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Dynamic changes in maternal immune biomarkers during labor in nulliparous vs multiparous women

      Background

      Immunomodulation is observed in human parturition. However, data from longitudinal studies for the prelabor phase and the active phase of labor are lacking, and no study had compared the immune responses during labor between nulliparous and multiparous women.

      Objective

      This study aimed to investigate the temporal changes of immune biomarkers in maternal blood from the prelabor phase to the latent and active phases of labor and to compare the dynamic changes between nulliparous and multiparous women.

      Study Design

      A prospective case-control study was conducted on women who had induction of labor at term followed by vaginal delivery. Maternal blood was serially collected at 3 consecutive time points: (1) before the onset of labor, (2) during the latent phase of labor, and (3) during the active phase of labor. Peripheral immune cells were measured by 4-color flow cytometry, and the plasma concentrations of cytokines and chemokines were measured by cytometric bead arrays. A longitudinal comparison was made to assess the dynamic changes in inflammatory parameters over 3 time points in nulliparous and multiparous women, respectively, and a cross-sectional comparison was made between nulliparous and multiparous women.

      Results

      A total of 40 women, including 20 nulliparous and 20 multiparous, were included in the study. Prelabor circulating levels of macrophage inflammatory protein-1β, monokine induced by gamma interferon, and interferon gamma-induced protein-10 were higher in multiparous women than in nulliparous women. In the latent phase of labor, the innate immune system in both groups responded with increases in neutrophils and interleukin 6, and the nulliparous women showed a more pronounced response. During the active phase of labor, such innate immune response continued with both groups, with additional increases in natural killer cells, monocyte chemoattractant protein-1, interleukin 8, and interleukin 10. Conversely, the adaptive immune system in nulliparous women showed a reduction in both cytotoxic and helper T cells, whereas the adaptive immune system in multiparous women only had a reduction in helper T cells, showing a smaller reduction.

      Conclusion

      Innate and adaptive immune responses partake in immunomodulation during human parturition. Nulliparous and multiparous women showed different responses in their blood levels of immune cells and biomarkers during the different phases of labor.

      Key words

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      References

        • Mitchell M.D.
        • Goodwin V.
        • Mesnage S.
        • Keelan J.A.
        Cytokine-induced coordinate expression of enzymes of prostaglandin biosynthesis and metabolism: 15-hydroxyprostaglandin dehydrogenase.
        Prostaglandins Leukot Essent Fatty Acids. 2000; 62: 1-5
        • Kumar D.
        • Fung W.
        • Moore R.M.
        • et al.
        Proinflammatory cytokines found in amniotic fluid induce collagen remodeling, apoptosis, and biophysical weakening of cultured human fetal membranes.
        Biol Reprod. 2006; 74: 29-34
        • Tribe R.M.
        • Moriarty P.
        • Dalrymple A.
        • Hassoni A.A.
        • Poston L.
        Interleukin-1beta induces calcium transients and enhances basal and store operated calcium entry in human myometrial smooth muscle.
        Biol Reprod. 2003; 68: 1842-1849
        • Roh C.R.
        • Oh W.J.
        • Yoon B.K.
        • Lee J.H.
        Up-regulation of matrix metalloproteinase-9 in human myometrium during labour: a cytokine-mediated process in uterine smooth muscle cells.
        Mol Hum Reprod. 2000; 6: 96-102
        • Rinaldi S.F.
        • Makieva S.
        • Saunders P.T.
        • Rossi A.G.
        • Norman J.E.
        Immune cell and transcriptomic analysis of the human decidua in term and preterm parturition.
        Mol Hum Reprod. 2017; 23: 708-724
        • Hamilton S.
        • Oomomian Y.
        • Stephen G.
        • et al.
        Macrophages infiltrate the human and rat decidua during term and preterm labor: evidence that decidual inflammation precedes labor.
        Biol Reprod. 2012; 86: 39
        • Gomez-Lopez N.
        • Vega-Sanchez R.
        • Castillo-Castrejon M.
        • Romero R.
        • Cubeiro-Arreola K.
        • Vadillo-Ortega F.
        Evidence for a role for the adaptive immune response in human term parturition.
        Am J Reprod Immunol. 2013; 69: 212-230
        • Ding W.
        • Chim S.S.C.
        • Wang C.C.
        • Lau C.S.L.
        • Leung T.Y.
        Molecular mechanism and pathways of normal human parturition in different gestational tissues: a systematic review of transcriptome studies.
        Front Physiol. 2021; 12: 730030
        • Osman I.
        • Young A.
        • Ledingham M.A.
        • et al.
        Leukocyte density and pro-inflammatory cytokine expression in human fetal membranes, decidua, cervix and myometrium before and during labour at term.
        Mol Hum Reprod. 2003; 9: 41-45
        • Young A.
        • Thomson A.J.
        • Ledingham M.
        • Jordan F.
        • Greer I.A.
        • Norman J.E.
        Immunolocalization of proinflammatory cytokines in myometrium, cervix, and fetal membranes during human parturition at term.
        Biol Reprod. 2002; 66: 445-449
        • Osmers R.G.
        • Bläser J.
        • Kuhn W.
        • Tschesche H.
        Interleukin-8 synthesis and the onset of labor.
        Obstet Gynecol. 1995; 86: 223-229
        • Hebisch G.
        • Grauaug A.A.
        • Neumaier-Wagner P.M.
        • Stallmach T.
        • Huch A.
        • Huch R.
        The relationship between cervical dilatation, interleukin-6 and interleukin-8 during term labor.
        Acta Obstet Gynecol Scand. 2001; 80: 840-848
        • Yuan M.
        • Jordan F.
        • McInnes I.B.
        • Harnett M.M.
        • Norman J.E.
        Leukocytes are primed in peripheral blood for activation during term and preterm labour.
        Mol Hum Reprod. 2009; 15: 713-724
        • Saftlas A.F.
        • Levine R.J.
        • Klebanoff M.A.
        • et al.
        Abortion, changed paternity, and risk of preeclampsia in nulliparous women.
        Am J Epidemiol. 2003; 157: 1108-1114
        • Eras J.L.
        • Saftlas A.F.
        • Triche E.
        • Hsu C.D.
        • Risch H.A.
        • Bracken M.B.
        Abortion and its effect on risk of preeclampsia and transient hypertension.
        Epidemiology. 2000; 11: 36-43
        • Trowsdale J.
        • Betz A.G.
        Mother’s little helpers: mechanisms of maternal-fetal tolerance.
        Nat Immunol. 2006; 7: 241-246
        • Redman C.W.
        • Sargent I.L.
        Immunology of pre-eclampsia.
        Am J Reprod Immunol. 2010; 63: 534-543
        • Lu J.
        • Cheng Y.K.Y.
        • Ho S.Y.S.
        • et al.
        The predictive value of cervical shear wave elastography in the outcome of labor induction.
        Acta Obstet Gynecol Scand. 2020; 99: 59-68
        • Cheng Y.K.
        • Lao T.T.
        • Sahota D.S.
        • Leung V.K.
        • Leung T.Y.
        Use of birth weight threshold for macrosomia to identify fetuses at risk of shoulder dystocia among Chinese populations.
        Int J Gynaecol Obstet. 2013; 120: 249-253
        • Chen K.
        • Satlof L.
        • Stoffels G.
        • et al.
        Cytokine secretion in breast cancer cells - MilliPlex assay data.
        Data Brief. 2020; 28: 104798
        • Neal J.L.
        • Lamp J.M.
        • Lowe N.K.
        • Gillespie S.L.
        • Sinnott L.T.
        • McCarthy D.O.
        Differences in inflammatory markers between nulliparous women admitted to hospitals in preactive vs active labor.
        Am J Obstet Gynecol. 2015; 212: 68.e1-68.e8
        • Ferguson K.K.
        • McElrath T.F.
        • Chen Y.H.
        • Mukherjee B.
        • Meeker J.D.
        Longitudinal profiling of inflammatory cytokines and C-reactive protein during uncomplicated and preterm pregnancy.
        Am J Reprod Immunol. 2014; 72: 326-336
        • Bakdash J.Z.
        • Marusich L.R.
        Repeated measures correlation.
        Front Psychol. 2017; 8: 456
        • Hassan S.S.
        • Romero R.
        • Tarca A.L.
        • et al.
        The transcriptome of cervical ripening in human pregnancy before the onset of labor at term: identification of novel molecular functions involved in this process.
        J Matern Fetal Neonatal Med. 2009; 22: 1183-1193
        • Winkler M.
        • Kemp B.
        • Fischer D.C.
        • Ruck P.
        • Rath W.
        Expression of adhesion molecules in the lower uterine segment during term and preterm parturition.
        Microsc Res Tech. 2003; 60: 430-444
        • Singh S.
        • Anshita D.
        • Ravichandiran V.
        MCP-1: function, regulation, and involvement in disease.
        Int Immunopharmacol. 2021; 101: 107598
        • Menten P.
        • Wuyts A.
        • Van Damme J.
        Macrophage inflammatory protein-1.
        Cytokine Growth Factor Rev. 2002; 13: 455-481
        • Gomez-Lopez N.
        • Estrada-Gutierrez G.
        • Jimenez-Zamudio L.
        • Vega-Sanchez R.
        • Vadillo-Ortega F.
        Fetal membranes exhibit selective leukocyte chemotaxic activity during human labor.
        J Reprod Immunol. 2009; 80: 122-131
        • Vaddi K.
        • Newton R.C.
        Regulation of monocyte integrin expression by beta-family chemokines.
        J Immunol. 1994; 153: 4721-4732
        • Weber C.
        • Alon R.
        • Moser B.
        • Springer T.A.
        Sequential regulation of alpha 4 beta 1 and alpha 5 beta 1 integrin avidity by CC chemokines in monocytes: implications for transendothelial chemotaxis.
        J Cell Biol. 1996; 134: 1063-1073
        • Holst R.M.
        • Hagberg H.
        • Wennerholm U.B.
        • Skogstrand K.
        • Thorsen P.
        • Jacobsson B.
        Prediction of spontaneous preterm delivery in women with preterm labor: analysis of multiple proteins in amniotic and cervical fluids.
        Obstet Gynecol. 2009; 114: 268-277
        • Romagnani P.
        • Crescioli C.
        CXCL10: a candidate biomarker in transplantation.
        Clin Chim Acta. 2012; 413: 1364-1373
        • Athanassakis I.
        Analysis of the IFN-gamma-induced signal transduction pathway in fetal rejection.
        Mediators Inflamm. 1995; 4: 209-216
        • Romero R.
        • Whitten A.
        • Korzeniewski S.J.
        • et al.
        Maternal floor infarction/massive perivillous fibrin deposition: a manifestation of maternal antifetal rejection?.
        Am J Reprod Immunol. 2013; 70: 285-298
        • Lee J.
        • Romero R.
        • Xu Y.
        • et al.
        Detection of anti-HLA antibodies in maternal blood in the second trimester to identify patients at risk of antibody-mediated maternal anti-fetal rejection and spontaneous preterm delivery.
        Am J Reprod Immunol. 2013; 70: 162-175
        • Romero R.
        • Chaemsaithong P.
        • Chaiyasit N.
        • et al.
        CXCL10 and IL-6: markers of two different forms of intra-amniotic inflammation in preterm labor.
        Am J Reprod Immunol. 2017; 78e12685
        • Almanzar G.
        • Schönlaub J.
        • Hammerer-Lercher A.
        • Koppelstaetter C.
        • Bernhard D.
        • Prelog M.
        Influence of the delivery modus on subpopulations and replication of lymphocytes in mothers and newborns.
        Early Hum Dev. 2015; 91: 663-670
        • Helmig B.R.
        • Romero R.
        • Espinoza J.
        • et al.
        Neutrophil elastase and secretory leukocyte protease inhibitor in prelabor rupture of membranes, parturition and intra-amniotic infection.
        J Matern Fetal Neonatal Med. 2002; 12: 237-246
        • Maymon E.
        • Romero R.
        • Pacora P.
        • et al.
        Human neutrophil collagenase (matrix metalloproteinase 8) in parturition, premature rupture of the membranes, and intrauterine infection.
        Am J Obstet Gynecol. 2000; 183: 94-99
        • Tecchio C.
        • Micheletti A.
        • Cassatella M.A.
        Neutrophil-derived cytokines: facts beyond expression.
        Front Immunol. 2014; 5: 508
        • McLoughlin R.M.
        • Hurst S.M.
        • Nowell M.A.
        • et al.
        Differential regulation of neutrophil-activating chemokines by IL-6 and its soluble receptor isoforms.
        J Immunol. 2004; 172: 5676-5683
        • Mitchell M.D.
        • Dudley D.J.
        • Edwin S.S.
        • Schiller S.L.
        Interleukin-6 stimulates prostaglandin production by human amnion and decidual cells.
        Eur J Pharmacol. 1991; 192: 189-191
        • Rauk P.N.
        • Friebe-Hoffmann U.
        • Winebrenner L.D.
        • Chiao J.P.
        Interleukin-6 up-regulates the oxytocin receptor in cultured uterine smooth muscle cells.
        Am J Reprod Immunol. 2001; 45: 148-153
        • Meisser A.
        • Cameo P.
        • Islami D.
        • Campana A.
        • Bischof P.
        Effects of interleukin-6 (IL-6) on cytotrophoblastic cells.
        Mol Hum Reprod. 1999; 5: 1055-1058
        • Guerrero B.
        • Hassouneh F.
        • Delgado E.
        • Casado J.G.
        • Tarazona R.
        Natural killer cells in recurrent miscarriage: an overview.
        J Reprod Immunol. 2020; 142: 103209
        • Zhao Y.
        • Chen X.
        • Zhang T.
        • et al.
        The use of multiplex staining to measure the density and clustering of four endometrial immune cells around the implantation period in women with recurrent miscarriage: comparison with fertile controls.
        J Mol Histol. 2020; 51: 593-603
        • Chen X.
        • Zhang T.
        • Liu Y.
        • et al.
        Uterine CD56+ cell density and euploid miscarriage in women with a history of recurrent miscarriage: a clinical descriptive study.
        Eur J Immunol. 2021; 51: 487-489
        • Edsparr K.
        • Johansson B.R.
        • Goldfarb R.H.
        • et al.
        Human NK cell lines migrate differentially in vitro related to matrix interaction and MMP expression.
        Immunol Cell Biol. 2009; 87: 489-495
        • Hanna J.
        • Goldman-Wohl D.
        • Hamani Y.
        • et al.
        Decidual NK cells regulate key developmental processes at the human fetal-maternal interface.
        Nat Med. 2006; 12: 1065-1074
        • Ghaebi M.
        • Abdolmohammadi-Vahid S.
        • Ahmadi M.
        • et al.
        T cell subsets in peripheral blood of women with recurrent implantation failure.
        J Reprod Immunol. 2019; 131: 21-29
        • Karin N.
        • Razon H.
        Chemokines beyond chemo-attraction: CXCL10 and its significant role in cancer and autoimmunity.
        Cytokine. 2018; 109: 24-28
        • Ronzoni S.
        • Steckle V.
        • D’Souza R.
        • Murphy K.E.
        • Lye S.
        • Shynlova O.
        Cytokine changes in maternal peripheral blood correlate With time-to-delivery in pregnancies complicated by premature prelabor rupture of the membranes.
        Reprod Sci. 2019; 26: 1266-1276
        • Hamilton S.A.
        • Tower C.L.
        • Jones R.L.
        Identification of chemokines associated with the recruitment of decidual leukocytes in human labour: potential novel targets for preterm labour.
        PLoS One. 2013; 8e56946
        • Esplin M.S.
        • Romero R.
        • Chaiworapongsa T.
        • et al.
        Amniotic fluid levels of immunoreactive monocyte chemotactic protein-1 increase during term parturition.
        J Matern Fetal Neonatal Med. 2003; 14: 51-56
        • Dudley D.J.
        • Hunter C.
        • Mitchell M.D.
        • Varner M.W.
        Elevations of amniotic fluid macrophage inflammatory protein-1 alpha concentrations in women during term and preterm labor.
        Obstet Gynecol. 1996; 87: 94-98
        • Zhao Y.
        • Koga K.
        • Osuga Y.
        • et al.
        Cyclic stretch augments production of neutrophil chemokines and matrix metalloproteinase-1 in human uterine smooth muscle cells.
        Am J Reprod Immunol. 2013; 69: 240-247
        • Metzemaekers M.
        • Vandendriessche S.
        • Berghmans N.
        • Gouwy M.
        • Proost P.
        Truncation of CXCL8 to CXCL8(9-77) enhances actin polymerization and in vivo migration of neutrophils.
        J Leukoc Biol. 2020; 107: 1167-1173
        • Djeu J.Y.
        • Matsushima K.
        • Oppenheim J.J.
        • Shiotsuki K.
        • Blanchard D.K.
        Functional activation of human neutrophils by recombinant monocyte-derived neutrophil chemotactic factor/IL-8.
        J Immunol. 1990; 144: 2205-2210
        • Robertson S.A.
        • Skinner R.J.
        • Care A.S.
        Essential role for IL-10 in resistance to lipopolysaccharide-induced preterm labor in mice.
        J Immunol. 2006; 177: 4888-4896
        • Moore K.W.
        • de Waal Malefyt R.
        • Coffman R.L.
        • O’Garra A.
        Interleukin-10 and the interleukin-10 receptor.
        Annu Rev Immunol. 2001; 19: 683-765
        • Chatterjee P.
        • Chiasson V.L.
        • Bounds K.R.
        • Mitchell B.M.
        Regulation of the anti-inflammatory cytokines interleukin-4 and interleukin-10 during pregnancy.
        Front Immunol. 2014; 5: 253
        • Menon R.
        • Bonney E.A.
        • Condon J.
        • Mesiano S.
        • Taylor R.N.
        Novel concepts on pregnancy clocks and alarms: redundancy and synergy in human parturition.
        Hum Reprod Update. 2016; 22: 535-560
        • Netea M.G.
        • Schlitzer A.
        • Placek K.
        • Joosten L.A.B.
        • Schultze J.L.
        Innate and adaptive immune memory: an evolutionary continuum in the host’s response to pathogens.
        Cell Host Microbe. 2019; 25: 13-26
        • Qin C.
        • Zhou L.
        • Hu Z.
        • et al.
        Dysregulation of immune response in patients with coronavirus 2019 (COVID-19) in Wuhan, China.
        Clin Infect Dis. 2020; 71: 762-768
        • Curbelo J.
        • Luquero Bueno S.
        • Galván-Román J.M.
        • et al.
        Inflammation biomarkers in blood as mortality predictors in community-acquired pneumonia admitted patients: importance of comparison with neutrophil count percentage or neutrophil-lymphocyte ratio.
        PLoS One. 2017; 12e0173947
        • Agard M.
        • Asakrah S.
        • Morici L.A.
        PGE(2) suppression of innate immunity during mucosal bacterial infection.
        Front Cell Infect Microbiol. 2013; 3: 45
        • Clodi M.
        • Vila G.
        • Geyeregger R.
        • et al.
        Oxytocin alleviates the neuroendocrine and cytokine response to bacterial endotoxin in healthy men.
        Am J Physiol Endocrinol Metab. 2008; 295: E686-E691
        • El-Shazly S.
        • Makhseed M.
        • Azizieh F.
        • Raghupathy R.
        Increased expression of pro-inflammatory cytokines in placentas of women undergoing spontaneous preterm delivery or premature rupture of membranes.
        Am J Reprod Immunol. 2004; 52: 45-52
        • Raghupathy R.
        • Al-Azemi M.
        • Azizieh F.
        Intrauterine growth restriction: cytokine profiles of trophoblast antigen-stimulated maternal lymphocytes.
        Clin Dev Immunol. 2012; 2012: 734865