Inflammation and Preterm Birth: A Systematic Review

American Journal of Reproductive Immunology, 2003

Preterm Birth - Mother and Child, 2012

Journal of Leukocyte Biology, 2015

Preterm birth is the leading cause of neonatal morbidity and mortality. Although the underlying causes of pregnancy-associated complication are numerous, it is well established that infection and inflammation represent a highly significant risk factor in preterm birth. However, despite the clinical and public health significance, infectious agents, molecular trigger(s), and immune pathways underlying the pathogenesis of preterm birth remain underdefined and represent a major gap in knowledge. Here, we provide an overview of recent clinical and animal model data focused on the interplay between infection-driven inflammation and induction of preterm birth. Furthermore, here, we highlight the critical gaps in knowledge that warrant future investigations into the interplay between immune responses and induction of preterm birth.

Journal of Reproductive Immunology, 2011

The major cause of spontaneous preterm birth (sPTB) at less than 32 weeks of gestation is intrauterine inflammation as a consequence of colonisation of the gestational membranes by pathogenic microorganisms which trigger activation of the local innate immune system. This results in release of inflammatory mediators, leukocytosis (chorioamnionitis), apoptosis, membrane rupture, cervical ripening and onset of uterine contractions. Recent PCR evidence suggests that in the majority of cases of inflammation-driven preterm birth, microorganisms are present in the amniotic fluid, but these are not always cultured by standard techniques. The nature of the organism and its cell wall constituents, residence time in utero, microbial load, route of infection and extent of tissue penetration are all factors which can modulate the timing and magnitude of the inflammatory response and likelihood of progression to sPTB. Administration of anti-inflammatory drugs could be a viable therapeutic option to prevent sPTB and improve fetal outcomes in women at risk of intrauterine inflammation. Preventing fetal inflammation via administration of placentapermeable drugs could also have significant perinatal benefits in addition to those related to extension of gestational age, as a fetal inflammatory response is associated with a range of significant morbidities. A number of potential drugs are available, effective against different aspects of the inflammatory process, although the pathways actually activated in spontaneous preterm labour have yet to be confirmed. Several pharmacological candidates are discussed, together with clinical and toxicological considerations associated with administration of anti-inflammatory agents in pregnancy.

Data Revues 00029378 V204i1ss S0002937810017862, 2011

To determine if peripheral blood mononuclear cell (PBMC) production of the anti-inflammatory cytokine interleukin 10 (IL10) and/or the pro-inflammatory cytokine tumor necrosis factor ␣ (TNF␣) differ between high risk women delivering preterm and those delivering at term. STUDY DESIGN: Ancillary to a randomized trial of omega-3 fatty acid (⍀-3) supplementation for the prevention of recurrent preterm birth. Women (nϭ852) with a history of singleton preterm delivery due to either preterm premature rupture of the membranes or preterm labor and currently pregnant with a singleton received weekly injections of 17-alpha hydroxyprogesterone caproate and were randomized to either an omega-3 supplement (2 gram daily) or placebo. PBMC production of IL10 and TNF␣ were measured without (Ϫ) and with (ϩ) stimulation with lipopolysaccharide (LPS) at baseline (B) randomization at 16-22 weeks gestation and again at follow up (FU) at 25-28 weeks gestation. The following values were recorded for both cytokines: BϪ, Bϩ. FUϪ, FUϩ, ⌬B and ⌬FU (difference between LPS stimulated and unstimulated at B and FU) and ⌬⌬ (⌬FU minus ⌬B). RESULTS: A total of 292 and 319 women had paired assays at both baseline and follow up for IL10 ⌬⌬ and TNF␣ ⌬⌬ respectively. The median IL10 ⌬⌬ value for the group delivering at term was positive and higher than that of the group delivering at 35 to 36 weeks. The median IL10 ⌬⌬ value was negative for the group delivering at Ͻ 35 weeks. Because some studies report an association between smoking and IL10 levels we controlled for smoking. The association between IL10 ⌬⌬ levels and preterm birth Ͻ 37 weeks persisted after controlling for smoking, pϭ0.01. There was no significant difference in TNF␣ ⌬⌬ levels between women delivering at term versus preterm, pϭ0.56. CONCLUSIONS: These data suggest that PBMC production of IL10 is depressed as gestation advances in women delivering preterm compared to women delivering at term.

Reproductive Sciences

Spontaneous preterm births (< 37 weeks gestation) are frequently associated with infection. Current treatment options are limited but new therapeutic interventions are being developed in animal models. In this PROSPERO-registered preclinical systematic review, we aimed to summarise promising interventions for infection/inflammation-induced preterm birth. Following PRISMA guidance, we searched PubMed, EMBASE, and Web of Science using the themes: "animal models", "preterm birth", "inflammation", and "therapeutics". We included original quantitative, peer-reviewed, and controlled studies applying prenatal interventions to prevent infection/inflammation-induced preterm birth in animal models. We employed two risk of bias tools. Of 4020 identified studies, 23 studies (24 interventions) met our inclusion criteria. All studies used mouse models. Preterm birth was most commonly induced by lipopolysaccharide (18 studies) or Escherichia coli (4 studies). Models varied according to infectious agent serotype, dose, and route of delivery. Gestational length was significantly prolonged in 20/24 interventions (83%) and markers of maternal inflammation were reduced in 20/23 interventions (87%). Interventions targeting interleukin-1, interleukin-6, and toll-like receptors show particular therapeutic potential. However, due to the heterogeneity of the methodology of the included studies, meta-analysis was impossible. All studies were assigned an unclear risk of bias using the SYRCLE risk of bias tool. Interventions targeting inflammation demonstrate therapeutic potential for the prevention of preterm birth. However, better standardisation of preterm birth models, including the dose, serotype, timing of administration and pathogenicity of infectious agent, and outcome reporting is urgently required to improve the reproducibility of preclinical studies, allow meaningful comparison of intervention efficacy, and aid clinical translation.

American Journal of Obstetrics and Gynecology, 1998

OBJECTIVE: There is no evidence for the participation of the human fetus in the mechanisms responsible for the onset of preterm labor. We propose that preterm labor in the setting of infection results from the actions of proinflammatory cytokines secreted as part of the fetal and/or maternal host response to microbial invasion. The objective of this study was to determine whether a systemic fetal inflammatory response, defined as an elevation of fetal plasma interleukin-6 concentrations, has a temporal relationship with the commencement of labor.STUDY DESIGN: After informed consent was obtained, amniocentesis and cordocentesis were performed in 41 patients with preterm premature rupture of membranes who were not in labor on admission. Amniotic fluid was cultured for both aerobic and anaerobic bacteria, as well as for mycoplasmas. Fetal plasma interleukin-6 was assayed by a sensitive and specific immunoassay. Statistical analyses included contingency tables and survival analysis with time-dependent Cox regression hazard modeling.RESULTS: Microbial invasion of the amniotic cavity was present in 58.5% (24/41) of patients. Fetuses with fetal plasma interleukin-6 concentrations >11 pg/mL had a higher rate of spontaneous preterm delivery within 48 and 72 hours of the procedure than those with fetal plasma interleukin-6 levels ≤11 pg/mL (88% vs 29% and 88% vs 35%, respectively; P < .05 for all comparisons). Moreover, patients with initiation of labor and delivery within 48 hours of the procedure had a higher proportion of fetuses with plasma interleukin-6 values >11 pg/mL than patients delivered >48 hours (58% [7/12] vs 8% [1/13], respectively; P < .05). Survival analysis indicated that fetuses with elevated fetal plasma interleukin-6 levels had a shorter cordocentesis-to-delivery interval than those without elevated fetal plasma interleukin-6 concentrations (median 0.8 days [range 0.1 to 5] vs median 6 days [range 0.2 to 33.6], respectively; P < .05). Time-dependent Cox regression hazard modeling indicated that fetal plasma interleukin-6 level was the only covariate significantly associated with the duration of pregnancy after we adjusted for gestational age, amniotic fluid interleukin-6 level, and the microbiologic state of the amniotic cavity (P < .01).CONCLUSION: A systemic fetal proinflammatory cytokine response is followed by the onset of spontaneous preterm parturition in patients with preterm premature rupture of membranes. (Am J Obstet Gynecol 1998;179:186-93.)

Scientific reports, 2024

During labor, monocytes infiltrate massively the myometrium and differentiate into macrophages secreting high levels of reactive oxygen species and of pro-inflammatory cytokines (i.e. IL-1β), leading to myometrial contraction. Although IL-1β is clearly implicated in labor, its function and that of the inflammasome complex that cleaves the cytokine in its active form, has never been studied on steps preceding contraction. In this work, we used our model of lipopolysaccharide-induced preterm labor to highlight their role. We demonstrated that IL-1β was secreted by the human myometrium during labor or in presence of infection and was essential for myometrial efficient contractions as its blockage with an IL-1 receptor antagonist (Anakinra) or a neutralizing antibody completely inhibited the induced contractions. We evaluated the implication of the inflammasome on myometrial contractions and differentiation stages of labor onset. We showed that the effects of macrophage-released IL-1β in myometrial cell transactivation were blocked by inhibition of the inflammasome, suggesting that the inflammasome by producing IL-1β was essential in macrophage/myocyte crosstalk during labor. These findings provide novel innovative approaches in the management of preterm labor, specifically the use of an inflammasome inhibitor to block the precursor stages of labor before the acquisition of the contractile phenotype. Preterm labor (PTL) occurs before 37 weeks of gestation and its prevalence rises in industrialized countries despite advancing knowledge of related mechanisms and risks factors . With approximately 15 million of premature births, PTL remains a major obstetric challenge and represents 75% of perinatal mortality and more than half of long-term morbidity 2 . If many cases of spontaneous PTL are unexplained, a significant proportion (40 up to 70%) is linked to genital tract infection or chorioamnionitis 2,3 . Genesis of term and preterm labor is strongly correlated with the inflammatory cascade of events physiologically activated at term but also pathologically activated preterm . Labor involves a transition to a contractile phenotype characterized by differentiation stages including cytoskeleton reorganization and synchronization of myometrial cells 7 . Understanding the mechanisms of term labor may then lead to identify therapeutic targets for the management of preterm labor. It is established that the inflammatory event, implicated in labor onset, results from the massive infiltration of primed macrophages and neutrophils into the myometrium 8,9 secreting inflammatory messengers (i.e., reactive oxygen species (ROS), cytokines, prostaglandins) and inducing the expression of specific labor markers . Previous data from our team highlighted the macrophage's role in myometrial cells activation . We demonstrated that, in laboring myometrium, ROS level was increased as a result of their production by macrophages 12 . Our co-culture model of primary human macrophages and myometrial cells confirmed ROS as major intermediate messengers during labor 13 . Pro-inflammatory cytokines have also been identified in labor induction 14 . These mediators are then produced by leukocytes during term labor and at an even higher level during preterm, particularly in the presence of infection (i.e., chorioamnionitis) 11,15-17 . Among others, IL-1β has been shown to be implicated in labor onset by inducing uterine activation proteins expression 18 , progesterone metabolism 19 and oxytocin secretion and an up-regulation of its receptor . Furthermore, in case of sterile inflammation, high concentration of IL-1 β in the serum or the amniotic fluid, is correlated with PTL and in vivo administration of IL-1β on animal models induces parturition within 48 h .

Pregnancy involves a continuing interplay between inflammatory mediators that facilitate implantation, gestation and the onset of labour. The latter in particular involves a reduction in the influence of hormonal and regulatory factors that promote myometrial quiescence and the activation of proinflammatory cascades that precede myometrial activation and contractions. In the majority of early pre-term labour cases (at less than 32 weeks of gestation), there is evidence of inflammation, often induced by infection. There is increasing evidence that nuclear factor kappa B is a key modulator of the major inflammatory signalling pathways involved in both term and pre-term labour. There is also increasing evidence of the anti-inflammatory role of current therapies such as progesterone, cerclage and non-steroidal anti-inflammatory drugs. Selectively targeting immune activation and key mediators of inflammation may therefore prove to be useful strategies for preventing pre-term labour and improving neonatal outcome by inhibiting immune-mediated damage to the foetus in utero. This article discusses the immunology of pregnancy, immune activation in term and pre-term labour and the neonatal sequale of infection-induced pre-term labour. Current and future strategies targeting immune activation in the prevention of pre-term labour are also explored.

American Journal of Obstetrics and Gynecology, 2006