Am J Perinatol 2018; 35(05): 455-462
DOI: 10.1055/s-0037-1608677
Original Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Patterns of Systemic and Cervicovaginal Fluid Inflammatory Cytokines throughout Pregnancy

Kristin B. Ashford
1   Perinatal Research and Wellness Center, University of Kentucky College of Nursing, Lexington, Kentucky
,
Niraj Chavan
2   Obstetrics and Gynecology, Maternal Fetal Medicine, University of Kentucky College of Medicine, Lexington, Kentucky
,
Jeffrey L. Ebersole
3   Center for Oral Health Research, University of Kentucky College of Dentistry, Lexington, Kentucky
,
Amanda T. Wiggins
1   Perinatal Research and Wellness Center, University of Kentucky College of Nursing, Lexington, Kentucky
,
Savita Sharma
1   Perinatal Research and Wellness Center, University of Kentucky College of Nursing, Lexington, Kentucky
,
Andrea McCubbin
1   Perinatal Research and Wellness Center, University of Kentucky College of Nursing, Lexington, Kentucky
,
Janine Barnett
1   Perinatal Research and Wellness Center, University of Kentucky College of Nursing, Lexington, Kentucky
,
John O'Brien
2   Obstetrics and Gynecology, Maternal Fetal Medicine, University of Kentucky College of Medicine, Lexington, Kentucky
› Author Affiliations
Funding Financial support for this research was provided in part by National Institutes for Health Building Interdisciplinary Research Careers in Women's Health (BIRCWH: K12DA14040) to K.B.A.; Center for Biomedical Research Excellence (COBRE: 5P20GM103538) and University of Kentucky Clinical and Translational Research Center KL2RR033171 to J.L.E. The project described was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through grant number UL1TR000117. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Further Information

Publication History

28 March 2017

06 October 2017

Publication Date:
13 November 2017 (online)

Abstract

Objective This study describes the normal variations in serum and cervicovaginal fluid (CVF) cytokine levels throughout pregnancy.

Study Design This multicenter, prospective study examined trimester-specific maternal serum and CVF cytokines (interleukin [IL]-1α, IL-1β, IL-6, IL-8, IL-10, tumor necrosis factor-α, and C-reactive protein [CRP]). A two-factor linear mixed modeling approach compared cytokine distribution, while pairwise comparisons evaluated differences over time.

Results Trimester-specific serum cytokine data were available for 288, 243, and 221 patients, whereas CVF cytokine data were available for 273, 229, and 198 patients. CVF had significantly higher concentrations of IL-1α, IL-1β, IL-6, IL-8, and matrix metalloproteinase-8 (p < 0.001), irrespective of the trimester. At all time points, IL-10 and CRP concentrations were higher in serum than CVF (p < 0.001). Serum IL-10 increased significantly throughout pregnancy (p < 0.001).

Conclusion Differences in cytokine distribution across different biological fluids are evident throughout pregnancy. These findings provide a framework for examining patterns of changes in cytokines throughout pregnancy.

Note

The findings were presented at the 36th Annual Meeting of the Society for Maternal Fetal Medicine: The pregnancy Meeting, Atlanta, GA, February 1–6, 2016.


 
  • References

  • 1 Sykes L, MacIntyre DA, Yap XJ, Ponnampalam S, Teoh TG, Bennett PR. Changes in the Th1:Th2 cytokine bias in pregnancy and the effects of the anti-inflammatory cyclopentenone prostaglandin 15-deoxy-Δ(12,14)-prostaglandin J2. Mediators Inflamm 2012; 2012: 416739
  • 2 Mor G, Cardenas I. The immune system in pregnancy: a unique complexity. Am J Reprod Immunol 2010; 63 (06) 425-433
  • 3 Romero R, Espinoza J, Gonçalves LF, Kusanovic JP, Friel L, Hassan S. The role of inflammation and infection in preterm birth. Semin Reprod Med 2007; 25 (01) 21-39
  • 4 Romero R, Espinoza J, Gonçalves LF, Kusanovic JP, Friel LA, Nien JK. Inflammation in preterm and term labour and delivery. Semin Fetal Neonat Med 2006; 11 (05) 317-326
  • 5 Romero R, Espinoza J, Kusanovic JP. , et al. The preterm parturition syndrome. BJOG 2006; 113 (Suppl. 03) 17-42
  • 6 Paulesu L, Bhattacharjee J, Bechi N, Romagnoli R, Jantra S, Ietta F. Pro-inflammatory cytokines in animal and human gestation. Curr Pharm Des 2010; 16 (32) 3601-3615
  • 7 Moorman NJ, Cristea IM, Terhune SS, Rout MP, Chait BT, Shenk T. Human cytomegalovirus protein UL38 inhibits host cell stress responses by antagonizing the tuberous sclerosis protein complex. Cell Host Microbe 2008; 3 (04) 253-262
  • 8 Graham C, Chooniedass R, Stefura WP. , et al; CHILD Study Investigators. In vivo immune signatures of healthy human pregnancy: inherently inflammatory or anti-inflammatory?. PLoS One 2017; 12 (06) e0177813
  • 9 Belo L, Santos-Silva A, Rocha S. , et al. Fluctuations in C-reactive protein concentration and neutrophil activation during normal human pregnancy. Eur J Obstet Gynecol Reprod Biol 2005; 123 (01) 46-51
  • 10 Curry AE, Vogel I, Skogstrand K. , et al. Maternal plasma cytokines in early- and mid-gestation of normal human pregnancy and their association with maternal factors. J Reprod Immunol 2008; 77 (02) 152-160
  • 11 Sharma A, Satyam A, Sharma JB. Leptin, IL-10 and inflammatory markers (TNF-alpha, IL-6 and IL-8) in pre-eclamptic, normotensive pregnant and healthy non-pregnant women. Am J Reprod Immunol 2007; 58 (01) 21-30
  • 12 Kraus TA, Sperling RS, Engel SM. , et al. Peripheral blood cytokine profiling during pregnancy and post-partum periods. Am J Reprod Immunol 2010; 64 (06) 411-426
  • 13 Chatterjee P, Chiasson VL, Bounds KR, Mitchell BM. Regulation of the anti-inflammatory cytokines interleukin-4 and interleukin-10 during pregnancy. Front Immunol 2014; 5: 253
  • 14 Barrera D, Díaz L, Noyola-Martínez N, Halhali A. Vitamin D and inflammatory cytokines in healthy and preeclamptic pregnancies. Nutrients 2015; 7 (08) 6465-6490
  • 15 Mosmann TR, Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today 1996; 17 (03) 138-146
  • 16 O'Garra A, Arai N. The molecular basis of T helper 1 and T helper 2 cell differentiation. Trends Cell Biol 2000; 10 (12) 542-550
  • 17 Wegmann TG, Lin H, Guilbert L, Mosmann TR. Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon?. Immunol Today 1993; 14 (07) 353-356
  • 18 Romero R, Gotsch F, Pineles B, Kusanovic JP. Inflammation in pregnancy: its roles in reproductive physiology, obstetrical complications, and fetal injury. Nutr Rev 2007; 65 (12 Pt 2): S194-S202
  • 19 Robinson DP, Klein SL. Pregnancy and pregnancy-associated hormones alter immune responses and disease pathogenesis. Horm Behav 2012; 62 (03) 263-271
  • 20 Ruiz RJ, Jallo N, Murphey C, Marti CN, Godbold E, Pickler RH. Second trimester maternal plasma levels of cytokines IL-1Ra, Il-6 and IL-10 and preterm birth. J Perinatol 2012; 32 (07) 483-490
  • 21 Sorokin Y, Romero R, Mele L. , et al. 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 2010; 27 (08) 631-640
  • 22 Paternoster DM, Stella A, Gerace P. , et al. Biochemical markers for the prediction of spontaneous pre-term birth. Int J Gynaecol Obstet 2002; 79 (02) 123-129
  • 23 Chan RL. Biochemical markers of spontaneous preterm birth in asymptomatic women. BioMed Res Int 2014; 2014: 164081
  • 24 Abdelazim IA. Relation between interleukin-6 in the cervicovaginal fluid and subclinical chorioamnionitis in patients with preterm premature rupture of membranes. Asian Pac J Reprod 2013; 2 (01) 38-41
  • 25 Georgiou HM, Thio YS, Russell C. , et al. Association between maternal serum cytokine profiles at 7-10 weeks' gestation and birthweight in small for gestational age infants. Am J Obstet Gynecol 2011; 204 (05) 415.e1-415.e12
  • 26 Heng YJ, Liong S, Permezel M, Rice GE, Di Quinzio MK, Georgiou HM. Human cervicovaginal fluid biomarkers to predict term and preterm labor. Front Physiol 2015; 6: 151
  • 27 Heng YJ, Liong S, Permezel M, Rice GE, Di Quinzio MK, Georgiou HM. The interplay of the interleukin 1 system in pregnancy and labor. Reprod Sci 2014; 21 (01) 122-130
  • 28 Menon R, Fortunato SJ. Infection and the role of inflammation in preterm premature rupture of the membranes. Best Pract Res Clin Obstet Gynaecol 2007; 21 (03) 467-478
  • 29 Romero R, Dey SK, Fisher SJ. Preterm labor: one syndrome, many causes. Science 2014; 345 (6198): 760-765
  • 30 Coussons-Read ME, Okun ML, Nettles CD. Psychosocial stress increases inflammatory markers and alters cytokine production across pregnancy. Brain Behav Immun 2007; 21 (03) 343-350
  • 31 Winkler G, Cseh K, Baranyi E. , et al. Tumor necrosis factor system in insulin resistance in gestational diabetes. Diabetes Res Clin Pract 2002; 56 (02) 93-99
  • 32 Larsson A, Palm M, Hansson LO, Basu S, Axelsson O. Reference values for alpha1-acid glycoprotein, alpha1-antitrypsin, albumin, haptoglobin, C-reactive protein, IgA, IgG and IgM during pregnancy. Acta Obstet Gynecol Scand 2008; 87 (10) 1084-1088
  • 33 Heng YJ, Di Quinzio MK, Liong S, Permezel M, Rice GE, Georgiou HM. Temporal investigation of matrix metalloproteinases and their inhibitors in human cervicovaginal fluid in late pregnancy and labor. Reprod Sci 2012; 19 (01) 55-63
  • 34 Coussons-Read ME, Lobel M, Carey JC. , et al. The occurrence of preterm delivery is linked to pregnancy-specific distress and elevated inflammatory markers across gestation. Brain Behav Immun 2012; 26 (04) 650-659
  • 35 Lockwood CJ, Ghidini A, Wein R, Lapinski R, Casal D, Berkowitz RL. Increased interleukin-6 concentrations in cervical secretions are associated with preterm delivery. Am J Obstet Gynecol 1994; 171 (04) 1097-1102
  • 36 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 (06) 551-557
  • 37 Hatzidaki E, Gourgiotis D, Manoura A. , et al. Interleukin-6 in preterm premature rupture of membranes as an indicator of neonatal outcome. Acta Obstet Gynecol Scand 2005; 84 (07) 632-638