1Cervical ripening is necessary for successful delivery. As cytokines are believed to be 2 involved in this process, the aim of this study was to investigate possible changes in the 3 mRNA and protein expression of pro-inflammatory (interleukin (IL)-1α, IL-1β, IL-12, IL-18) 4 and anti-inflammatory (IL-4, IL-10, IL-13) cytokines in the human cervix during pregnancy, 5 term and preterm labor. Cervical biopsies were taken from 59 women: 21 at preterm labor, 24 6 at term labor, 10 at term not in labor and 4 from non-pregnant women. mRNA was analyzed 7 with real-time RT-PCR and protein expression and/or secretion with immunohistochemistry 8 and ELISA. There was an upregulation of mRNA for IL-10, IL-13, IL-1α and IL-1β in the 9 laboring groups, while mRNA for IL-12 and IL-18 was downregulated (p<0.05). IL-4 mRNA 10 was detected more frequently, while IL-12 mRNA expression was lower, in the preterm labor 11 group than in the term labor group (p<0.05). The protein levels of IL-4 and IL-12 were lower 12 and IL-18 tended to be higher in the labor groups, while IL-10 protein levels were unaffected 13 by labor. IL-4 protein levels were significantly higher in the preterm subgroup with bacterial 14 infection than in the non-infected group (p<0.05). IL-10 had higher expression in squamous 15 epithelium at preterm labor than at term (p<0.05). In conclusion, the major changes in pro-16 inflammatory and anti-inflammatory cytokine mRNA and protein expression in cervix occur 17 during the labor process irrespective of the length of gestation. However, our results indicate 18 that dysregulation of anti-inflammatory cytokines in the human cervix could be involved in 19 the pathogenesis of preterm labor. 20 21

A possible underlying mechanism for the shortened labor time after low molecular weight heparin treatment is enhanced myometrial contractility and an increased IL-8 secretion in cervical fibroblast, mimicking the final cervical ripening in vivo. Our data support the notion that anticoagulant activity is not required to promote labor.

Remodeling of the cervix occurs in advance of labor both at term and at preterm birth. Morphological characteristics associated with remodeling in rodents were assessed in cervix biopsies from women at term (39 weeks' gestation) and preterm (<33 weeks' gestation). Collagen I and III messenger RNA and hydroxyproline concentrations declined in cervix biopsies from women in labor at term and preterm compared to that in the cervix from nonlaboring women. Extracellular collagen was more degraded in sections of cervix from women at term, based on optical density of picrosirius red stain, versus that in biopsies from nonpregnant women. However, collagen structure was unchanged in the cervix from women at preterm labor versus the nonpregnant group. As an indication of inflammation, cell nuclei density was decreased in cervix biopsies from pregnant women irrespective of labor compared to the nonpregnant group. Moreover, CD68-stained macrophages increased to an equivalent extent in cervix subepithelium and stroma from groups in labor, both at term and preterm, as well as in women not in labor at term. Evidence for a similar inflammatory process in the remodeled cervix of women at term and preterm birth parallels results in rodent models. Thus, a conserved final common mechanism involving macrophages and inflammation may characterize the transition to a ripe cervix before birth at term and in advance of premature birth.

The findings indicate associations in preterm delivery between negative emotions and both maternal and neonate immune activity. Future studies should investigate whether such associations are part of the etiology of preterm delivery.