Inflammatory Proteins in the Amniotic Fluid, Plasma, and Cervicovaginal Fluid for the Prediction of Intra-Amniotic Infection/Inflammation and Imminent Preterm Birth in Preterm Labor

Abstract

Objective This study was aimed to develop models using multiple cytokine/chemokine levels in cervicovaginal fluid (CVF) and plasma and widely used noninvasive parameters that have better accuracy for predicting intra-amniotic infection and/or inflammation (IAI) and imminent spontaneous preterm delivery (SPTD, ≤48 hours) in women with preterm labor (PTL). Study Design This was a retrospective cohort study of 95 singleton pregnant women with PTL (23–34 weeks) who underwent amniocentesis. Both CVF and plasma samples were obtained at the time of amniocentesis, and serum C-reactive protein (CRP) levels were measured. The amniotic fluid (AF), CVF, and plasma samples were assayed for interleukin (IL)-6, IL-8, IL-10, monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein-1β (MIP-1β) levels using a multiplex immunoassay kit. Results The levels of most cytokines/chemokines measured in the AF and CVF were significantly higher in the women with than in those without IAI and imminent SPTD, whereas only high-plasma IL-10 level showed a significant association with imminent SPTD. In predicting IAI, proteins in AF had significantly higher areas under the curves (AUCs) than those in CVF and plasma. However, for predicting imminent SPTD, no significant differences in the AUCs of the outcome-associated proteins were observed among the measurements in AF, CVF, and maternal plasma. By using stepwise regression analyses, noninvasive models (using protein levels in CVF and baseline clinical parameters) were developed for the prediction of IAI and imminent SPTD. The AUC of these noninvasive models were similar to those of the invasive models (using AF protein levels and baseline clinical parameters). Conclusion Noninvasive models based on CVF cytokine/chemokine levels and widely used noninvasive parameters (especially CRP) act as good indicators for predicting the risk of IAI and imminent SPTD in women with PTL. Evaluation of cytokine/chemokine levels in plasma samples did not add valuable information regarding the two outcome measures in the PTL setting. Key Points

Breaking Down the Barrier: The Role of Cervical Infection and Inflammation in Preterm Birth

“…The PTB risk was low when the Lactobacillus iners ratio was high. A moderate and high risk was classified when the L. iners ratio was low, and the U. parvum ratio was high ( 55 ).…”

The Role of Innate Immune System in the Human Amniotic Membrane and Human Amniotic Fluid in Protection Against Intra-Amniotic Infections and Inflammation

“…Presence of IL-6, IL-1b, IL-10, IL-18, TNFa, macrophage migration inhibitory factor, nicotinamide phosphoribosyltransferase, TGFb, granulocyte-macrophage colony-stimulating factor, high-mobility group protein 1, IL-10 and IL-6 in the hAF with IAI or preterm labor conditions (118,121,128,129,(140)(141)(142)(143)(144)(145)(146)(147)(148)(149)(150)(151)(152)(153)).…”

“…The intra-amniotic infection leads to an increased level of cytokines and chemokines IL-1b, IL-6, IL-8, TNFa, IFNg, EGF, MIP3a, MIP1a, Eotaxin, IL-16, IL-8, monocyte chemoattractant protein-1, chemokine (C-X-C motif) ligands (CXCLs)-1, -3, -4, -5, -6, -10, -11 and L-selectin (128,146,147,(154)(155)(156)(157)(158)(159). 102) have seen an increase in total levels of MMP-2 and in catalitically active levels of MMP-2 (tissue inhibitor of metalloproteinases (TIMP)-free MMP2) in the hAF samples, while Flores-Herrera et al (99) used an in vitro model of infected amnio-chorionic membrane and did not observe an increase in the secretion of proMMP-2.…”

“…In fact, the IL-6 is considered as an important biomarker of IAI (241)(242)(243) and an increased presence of IL-6 (>2.6 ng/ml) in the hAF is used to define inflammation (244). Moreover, chemokines IL-16, IL-8, IP-10, monocyte chemoattractant protein-1, chemokine (C-X-C motif) ligands (CXCLs)-1, -3, -4, -5, -6, -11, and L-selectin have also been upregulated with IAI and related in vitro models (128,146,147,(154)(155)(156)(157)(158)(159). Two comprehensive studies by Bhatti et al (152) and Romero et al (140) further reveal the plethora of IAIinduced cytokines in the hAF (140,152).…”

“…Numerous studies demonstrated an increase in pro-inflammatory IL-1β, IL18, TNFα, granulocyte-macrophage colony-stimulating factor, macrophage migration inhibitory factor, high-mobility group protein 1 ( 118 , 121 , 128 , 129 , 141 – 146 , 201 ), anti-inflammatory IL10, nicotinamide phosphoribosyltransferase ( 128 , 147 , 201 , 241 ),, and regulatory IL-6 ( 128 , 129 , 144 , 146 – 151 , 201 , 241 ) cytokines in the hAF with IAI or preterm labor conditions. In fact, the IL-6 is considered as an important biomarker of IAI ( 241 – 243 ) and an increased presence of IL-6 (>2.6 ng/ml) in the hAF is used to define inflammation ( 244 ).…”