586/eci.11.65
[27]
Hannan NJ, Salamonsen LA (2007) Role of chemokines in the endometrium and in embryo implantation. Curr Opin Obstet Gynecol 19: 266–272. doi: 10.1097/gco.0b013e328133885f
[28]
Tabibzadeh S, Sun XZ (1992) Cytokine expression in human endometrium throughout the menstrual cycle. Hum Reprod 7: 1214–1221.
[29]
von Wolff M, Thaler CJ, Zepf C, Becker V, Beier HM, et al. (2002) Endometrial expression and secretion of interleukin-6 throughout the menstrual cycle. Gynecol Endocrinol 16: 121–129. doi: 10.1080/gye.16.2.121.129
[30]
Wegmann TG, Lin H, Guilbert L, Mosmann TR (1993) Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon? Immunol Today 14: 353–356. doi: 10.1016/0167-5699(93)90235-d
[31]
Hanna J, Wald O, Goldman-Wohl D, Prus D, Markel G, et al. (2003) CXCL12 expression by invasive trophoblasts induces the specific migration of CD16- human natural killer cells. Blood 102: 1569–1577. doi: 10.1182/blood-2003-02-0517
[32]
Zhang J, Lathbury LJ, Salamonsen LA (2000) Expression of the chemokine eotaxin and its receptor, CCR3, in human endometrium. Biol Reprod 62: 404–411. doi: 10.1095/biolreprod62.2.404
[33]
Sato Y, Higuchi T, Yoshioka S, Tatsumi K, Fujiwara H, et al. (2003) Trophoblasts acquire a chemokine receptor, CCR1, as they differentiate towards invasive phenotype. Development 130: 5519–5532. doi: 10.1242/dev.00729
[34]
Segerer SE, Rieger L, Kapp M, Dombrowski Y, Muller N, et al. (2012) MIC-1 (a multifunctional modulator of dendritic cell phenotype and function) is produced by decidual stromal cells and trophoblasts. Hum Reprod 27: 200–209. doi: 10.1093/humrep/der358
[35]
Arslan E, Colakoglu M, Celik C, Gezginc K, Acar A, et al. (2004) Serum TNF-alpha, IL-6, lupus anticoagulant and anticardiolipin antibody in women with and without a past history of recurrent miscarriage. Arch Gynecol Obstet 270: 227–229. doi: 10.1007/s00404-003-0547-0
[36]
Koumantaki Y, Matalliotakis I, Sifakis S, Kyriakou D, Neonaki M, et al. (2001) Detection of interleukin-6, interleukin-8, and interleukin-11 in plasma from women with spontaneous abortion. Eur J Obstet Gynecol Reprod Biol 98: 66–71. doi: 10.1016/s0301-2115(01)00289-5
[37]
Zenclussen AC, Fest S, Busse P, Joachim R, Klapp BF, et al. (2002) Questioning the Th1/Th2 paradigm in reproduction: peripheral levels of IL-12 are down-regulated in miscarriage patients. Am J Reprod Immunol 48: 245–251. doi: 10.1034/j.1600-0897.2002.01136.x
[38]
Bates MD, Quenby S, Takakuwa K, Johnson PM, Vince GS (2002) Aberrant cytokine production by peripheral blood mononuclear cells in recurrent pregnancy loss? Hum Reprod 17: 2439–2444. doi: 10.1093/humrep/17.9.2439
[39]
Kauma S, Matt D, Strom S, Eierman D, Turner T (1990) Interleukin-1 beta, human leukocyte antigen HLA-DR alpha, and transforming growth factor-beta expression in endometrium, placenta, and placental membranes. Am J Obstet Gynecol 163: 1430–1437. doi: 10.1016/0002-9378(90)90601-3
