Regulation of inflammatory response pathways during pregnancy and labor

There is considerable evidence that the initiation of labor, both preterm and at term, is associated with an inflammatory response. Up to 30% of pregnancies ending in preterm labor (with intact membranes) are associated with infection.1 Furthermore, it has been suggested that even in those cases of preterm labor in which there are no clinical symptoms, there is a ‘silent’ infection.2 Interleukin (IL) 1 has been detected in amniotic fluid samples from around 30% of pregnancies ending in preterm labor, and in a comparable proportion of amniotic fluid samples from women in spontaneous labor at term.3, 4 In studies with pregnant rhesus monkeys, intra-amniotic infusion of IL-1 caused a rapid increase in amniotic fluid levels of tumor necrosis factor (TNF), prostaglandin E2 (PGE2) and prostaglandin F2 (PGF2), followed by preterm uterine contractions.5 The potential role of IL-1 in the initiation of human labor, both preterm and at term, is emphasized by the finding that IL-1 is undetectable in amniotic fluids from pregnancies with intact membranes before the onset of labor at any stage of gestation.4 Concentrations of IL-1, IL-1 and TNF- also were found to be increased in cervicovaginal secretions of women at normal term labor in the absence of infection, as compared to women at term who were not in labor.6 It is likely that the inflammatory cytokines present in amniotic fluid are produced by macrophages, monocytes and neutrophils which are recruited into the amniotic space.7 The mechanism whereby activated inflammatory cells within the amniotic cavity traverse fetal membranes and decidua to enter the myometrium is uncertain. However, neutrophils and macrophages were observed to densely infiltrate both upper and lower uterine segments of the human myometrium during spontaneous labor at term, whereas few inflammatory cells were detected in the myometrium of nonlaboring women.8 IL-1 and IL-1 mRNA levels were also observed to increase markedly in rat9 and mouse7 myometrium towards term.