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Aim: To examine the relationship between preterm birth and socioeconomic factors, past history, cervical length, cervical interleukin-8, bacterial vaginosis, underlying diseases, use of medication, employment status, sex of the fetus and multiple pregnancy., Methods: In a multicenter, prospective, observational study, 1810 Japanese women registering their future delivery were enrolled at 8⁺⁰ to 12⁺⁶ weeks of gestation. Data on cervical length and delivery were obtained from 1365 pregnant women. Multivariate logistic regression analysis was performed., Results: Short cervical length, steroid use, multiple pregnancy and male fetus were risk factors for preterm birth before 34 weeks of gestation. Multiple pregnancy, low educational level, short cervical length and part-timer were risk factors for preterm birth before 37 weeks of gestation., Conclusion: Multiple pregnancy and cervical shortening at 20-24 weeks of gestation was a stronger risk factor for preterm birth. Any pregnant woman being part-time employee or low educational level, having a male fetus and requiring steroid treatment should be watched for the development of preterm birth., (© 2013 The Authors. Journal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology.)

Amniotic fluid embolism (AFE) is a rare, high-risk obstetric complication primarily found in the lungs and potentially related to anaphylaxis. Tryptase release from the mast cell reflects anaphylaxis. Case report and findings: A female, aged over 40 years, presented with uterine atony and lethal hemorrhage after induced vaginal labor. Cervical laceration was accompanied by severe hemorrhage. Stromal edema and myometrial swelling were consistent with uterine atony. Alcian blue staining and zinc coproporphyrin immunostaining disclosed AFE, which was more prominent in the uterus than in the lungs. Tryptase immunostaining was diffuse and prominent around the activated mast cells (halos) in the uterus, including the cervix. Similar distribution of findings on the AFE markers, tryptase halos, complement receptor C5aR, and atony in the uterus suggested the causality of AFE to anaphylaxis, complement activation and atony. It is probable that disseminated intravascular coagulation (DIC), induced by AFE, uterine atony and cervical laceration, caused the lethal hemorrhage. It is likely that AFE, in association with cervical laceration, induces uterine anaphylaxis, complement activation, atony, DIC and lethal hemorrhage., (© 2014 S. Karger AG, Basel.)

Objective: To determine whether the concentration of hCG in cervical fluid can predict miscarriage during early pregnancy., Design: Prospective clinical study., Setting: University hospital., Patient(s): Ninety-nine women with singleton pregnancies, 17 of whom suffered a miscarriage., Intervention(s): None., Main Outcome Measure(s): Miscarriage and the cervical fluid/serum hCG concentration ratio., Result(s): With a cutoff value of 1.0, the sensitivity, specificity, and positive and negative predictive values of the cervical fluid/serum hCG concentration ratio for predicting miscarriage were 88.2%, 94.9%, 83.3%, and 96.6%, respectively., Conclusion(s): The cervical fluid/serum hCG concentration ratio might be a useful predictor of miscarriage during early pregnancy.

Cervical ripening is a cytokine-triggered process with substantial remodelling of the cervical extracellular matrix. Interleukin-8 (IL-8) is an important cytokine in cervical maturation. Glycosaminoglycans are also included in this process, but their role in not clearly understood. The effects of heparan sulphate (HS), hyaluronic acid (HA), IL-8, HS + IL-8 and HA + IL-8 on biochemical properties of the cervix were examined in non-pregnant rabbits. The changes in vascular pattern with collagen structure of the cervices and immunohistochemical studies, together with the relative collagen concentrations, were determined. A reduction in relative collagen concentration was significant after HS + IL-8, IL-8 and HA + IL-8 treatment (all P < 0.0001). Gel electrophoresis analysis showed that IL-8 bound preferentially to HS than to HA. Neutrophils were significantly increased in number (P < 0.0001) and located predominantly beneath the glandular epithelium and around the blood vessels after HS + IL-8 treatment. HS + IL-8 treatment caused cervices to increase their water content and become oedematous. The collagen fibres were considerably dissociated, the interfibrillar spaces markedly dilated, and the blood vessels notably increased and dilated. We conclude that binding to HS enhances the activity of IL-8 in inducing cervical maturation.

We investigated the effects of dehydroepiandrosterone sulfate (DHA-S) on the production of interleukin-8 (IL-8) and expression of the interleukin-8 receptor (IL-8 R) in human cervical tissue. DHA-S increased the levels of IL-8 in cultured human cervical fibroblasts and in the supernatant in a time- and dose-dependent manner. DHA-S induced IL-8 and IL-8 R expression in human cervical fibroblasts and human pregnant cervical tissue at term in a dose-dependent manner. In addition, it induced the expression of IL-8 R in an explant culture of human cervical tissue and cultured human cervical fibroblasts in a time- and dose-dependent manner. However, dehydroepiandrosterone (DHA) only slightly induced the production of IL-8 and the expression of IL-8 R in the same cells and tissue. These results suggest that DHA-S up-regulates the autocrine system of IL-8 through the expression of IL-8 R.

The mechanisms by which urinary trypsin inhibitor (UTI) prevents preterm premature rupture of fetal membrane and premature cervical ripening were investigated. We, therefore, examined the effects of UTI on the production of matrix metalloproteinases (MMPs) which closely participate in the breakdown of extracellular matrix in cultured human uterine cervical fibroblasts and human chorionic cells. UTI suppressed specifically the production of interstitial procollagenase/proMMP-1 and prostromelysin 1/proMMP-3 from both cells in a dose-dependent manner (0.32-1.28 microM). This suppression was accompanied by a decrease in steady-state levels of their mRNAs. These results indicate for the first time that UTI down-regulates the production of proMMP-1 and proMMP-3 accompanying with the decrease in the expression of their mRNAs, and therefore UTI actually participates in the maintenance of fetal membranes and/or uterine cervix by overall suppression of MMP production along with the known inhibitory actions towards serine proteinases.

During pregnancy, hyaluronic acid (HA) concentration in the human cervix is very low, but increases rapidly at the onset of labour. HA has a high affinity for water molecules and hence can maintain tissue hydration. HA can stimulate collagenase production in rabbit cervix, and also stimulates migration and function of polymorphonuclear leukocytes in the tissues. It is an endogenous regulator of interleukin-1 (IL-1). We hypothesized that HA plays an essential role during cervical ripening. The effect of exogenous application of HA (20 mg) on non-pregnant and pregnant (day 23) rabbit cervices was compared with controls. HA induced cervical ripening in both pregnant and non-pregnant animals, and cervical water content was significantly increased. Tissue collagen was markedly decreased. The localization and distribution of HA and HA receptor CD44 was determined in non-pregnant and pregnant human cervical connective tissue using biotinylated HA binding protein and CD44 monoclonal antibodies. Both were widely distributed in the connective tissues, especially around the blood vessels and cervical glands. The effect of IL-8 (50, 100, 150 and 200 ng/ml) on HA production and hyaluronidase (HAase) activity was investigated in cultures of lower uterine segment collected during elective Caesarean sections. HA production was stimulated in a dose-dependent manner; there was no effect on hyaluronidase activity. HA administration (0.5, 1 and 2 mg/ml) stimulated the activities of collagenase and gelatinase together with IL-8 production in the culture supernatants. Thus HA may play an important role in cervical ripening, being involved in the regulation of cervical tissue water content, collagenolytic enzymes and cytokines.

The aim of this research was to study and compare the mechanism of action of interleukin (IL)-8, IL-1beta dehydroepiandrosterone sulphate (DHEA-S) and prostaglandin (PG)E2 on the cervix. Five equal groups of pregnant rabbits (n = 45) were tested by either placebo or tested drugs in the form of vaginal suppositories once daily for 3 days. The suppositories contained human recombinant IL-8 (100 ng), IL-1beta (200 ng), DHEA-S (10 mg) or PGE2 (1 mg). All rabbits were tested by one dose, two doses or three doses. Consistency, dilatation and water contents were estimated 24 h after the last dose of treatment. Leukocyte infiltration of the cervices was studied after staining the cervical tissue sections with antirabbit RT2 monoclonal antibodies. Relative collagen concentration was assessed after staining with Picrosirius Red. Collagenase, gelatinase and elastase activities were measured in 100 mg of homogenized cervical connective tissue. Water contents were significantly increased in all tested cervices. Neutrophil numbers were increased in IL-8 and IL-1beta groups after the second dose of treatment (P < 0.0005 and 0.001 respectively). In the PGE2 group, neutrophils were increased after the third dose of treatment, whereas in DHEA-S group no significant changes were observed. Collagen content was significantly decreased in IL-8, IL-1beta and PGE2 groups after the first dose of treatment (P < 0.004, and 0.005 and 0.03 respectively). In the DHEA-S group, the decrease in collagen content occurred after the third dose (P < 0.05). Collagenase activity was markedly increased in IL-8, IL-1, and DHEA-S groups after the second dose of treatment (P < 0.001, 0.003 and 0.007 respectively). No significant increase in collagenase activity was found in PGE2 group. Gelatinase activity was significantly increased in IL-8, IL-1beta, PGE2 and DHEA-S groups after the second dose of treatment (P < 0.008, 0.01, 0.003 and 0.05 respectively). Also, elastase activity was increased after the second dose of treatment in all groups (P < 0.001, 0.001, 0.001 and 0.006 respectively). Our data suggest that ripening of the cervix in rabbit can be initiated by different mechanisms. Cytokines play a vital role in cervical ripening, especially IL-8 and IL-1. IL-8 is one of the factors which could ripen the cervix in a manner similar to the physiological process at term.

Dehydroepiandrosterone sulfate (DHA-S) is one of the successful drugs used to induce cervical ripening. There is growing evidence that interleukin-8 (IL-8) plays an essential role during cervical ripening. IL-8 was found to be hormonally controlled in the cervix. The aim of this research was to study the effect of DHA-S on the function of IL-8 on the cervix. Sixteen pregnant white New Zealand rabbits where tested either by placebo (adeps solidus, n = 4), DHA-S (10 mg, n = 4), IL-8 (100 ng, n = 4) or combination of DHA-S and IL-8 (n = 4). Collagen contents in the cervices were assessed histologically after staining with picrosirius red. The number of neutrophils in 5 random fields of the cervical tissue was counted in all groups. Collagenase, elastase and gelatinase were measured in those groups. The collagen content of the cervices was significantly decreased after treatment with DHA-S, IL-8 or a combination of both drugs compared to the control group (p < 0.004, 0.001 and 0.001, respectively). A maximal decrease in collagen content was found in the DHA-S + IL-8-treated group (71.5%). Neutrophil infiltration was significantly increased in the IL-8 and DHA-S + IL-8-treated groups (p < 0.0001). Neutrophil numbers in the DHA-S + IL-8-treated group were significantly higher than in the IL-8 group (p < 0.006). Collagenase activity was increased in the DHA-S, IL-8 and DHA-S + IL-8 groups compared to the control group (p < 0.02, 0.008 and 0.001, respectively). Elastase activity was also significantly increased in the same groups (p < 0.002, 0.005 and 0.001, respectively). A similar increment was found in gelatinase activity (p < 0.004, 0.0001 and 0.0001, respectively). DHA-S has a synergistic effect with IL-8 during cervical ripening.

Unlabelled: Unknown signals from the fetus are thought to be involved in the onset of parturition. We recently discovered that urinary trypsin inhibitor (UTI) from fetal urine inhibits uterine muscle contraction., Objectives: The aim of this research was to elucidate the mechanism of action of UTI in suppressing cervical maturation., Study Design: Non-pregnant and pregnant rabbits pretreated with and without UTI suppositories containing 1000 U (400 micrograms) for 3 days were treated for 2 days with vaginal suppositories containing 100 ng of interleukin-8 (IL-8)., Results: IL-8 induced softening and dilatation of the rabbit cervices. In contrast UTI inhibited IL-8 induced cervical softening and dilatation. Water content, collagen content, neutrophil counts, elastase activity and collagenase activity of the cervix were increased by IL-8, but they did not increase by IL-8 with UTI., Conclusion: These results suggest that UTI inhibits cervical maturation induced by IL-8.

Bestatin is an immunomodulatory peptide that stimulates the humoral and cell-mediated immune system. It also has an inhibitory effect on multiple aminopeptidases. Recently we found that aminopeptidase N inactivates interleukin-8 in vitro. Bestatin successfully suppresses the effect of aminopeptidase N on interleukin-8. During cervical maturation many biochemical changes occur including decrease in collagen concentration and increase in collagenase and elastase activities. Interleukin-8, which has a potent neutrophil chemotactic effect, was found to induce cervical ripening in rabbits. The combination of interleukin-8 with bestatin also induced cervical ripening by providing approximately regular levels of neutrophil numbers, collagenase, and elastase activities. We therefore suggest that this regulatory mechanism also takes place in vivo through the inhibitory effect of bestatin on aminopeptidase N.

Objective: In this research we studied the effect of interleukin-1 beta (IL-1 beta) on the cervix., Study Design: Vaginal suppositories of a low dose of IL-1 beta (200 ng) were applied to non-pregnant and pregnant rabbits. Results were compared with a control group which were treated only by placebo. Water concentration, collagen content, collagenase and elastase activities were measured. Neutrophil numbers in the cervical connective tissue were counted. Also, interleukin-8 (IL-8) was measured in the supernatant of homogenized cervical tissue treated by IL-1 beta., Results: Water contents of the tested cervices were increased (P < 0.006 and 0.03, respectively), whereas collagen content was markedly decreased (P < 0.0004 and 0.001, respectively). Collagenase activity was found to be increased in non-pregnant and pregnant cervices treated by IL-1 beta (P < 0.02 and 0.002, respectively). Also, elastase activity of these cervices were significantly increased compared to the control group (P < 0.0007 and 0.001, respectively). Neutrophil invasion was observed in the cervical connective tissues after application of IL-1 beta. IL-8 was significantly elevated (P < 0.0001) in the treated cervices., Conclusion: Interaction between IL-1 and IL-8 is suspected to be essential for cervical ripening.

Our aim was to study the effects of infection mediated by bacterial endotoxins (lipopolysaccharides LPS) and bacterial substrate (N-formyl-methionyl-leucyl-phenylalanine FMLP) on pathological cervical ripening, and compare their effects with the normal physiological mediator interleukin-8 (IL-8). Twenty non-pregnant rabbits were treated vaginally either by placebo, LPS, FMLP or IL-8 for 3 successive days. Water concentration was measured. Neutrophils were counted in 5 random fields of each specimen. Collagen and glycosaminoglycan concentrations were assessed histologically by using picrosirius red and alcian blue staining and optical density was calculated. LPS FMLP as well as IL-8 can induce cervical ripening. Water concentration was found to be significantly increased in these groups (p < 0.0001). Also, significant numbers of neutrophils were found to accumulate in the connective tissue of these cervices (p < 0.0001). Collagen concentration was significantly decreased in the cervices treated by LPS, FMLP and IL-8 (p < 0.0001). Glycosaminoglycan concentration was significantly increased in cervices treated by LPS, FMLI as well as IL-8 (p < 0.0001, 0.006 and 0.001 respectively). LPS, FMLP and IL-8 stimulate cervical ripening in non-pregnant rabbits. This ripening was mediated through the accumulated neutrophils in the connective tissue. IL-8 has a physiological type effect to induce ripening of the cervix.

Objective: The purpose of this study was to determine whether cervical ripening can be induced in rabbits by interleukin-8., Study Design: Nonpregnant and pregnant rabbits were treated for 5 days with vaginal suppositories containing 100 ng of interleukin-8. Collagen and glycosaminoglycan concentration in the cervices were assessed histologically by picrosirius red and alcian blue, and the mean optical density was calculated. The mean neutrophil count in five random fields was calculated from each biopsy specimen., Results: Interleukin-8 induced softening and dilatation of the rabbit cervices. Water content was significantly increased (p < 0.0001 and p < 0.001, respectively). Cervical collagen concentration was found to be significantly decreased (p < 0.0004 and p < 0.0001, respectively). Glycosaminoglycan concentration was significantly increased in nonpregnant and pregnant cervices (p < 0.0009 and p < 0.1, respectively). The mean number of neutrophils was significantly increased (p < 0.0005 and p < 0.006, respectively)., Conclusion: Interleukin-8 can induce cervical ripening in nonpregnant and pregnant rabbits.

The serum levels of pro-type I collagen peptide (PIP), pro-type III collagen peptide (PIIIP) and type IV 7S collagen (7S collagen) were measured in 41 women in various gestational weeks of pregnancy (5-41 weeks). The PIP level did not change during pregnancy, being 450 +/- 380 mg/ml before week 37 and 448 +/- 280 mg/ml after week 37. The PIIIP level also did not change being 0.55 +/- 0.21 and 0.59 +/- 0.22 U/ml before and after 37 weeks. The PIIIP level increased slightly but not significantly after week 37. The 7S collagen level, however, increased significantly (p less than 0.01), being 5.1 +/- 0.8 and 6.6 +/- 0.8 mg/ml before and after week 37. The correlation coefficients with the Bishop score were 0.22 for PIP, 0.42 for PIIIP, and 0.72 for 7S collagen. These data suggest that serum 7S collagen closely reflects collagen degradation in the cervix and so should be a good marker of cervical maturation.

Granulocyte elastase (elastase)-like activity in 119 samples of cervical mucus from pregnant women was measured. Though elastase-like activity in normal pregnant women was low in 2nd and 3rd trimesters (less than 20 units), it increased during labor (1st stage of labor: 70 +/- 50 U/l; 2nd stage: 72 +/- 56). Elastase-like activity in pregnant women with imminent premature delivery (24-30 gestational weeks) was also high (78 +/- 57). Elastase-like activity of cervical mucus correlated with Bishop score in both normal term and preterm labor. Elastase-containing granulocytes were identified by immunohistochemistry in ripened cervix in normal and preterm labor. Some granulocytes degranulate and release elastase into the cervical stroma. Others migrate through the basement membrane of the endocervix to reach the cervical canal. Elastase could not be demonstrated in immature cervix as assessed by Bishop score. The staining intensity of elastase in the cervix correlated closely with elastase-like activity in cervical mucus. Thus elastase-like activity in cervical mucus reflects the degree of cervical maturation. These results lead one to speculate that elastase is one of the neutral proteases which depolymerize and degrade collagen in the ripening cervix.