Tafoxiparin, a novel drug candidate for cervical ripening and labor augmentation: results from 2 randomized, placebo-controlled studies.

BACKGROUND: Slow progression of labor is a common obstetrical problem with multiple associated complications. Tafoxiparin is a depolymerized form of heparin with a molecular structure that eliminates the anticoagulant effects of heparin. We report on 2 phase II clinical studies of tafoxiparin in primiparas. Study 1 was an exploratory, first-in-pregnant-women study and study 2 was a dose-finding study. OBJECTIVE: Study 1 was performed to explore the effects on labor time of subcutaneous administration of tafoxiparin before onset of labor. Study 2 was performed to test the hypothesis that intravenous treatment with tafoxiparin reduces the risk for prolonged labor after spontaneous labor onset in situations requiring oxytocin stimulation because of dystocia. STUDY DESIGN: Both studies were randomized, double-blind, and placebo-controlled. Participants were healthy, nulliparous females aged 18 to 45 years with a normal singleton pregnancy and gestational age confirmed by ultrasound. The primary endpoints were time from onset of established labor (cervical dilation of 4 cm) until delivery (study 1) and time from start of study treatment infusion until delivery (study 2). In study 1, patients at 38 to 40 weeks of gestation received 60 mg tafoxiparin or placebo daily as 0.4 mL subcutaneous injections until labor onset (maximum 28 days). In study 2, patients experiencing slow progression of labor, a prolonged latent phase, or labor arrest received a placebo or 1 of 3 short-term tafoxiparin regimens (initial bolus 7, 21, or 35 mg followed by continuous infusion at 5, 15, or 25 mg/hour until delivery; maximum duration, 36 hours) in conjunction with oxytocin. RESULTS: The number of participants randomized in study 1 was 263, and 361 were randomized in study 2. There were no statistically significant differences in the primary endpoints between those receiving tafoxiparin and those receiving the placebo in both studies. However, in study 1, the risk for having a labor time exceeding 12 hours was significantly reduced by tafoxiparin (tafoxiparin 6/114 [5%] vs placebo 18/101 [18%]; P=.0045). Post hoc analyses showed that women who underwent labor induction had a median (range) labor time of 4.44 (1.2-8.5) hours with tafoxiparin and 7.03 (1.5-14.3) hours with the placebo (P=.0041) and that co-administration of tafoxiparin potentiates the effect of oxytocin and facilitates a shorter labor time among women with a labor time exceeding 6 to 8 hours (P=.016). Among women induced into labor, tafoxiparin had a positive effect on cervical ripening in 11 of 13 cases (85%) compared with 3 of 13 participants (23%) who received the placebo (P=.004). For women requiring oxytocin because of slow progression of labor, the corresponding results were 34 of 51 participants (66%) vs 16 of 40 participants (40%) (P=.004). In study 2, tafoxiparin had no positive effects on the secondary endpoints when compared with the placebo. Except for injection-site reactions in study 1, adverse events were no more common for tafoxiparin than for the placebo among either mothers or infants. There were few serious or treatment-related adverse events. CONCLUSION: Subcutaneous treatment with tafoxiparin before labor onset (study 1) may be effective in reducing the labor time among women undergoing labor induction and among those requiring oxytocin for slow progression of labor. Moreover, tafoxiparin may have a positive effect on cervical ripening. Short-term, intravenous treatment with tafoxiparin as an adjunct to oxytocin in patients with labor arrest (study 2) did not affect labor time or other endpoints. Both studies suggest that tafoxiparin has a favorable safety profile in mothers and their infants.

Heparin fragments induce cervical inflammation by recruiting immune cells through Toll-like receptor 4 in nonpregnant mice.

Inflammation is a hallmark in the human cervix remodelling. A possible candidate inducing the inflammatory driven ripening of the cervix is the matrix component heparan sulphate, which has been shown to be elevated in late pregnancy in the cervix and uterus. Heparin and a glycol-split low molecular weight heparin (gsHep) with low anticoagulant potency has been shown to enhance myometrial contraction and interleukin (IL)-8 production by cervical fibroblasts. The aim of this study was to investigate the mechanism by which heparin promotes cervical inflammation. Wild-type, Toll-like receptor 4 (TLR4), Myeloid differentiation primary response gene 88 (MyD88) and Interferon regulatory factor 3 (IRF3)-deficient mice were treated by deposition of gsHep into the vaginas of nonpregnant mice. To identify which cells that responded to the heparin fragments, a rhodamine fluorescent construct of gsHep was used, which initially did bind to the epithelial cells and were at later time points located in the sub-mucosa. The heparin fragments induced a strong local inflammatory response in wild-type mice shown by a rapid infiltration of neutrophils and to a lesser extent macrophages into the epithelium and the underlying extracellular matrix of the cervix. Further, a marked migration into the cervical and vaginal lumen was seen by both neutrophils and macrophages. The induced mucosal inflammation was strongly reduced in TLR4- and IRF3-deficient mice. In conclusion, our findings suggest that a TLR4/IRF3-mediated innate immune response in the cervical mucosa is induced by gsHep. This low anticoagulant heparin version, a novel TLR4 agonist, could contribute to human cervical ripening during the initiation of labour.

Hyponatraemia reversibly affects human myometrial contractility. An in vitro pilot study.

BACKGROUND: In a previous study we found a significant correlation between dystocia and hyponatraemia that developed during labour. The present study examined a possible causal relationship. In vitro studies often use area under the curve (AUC) determined by frequency and force of contractions as a measure of myometrial contractility. However, a phase portrait plot of isometric contraction, obtained by plotting the first derivate of contraction against force of contraction, could indicate that bi-or multiphasic contractions might be less effective compared to the smooth contractions. MATERIAL AND METHODS: Myometrial biopsies were obtained from 17 women undergoing elective caesarean section at term. Each biopsy was divided into 8 strips and mounted isometrically in a force transducer. Seven biopsies were used in the first part of the study when half of the strips were immersed in the hyponatraemic study solution S containing Na+ 120 mmol/L and observed for 1 hour, followed by 1 hour in normonatraemic control solution C containing Na+ 136 mmol/L, then again in S for 1 hour, and finally 1 hour in C. The other half of the strips were studied in reverse order, C-S-C-S. The remaining ten biopsies were included in the second part of the study. Response to increasing doses of oxytocin (OT) in solutions S and C was studied. In the first part of the study we calculated AUC, and created phase portrait plots of two different contractions from the same strip, one smooth and one biphasic. In both parts of the study we registered frequency and force of contractions, and described appearance of the contractions. RESULTS: First part of the study: Mean (median) contractions per hour in C: 8.7 (7.6), in S 14,3 (13). Mean (SD) difference between groups 5.6 (4.2), p = 0.018. Force of contractions in C: 11.8 (10.2) mN, in S: 10.8 (9.2) mN, p = 0.09, AUC increased in S; p = 0.018. Bi-/multiphasic contractions increased from 8% in C to 18% in S, p = 0.001. All changes were reversible in C. Second part of the study: Frequency after OT 1.65 x 10-9 M in C:3.4 (2.9), in S: 3.8 (3.2), difference between groups: p = 0.48. After OT 1.65 x 10-7 M in C: 7.8 (8.9), increase from previous OT administration: p = 0.09, in S: 8.7 (9.0), p = 0.04, difference between groups, p = 0.32. Only at the highest dose of OT dose was there an increase in force of contraction in S, p = 0.05, difference between groups, p = 0.33. Initial response to OT was more frequently bi/multiphasic in S, reaching significance at the highest dose of OT(1.65 x 10-7 M), p = 0.015. when almost all contractions were bi/multiphasic. CONCLUSION: Hyponatraemia reversibly increased frequency of contractions and appearance of bi-or multiphasic contractions, that could reduce myometrial contractility. This could explain the correlation of hyponatraemia and instrumental delivery previously observed. Contractions in the hyponatraemic solution more frequently showed initial multiphasic contractions when OT was added in increasing doses. Longer lasting labours carry the risk both of hyponatraemia and OT administration, and their negative interaction could be significant. Further studies should address this possibility.

Low levels of anti-secretory factor in placenta are associated with preterm birth and inflammation.

INTRODUCTION: Anti-secretory factor is a protein that regulates secretory and inflammatory processes and preterm birth is associated with inflammation. Therefore, our hypothesis was that anti-secretory factor might play a role in immune reactivity and homeostasis during pregnancy. MATERIAL AND METHODS: Following spontaneous onset of labor and preterm or term delivery, placenta biopsies were collected. The levels of anti-secretory factor and markers of inflammation (CD68, CD163) and vascularization (CD34, smooth muscle actin) were analyzed by immunohistochemistry. RESULTS: The 61 placental biopsies included 31 preterm (<37 weeks of gestation) and 30 term (37-41 weeks) samples. The preterm placentas exhibited lower levels of anti-secretory factor (p = 0.008) and larger numbers of CD68-positive cells (p < 0.001) compared to term. Preterm placentas had blood vessel of smaller diameter (p = 0.036) indicative of immaturity. The level of interleukin-6 in cord blood was higher after very preterm than term birth, suggesting a fetal inflammatory response. The placenta level of anti-secretory factor was positively correlated to the length of gestation (p = 0.025) and negatively correlated to the levels of the inflammatory markers CD68 (p = 0.015) and CD163 (p = 0.028). CONCLUSIONS: Preterm delivery is associated with low levels of anti-secretory factor in placenta. Inflammation, a potential trigger of preterm birth, is more pronounced in the preterm placenta and inversely related to the placental level of anti-secretory factor, suggesting both a link and a potential target for intervention.

The preterm cervix reveals a transcriptomic signature in the presence of premature prelabor rupture of membranes.

BACKGROUND: Premature prelabor rupture of fetal membranes accounts for 30% of all premature births and is associated with detrimental long-term infant outcomes. Premature cervical remodeling, facilitated by matrix metalloproteinases, may trigger rupture at the zone of the fetal membranes overlying the cervix. The similarities and differences underlying cervical remodeling in premature prelabor rupture of fetal membranes and spontaneous preterm labor with intact membranes are unexplored. OBJECTIVES: We aimed to perform the first transcriptomic assessment of the preterm human cervix to identify differences between premature prelabor rupture of fetal membranes and preterm labor with intact membranes and to compare the enzymatic activities of matrix metalloproteinases-2 and -9 between premature prelabor rupture of fetal membranes and preterm labor with intact membranes. STUDY DESIGN: Cervical biopsies were collected following preterm labor with intact membranes (n = 6) and premature prelabor rupture of fetal membranes (n = 5). Biopsies were also collected from reference groups at term labor (n = 12) or term not labor (n = 5). The Illumina HT-12 version 4.0 BeadChips microarray was utilized, and a novel network graph approach determined the specificity of changes between premature prelabor rupture of fetal membranes and preterm labor with intact membranes. Quantitative reverse transcription-polymerase chain reaction and Western blotting confirmed the microarray findings. Immunofluorescence was used for localization studies and gelatin zymography to assess matrix metalloproteinase activity. RESULTS: PML-RARA-regulated adapter molecule 1, FYVE-RhoGEF and PH domain-containing protein 3 and carcinoembryonic antigen-ralated cell adhesion molecule 3 were significantly higher, whereas N-myc downstream regulated gene 2 was lower in the premature prelabor rupture of fetal membranes cervix when compared with the cervix in preterm labor with intact membranes, term labor, and term not labor. PRAM1 and CEACAM3 were localized to immune cells at the cervical stroma and NDRG2 and FGD3 were localized to cervical myofibroblasts. The activity of matrix metalloproteinase-9 was higher (1.22 ± 4.403-fold, P < .05) in the cervix in premature prelabor rupture of fetal membranes compared with preterm labor with intact membranes. CONCLUSION: We identified 4 novel proteins with a potential role in the regulation of cervical remodeling leading to premature prelabor rupture of fetal membranes. Our findings contribute to the studies dissecting the mechanisms underlying premature prelabor rupture of fetal membranes and inspire further investigations toward the development of premature prelabor rupture of fetal membranes therapeutics.

Density of Stromal Cells and Macrophages Associated With Collagen Remodeling in the Human Cervix in Preterm and Term Birth.

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.

Novel topical formulation of lidocaine provides significant pain relief for intrauterine device insertion: pharmacokinetic evaluation and randomized placebo-controlled trial.

OBJECTIVE: To investigate the pharmacokinetics, safety, and analgesic efficacy of a novel topical formulation of lidocaine at insertion of an intrauterine device (IUD). DESIGN: Randomized controlled trial; phase-I and phase-II studies. SETTING: University and public hospitals. PATIENT(S): Women aged ≥18 years who wanted to receive an IUD. Four women were parous in phase I; all in phase II were nulliparous. INTERVENTION(S): A single, 8.5-mL dose of lidocaine formulation (SHACT) was administered (to the portio, cervix, and uterus) with a specially designed applicator. MAIN OUTCOME MEASURE(S): The phase-I study (single-arm) was designed for pharmacokinetic assessment; the phase-II study (randomized) was intended for investigation of efficacy and safety. RESULT(S): From the phase-I study (15 participants), mean pharmacokinetic values were: maximum plasma concentration: 351 ± 205 ng/mL; time taken to reach maximum concentration: 68 ± 41 minutes; and area under the concentration-time curve from 0 to 180 minutes: 717 ± 421 ng*h/mL. Pain relief was observed with lidocaine vs. placebo in the phase-II study (218 women, randomized). Mean visual analog scale score for maximum pain during the first 10 minutes after IUD insertion was 36% lower with lidocaine than with placebo (28.3 ± 24.6 vs. 44.2 ± 26.0). Pain intensity was also significantly lower in the lidocaine group at 30 minutes. On average, 3 of 4 patients will have less pain with lidocaine than with placebo. Adverse events were similar in the placebo and lidocaine groups. No serious adverse events were reported. CONCLUSION(S): Lidocaine provides pain relief lasting for 30-60 minutes for women undergoing IUD insertion, without any safety concerns. Further studies of this lidocaine formulation, for IUD insertion and other clinical applications, are planned. CLINICAL TRIAL REGISTRATION NUMBER: 2011-005660-18 and 2011-006220-20 (EudraCT).

The expression of prostaglandin receptors EP3 and EP4 in human cervix in post-term pregnancy differs between failed and successful labor induction.

OBJECTIVE: To investigate expression and localization of prostaglandin receptors EP1-4 and FP and localization of stromal factors CTGF (connective tissue growth factor), furin, calgranulin B and ALOX15 (arachidonate 15-lipooxygenase) in human cervical tissue from post-term women with failed or successful labor induction after prostaglandin priming. DESIGN: Experimental prospective clinical study. SETTING: Tertiary obstetric care center. POPULATION: Twenty-six women giving birth post-term, with failed or successful labor induction, and a control group consisting of 19 women with spontaneous onset of labor and delivery at term. METHODS: Biopsies were obtained from post-term women with successful (responders; R) and failed (non-responders; NR) labor induction. Women with spontaneous delivery at term were included as controls (C). mRNA expression was determined with real time PCR, protein expression and localization with immunohistochemistry. MAIN OUTCOME MEASURES: Comparisons of mRNA and protein expressions between post-term pregnancies with failed and successful labor induction as well as term controls. RESULTS: EP4 mRNA expression was down-regulated concomitant with an up-regulation of EP3 mRNA expression in cervix from the NR group as compared with the R group. In stroma, immunoreactivity of the EP4 protein was increased in the NR group as compared with R and C groups. CONCLUSIONS: Failure of cervical ripening, after local application of prostaglandins for labor induction, may be caused by the increased expression of EP3 and concomitant decrease in EP4 expression.

Fetal monitoring with computerized ST analysis during labor: a systematic review and meta-analysis.

BACKGROUND: Computerized ST analysis of fetal electrocardiography (ECG) combined with cardiotochography (CTG) has been introduced for intrapartum monitoring and is the prevailing method when ST analysis (STAN®) is used. OBJECTIVE: To assess the evidence that computerized ST analysis during labor reduces the incidence of fetal metabolic acidosis, hypoxic ischemic encephalopathy, cesarean section, instrumental vaginal delivery or the number of instances where fetal scalp blood sampling is used as compared with CTG only. METHODS: Search of PubMed, Cochrane Library, EMBASE, Web of Science, CINAHL and CRD databases. SELECTION CRITERIA: CTG only compared with CTG + computerized ST analysis. DATA COLLECTION AND ANALYSIS: Studies were assessed using pre-designed templates. Meta-analyses of included randomized controlled trials were performed using a random effects model. RESULTS: Risk ratio for cord metabolic acidosis with STAN® was 0.96 [95% confidence interval (CI) 0.49-1.88]. Risk ratio for cesarean sections or instrumental vaginal deliveries for fetal distress was 0.93 (95%CI 0.80-1.08) and for fetal scalp blood sampling 0.55 (95%CI 0.40-0.76). Encephalopathy cases were not assessed due to their low incidence. CONCLUSIONS: There is not enough scientific evidence to conclude that computerized ST analysis reduces the incidence of metabolic acidosis. Cesarean sections and instrumental vaginal deliveries due to fetal distress or other indications are the same, regardless of method, but STAN® reduces the number of instances which require scalp blood sampling.

Negative emotions and cytokines in maternal and cord serum at preterm birth.

PROBLEM: This study investigates whether affectivity differs between mothers delivering preterm and term and whether maternal and umbilical cord serum cytokines differ between these groups. Further, whether there are associations between mothers' emotions and maternal and cord cytokines at preterm and term birth. METHOD OF STUDY: Twenty-seven mothers delivering preterm and 37 mothers delivering at term reported positive/negative affect and previous depressive symptoms during pregnancy. Blood samples from mothers in labor and cord samples (23 preterm and 33 term) were analyzed for cytokines. RESULTS: Maternal IL-8 was lower at preterm delivery compared with term. In the preterm group only, associations were found between negative emotions and maternal IL-6, IL-8 and cord IL-6, IL-8, IL-10, IL-13, and IL-18. CONCLUSION: 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.

An integrated systems biology approach to the study of preterm birth using "-omic" technology--a guideline for research.

Preterm birth is the leading cause of neonatal mortality and perinatal morbidity. The etiology of preterm is multi-factorial and still unclear. As evidence increases for a genetic contribution to PTB, so does the need to explore genomics, transcriptomics, proteomics and metabolomics in its study. This review suggests research guidelines for the conduct of high throughput systems biology investigations into preterm birth with the expectation that this will facilitate the sharing of samples and data internationally through consortia, generating the power needed to study preterm birth using integrated "-omics" technologies. The issues to be addressed include: (1) integrated "-omics" approaches, (2) phenotyping, (3) sample collection, (4) data management-integrative databases, (5) international consortia and (6) translational feasibility. This manuscript is the product of discussions initiated by the "-Omics" Working Group at the Preterm Birth International Collaborative Meeting held at the World Health Organization, Geneva, Switzerland in April 2009.

Risk of adverse pregnancy outcomes in women with polycystic ovary syndrome: population based cohort study.

OBJECTIVE: To study the risk of adverse pregnancy outcomes in women with polycystic ovary syndrome, taking into account maternal characteristics and assisted reproductive technology. DESIGN: Population based cohort study. SETTING: Singleton births registered in the Swedish medical birth register between 1995 and 2007. PARTICIPANTS: By linkage with the Swedish patient register, 3787 births among women with a diagnosis of polycystic ovary syndrome and 1,191,336 births among women without such a diagnosis. MAIN OUTCOME MEASURES: Risk of adverse pregnancy outcomes (gestational diabetes, pre-eclampsia, preterm birth, stillbirth, neonatal death, low Apgar score (<7 at five minutes), meconium aspiration, large for gestational age, macrosomia, small for gestational age), adjusted for maternal characteristics (body mass index, age), socioeconomic factors (educational level, and cohabitating with infant's father), and assisted reproductive technology. RESULTS: Women with polycystic ovary syndrome were more often obese and more commonly used assisted reproductive technology than women without such a diagnosis (60.6% v 34.8% and 13.7% v 1.5%). Polycystic ovary syndrome was strongly associated with pre-eclampsia (adjusted odds ratio 1.45, 95% confidence interval 1.24 to 1.69) and very preterm birth (2.21, 1.69 to 2.90) and the risk of gestational diabetes was more than doubled (2.32, 1.88 to 2.88). Infants born to mothers with polycystic ovary syndrome were more prone to be large for gestational age (1.39, 1.19 to 1.62) and were at increased risk of meconium aspiration (2.02, 1.13 to 3.61) and having a low Apgar score (<7) at five minutes (1.41, 1.09 to 1.83). CONCLUSIONS: Women with polycystic ovary syndrome are at increased risk of adverse pregnancy and birth outcomes that cannot be explained by assisted reproductive technology. These women may need increased surveillance during pregnancy and parturition.

Maternal risk factors for postterm pregnancy and cesarean delivery following labor induction.

OBJECTIVE: To investigate risk factors associated with postterm pregnancy and cesarean delivery following labor induction. DESIGN: Population-based cohort study. SETTING: Sweden. POPULATION: From the Swedish Medical Birth Register, a total of 1,176,131 singletons births from gestational week 37 and onwards, between 1992 and 2006. METHODS: Unconditional logistic regression analysis. MAIN OUTCOME MEASURES: Risk of postterm pregnancy (delivery at >or=42 weeks) and cesarean delivery following labor induction. RESULTS: Among 1,176,131 births, 8.94% were delivered postterm. Compared to normal weight women, the risk of postterm pregnancy in obese women was almost doubled (adjusted OR: 1.63, 95% CI 1.59-1.67). The risk of postterm pregnancy increased with increasing maternal age and was higher among primiparous women. The risk of cesarean section (CS) following labor induction postterm, increased with maternal age and BMI, and was more than doubled among women 35 years and older (adjusted OR 2.28, 95% CI 2.04-2.56). A fivefold risk of CS was seen among nulliparous women (adjusted OR 5.05, 95% CI 4.71-5.42). Parous women with a previous CS undergoing labor induction had a sevenfold increased risk of CS postterm (adjusted OR 7.19, 95% CI 5.93-8.71). CONCLUSIONS: Nulliparity, advanced maternal age and obesity were the strongest risk factors for postterm pregnancy and CS following labor induction in postterm pregnancy. Including maternal risk factors to the cervical assessment may improve prediction of vaginal delivery following labor induction in postterm pregnancy.

Pro-inflammatory and anti-inflammatory cytokines in human preterm and term cervical ripening.

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

High-mobility group box protein 1 and its signalling receptors in human preterm and term cervix.

The objective of this study was to identify possible changes in mRNA and protein expression of high-mobility group box protein 1 (HMGB1) and its suggested receptors - receptor for advanced glycation end-products (RAGE) and Toll-like receptor 2 (TLR2) and TLR4 - in human cervix during pregnancy, term and preterm labor. Cervical biopsies were taken from 58 women: 20 at preterm labor, 24 at term labor, 10 at term not in labor and 4 from non-pregnant women. Real-time RT-PCR was used to quantify mRNA expression, and immunohistochemistry and ELISA for protein analysis. HMGB1, RAGE, TLR2 and TLR4 proteins were localized and their mRNA expression was detected in the cervix. There was more extranuclear HMGB1 in the cervical epithelium and stroma in preterm and term labor compared to the term not in labor. TLR2 mRNA expression was upregulated 5-fold in term labor and 3-fold in preterm labor compared to term not in labor and non-pregnant controls. There was lower expression of TLR2 and TLR4 mRNAs in preterm labor compared to term. Lower mRNA expression of HMGB1 was found in the subgroup with preterm premature rupture of membranes than in the rest of the preterm group, where levels were significantly higher than in term labor. In conclusion, extranuclear expression of HMGB1 during labor suggests a possible role of HMGB1 during the process of cervical ripening. Changes in expression of mRNAs encoding HMGB1, TLR2 and TLR4 in preterm labor suggest differences in the mechanism of cervical ripening at preterm and term delivery.

Does low molecular weight heparin shorten term labor?

Dalteparin, a low molecular weight heparin (LMWH), is given to pregnant women with thrombotic disorders. Clinical observations together with the documented changes of heparan sulfate proteoglycans in normal and protracted labor fostered the idea that LMWH shortens delivery time. Labor time was retrospectively determined among nulliparous pregnant women treated with dalteparin because of previous venous thromboembolism (VTE), thrombophilia or acute VTE during current pregnancy. Their labor time was compared to matched untreated controls. The proportion of instrumental deliveries and neonatal outcome was also compared. The dalteparin-treated group showed a significantly (30%) shorter labor time compared to matched controls. Total instrumental deliveries were the same in the two groups but operative intervention due to protracted labor was significantly less common in dalteparin-treated women. There was no difference in neonatal outcome. Dalteparin most likely shortens parturition time and may decrease the number of operative interventions due to protracted labor.

Decreased gene expression of fibrillin-1 in stress urinary incontinence.

AIMS: Studies to show impairments in the pelvic floor extracellular matrix (ECM) associated with stress urinary incontinence (SUI) has earlier been performed, but the results are contradictory. Collagen I and III, the elastin associated proteins fibrillin-1 and fibulin-5 and the small leucine-rich repeat proteoglycans (SLRPs) decorin, lumican and fibromodulin are involved in giving the tissue its mechanical properties. Their gene signals and tissue localizations were investigated. METHODS: Para-urethral punch biopsies were obtained from 24 women, 12 pre- and 12 postmenopausals, during surgery for SUI. As controls, biopsies were collected from 14 women, 8 pre- and 6 postmenopausals, undergoing surgery for other benign conditions. The mRNA expression by real-time RT-PCR and protein localization by immunohistochemistry were analyzed concerning collagen I and III, the small leucine rich repeat proteoglycans (SLRPs) decorin, lumican and fibromodulin and the elastic fiber associated proteins fibulin-5 and fibrillin-1. Statistical comparisons controlled for age changes in gene expressions. RESULTS: A significant decrease in mRNA expression of fibrillin-1 was discovered in all SUI women compared to all controls, P = 0.03. All molecules were down-regulated by age, but no other differences between SUI and controls reached significance. All proteins were adequately expressed by immunohistochemistry. A weaker staining for fibrillin-1 was seen in the pre-menopausal SUI group compared to the pre-menopausal controls. CONCLUSIONS: A decreased gene signal and weaker immunoreactivity for fibrillin-1, important for the elastic fiber assembly, was discovered in women with SUI. Loss of tissue elasticity could lead to increased urethra hypermobility and SUI.

Prostaglandin treatment is associated with a withdrawal of progesterone and androgen at the receptor level in the uterine cervix.

Treatment with prostaglandin(PG)-E2 is clinically efficient for cervical priming. The aim of this study was to evaluate the impact of PG-E2 on the expression of the progesterone (PR), androgen (AR) and glucocorticoid (GR) receptors in human uterine cervix in prolonged pregnancy. The study groups were postterm nulliparous women with unripe cervices undergoing cervical priming with PG-E2 before labor induction. Responders (n = 12) who delivered vaginally were compared with non-responders (n = 10), who underwent cesarean section due to failure to progress to the active phase of labor. Controls (n = 18) with vaginal partus at a normal gestational age served as a reference group. Cervical levels of PR-A and PR- B isoforms, AR and GR, serum levels of their ligands and sex hormone-binding globulin (SHBG) were quantified. The responder group displayed lower total PR-AB and AR protein levels as compared to non-responders, and lower PR-B and AR protein levels as compared to controls. In addition, the PR mRNA level was lower in responders as compared to non-responders. The GR protein level did not differ between the groups. We conclude that successful PG-E2 priming was followed by a progesterone and androgen withdrawal at the receptor level in the uterine cervix.

Low molecular weight heparin stimulates myometrial contractility and cervical remodeling in vitro.

OBJECTIVES: The low molecular weight heparin, Dalteparin, shortens human labor time. The aim of this study was to investigate if the mechanism behind this effect involves myometrial contractility and cervical ripening and if the anticoagulative activity is necessary for its effect. DESIGN: Experimental in vitro study. SETTING: Lund University and Karolinska Institute, Sweden. METHODS: The effect of low molecular weight heparins with or without anticoagulative properties on myometrial contractility was measured in vitro on smooth muscle strips from biopsies obtained at elective cesarean sections. The effects on cervical ripening were assessed in cervical fibroblasts cultured from explants of cervical biopsies obtained at delivery. MAIN OUTCOME MEASURES: Mean force and number of contractions in uterine smooth muscle strips and interleukin-8 (IL-8) secretion in cervical fibroblasts. RESULTS: Myometrial smooth muscle strips pretreated with low molecular weight heparins showed increased contractile activity compared to untreated smooth muscle strips. Secretion of IL-8 from cultured cervical fibroblasts was significantly increased after treatment with low molecular weight heparin. Both these effects were independent of anticoagulative activity of the low molecular weight heparin. CONCLUSIONS: 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.