Hair cortisol moderates the association between obstetric complications and child wellbeing.

Obstetric complications (OC) may have implications for later health outcomes. However, there is a lack of research examining the association between OC and behavior problems or quality of life (HRQoL). We aimed to close this gap and further investigate functioning of the hypothalamus-pituitary-adrenal (HPA)-axis as a potential physiological vulnerability moderating the association between OC and behavior problems and HRQoL. We investigated 232 mothers and their five to 12-year-old children. Presence of OC during the pre-, peri-, and postnatal phases was determined by interviewing mothers. Children's behavior problems (CBCL, TRF) and HRQoL (Kidscreen rated by mothers and children) were assessed. Children gave 3 cm strands of hair for analysis of hair cortisol (HC). Structural equation modeling analyses with a latent variable of child outcome ("distress"), OC as predictor and HC as a potential moderator were conducted. OC significantly predicted distress (ß = .33, p < .01). The model showed a good fit to the data: χ2(14)=15.66, p < .33, CFI=.99, TLI=.99, RMSEA=.02, 90 %CI [.00, .06], SRMR=.04. In addition, HC moderated the association between OC and distress (ß=-.32, p < .01). The moderation model also showed a good fit: χ2(14) =7.13, p = .93, CFI=1.00, TLI=1.06, RMSEA=.00, 90 %CI [.00, .02], SRMR=.03. Results indicated that the association between OC and distress was significant only when children had low HC-levels. This was also the case for both externalizing and internalizing behavior problems. Our results underline the notion of OC as a risk factor for child behavior problems and wellbeing and point to an important role of the children's physiological set-up such as HPA-functioning.

Pharmacokinetic and Biochemical Profiling of Sodium Dichloroacetate in Pregnant Ewes and Fetuses.

Sodium dichloroacetate (DCA) is an investigational drug that shows promise in the treatment of acquired and congenital mitochondrial diseases, including myocardial ischemia and failure. DCA increases glucose utilization and decreases lactate production, so it may also have clinical utility in reducing lactic acidosis during labor. In the current study, we tested the ability of DCA to cross the placenta and be measured in fetal blood after intravenous administration to pregnant ewes during late gestation and labor. Sustained administration of DCA to the mother over 72 hours achieved pharmacologically active levels of DCA in the fetus and decreased fetal plasma lactate concentrations. Multicompartmental pharmacokinetics modeling indicated that drug metabolism in the fetal and maternal compartments is best described by the DCA inhibiting lactate production in both compartments, consistent with our finding that the hepatic expression of the DCA-metabolizing enzyme glutathione transferase zeta1 was decreased in the ewes and their fetuses exposed to the drug. We provide the first evidence that DCA can cross the placental compartment to enter the fetal circulation and inhibit its own hepatic metabolism in the fetus, leading to increased DCA concentrations and decreased fetal plasma lactate concentrations during its parenteral administration to the mother. SIGNIFICANCE STATEMENT: This study was the first to administer sodium dichloroacetate (DCA) to pregnant animals (sheep). It showed that DCA administered to the mother can cross the placental barrier and achieve concentrations in fetus sufficient to decrease fetal lactate concentrations. Consistent with findings reported in other species, DCA-mediated inhibition of glutathione transferase zeta1 was also observed in ewes, resulting in reduced metabolism of DCA after prolonged administration.

Amniotic fluid lactate level as a diagnostic tool for prolonged labour.

Prolonged labour can lead to postpartum complications and adverse outcomes for both mother and baby. Measurable parameters can help in the active management of labour, timely diagnosis of dystocia and in the choice of the method of delivery. Progressive uterine contractions are necessary to complete labour successfully. Myometrial fatigue during prolonged labour causes a change from aerobic to anaerobic metabolism, resulting in an accumulation of intramuscular lactic acid and probably a subsequent increase in amniotic fluid lactate concentration. High amniotic fluid lactate level has been associated with ineffective uterine contractions leading to labour arrest. A considerable number of studies conducted so far indicate that the level of lactate in amniotic fluid may be a new non-invasive diagnostic tool for early prediction of prolonged labour and the need for immediate obstetric intervention. Low amniotic fluid lactate level may facilitate a decision to continue vaginal labour by oxytocin augmentation. A high level of amniotic fluid lactate is associated with surgical obstetric procedures. Measuring amniotic fluid lactate level might simplify the patient's allocation to a group, which will benefit from the administration of oxytocin and to a group that will not benefit from further prolongation of labour. This study aimed to briefly review current knowledge on amniotic fluid lactate concentrations measured using standard biochemical methods during the first stage of labour following normal pregnancy, as a possible diagnostic tool for prolonged labour. For this purpose, PubMed, EMBASE, Medline (1990 to July 2020) trials register and reference lists of relevant articles were searched.

Inflammation and Epidural-Related Maternal Fever: Proposed Mechanisms.

Intrapartum fever is associated with excessive maternal interventions as well as higher neonatal morbidity. Epidural-related maternal fever (ERMF) contributes to the development of intrapartum fever. The mechanism(s) for ERMF has remained elusive. Here, we consider how inflammatory mechanisms may be modulated by local anesthetic agents and their relevance to ERMF. We also critically reappraise the clinical data with regard to emerging concepts that explain how anesthetic drug-induced metabolic dysfunction, with or without activation of the inflammasome, might trigger the release of nonpathogenic, inflammatory molecules (danger-associated molecular patterns) likely to underlie ERMF.

Pathophysiology of foetal oxygenation and cell damage during labour.

A foetus exposed to oxygenation compromise is capable of several adaptive responses, which can be categorised into those affecting metabolism and those affecting oxygen transport. However, both the extent and duration of the impairment in oxygenation will have a bearing on these adaptive responses. Although intrapartum events may account for no more than one-third of cases with an adverse neurological outcome, they are important because they can be influenced successfully. This review describes the mechanisms underlying foetal hypoxia during labour, acid-base balance and gas exchange, and the current scientific understanding of the role of intrauterine asphyxia in the pathophysiology of neonatal encephalopathy and cerebral palsy. Although the mechanisms involved include similar initiating events, principally ischaemia and excitotoxicity, and similar final common pathways to cell death, there are certain unique maturational factors that influence the type and pattern of cellular injury.

Elevated amniotic fluid lactate predicts labor disorders and cesarean delivery in nulliparous women at term.

OBJECTIVE: We sought to assess amniotic fluid lactate (AFL) at diagnosis of spontaneous labor at term (≥37 weeks) as a predictor of labor disorders (dystocia) and cesarean delivery (CD). STUDY DESIGN: This was a single-institution, prospective cohort study of 905 singleton, cephalic, term (≥37 weeks) nulliparous women in spontaneous labor. A standard management of labor (active management of labor) including a standard oxytocin regimen up to a maximum dose of 30 mU/min was applied. AFL was measured using a point-of-care device (LMU061; ObsteCare, Stockholm, Sweden). Labor arrest in the first stage of labor was defined as the need for oxytocin when cervical dilatation was <1 cm/h over 2 hours and in the second stage of labor by poor descent and rotation over 1 hour. Standard statistical analysis included analysis of variance, Pearson correlations, and binary logistic regression. Unsupervised decision tree analysis with 10-fold cross-validation was used to identify AFL thresholds. RESULTS: AFL was normally distributed and did not correlate with age, body mass index, or gestation. Unsupervised decision tree analysis demonstrated that AFL could be divided into 3 groups: 0-4.9 mmol/L (n = 118), 5.0-9.9 mmol/L (n = 707), and ≥10.0 mmol/L (n = 80). Increasing AFL was associated with higher total oxytocin dose (P = .001), labor disorders (P = .005), and CD (P ≤ .001). Multivariable regression analysis demonstrated that women with AFL ≥5.0-9.9 mmol/L (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.06-2.39) and AFL ≥10.0 mmol/L (OR, 1.72; 95% CI, 1.01-2.93) were independent predictors of a labor disorder. AFL ≥5.0-9.9 mmol/L did not predict CD but multivariable analysis confirmed that AFL ≥10.0 mmol/L was an independent predictor of CD (OR, 3.35; 95% CI, 1.73-6.46). AFL ≥5.0-9.9 mmol/L had a sensitivity of 89% in predicting a labor disorder and a sensitivity of 93% in predicting CD with a 97% negative predictive value. AFL ≥10.0 mmol/L was highly specific but lacked sensitivity for CD. There was no difference in birthweight of infants according to labor disorder and delivery method. CONCLUSION: AFL at diagnosis of labor in spontaneously laboring single cephalic nulliparous term women is an independent predictor of a labor disorder and CD. These data suggest that women with AFL between 5.0-9.9 mmol/L with a labor disorder may be amenable to correction using the active management of labor protocol.

A short review of adipokines, smooth muscle and uterine contractility.

Obesity is a major health problem worldwide. The prevalence of obesity is increasing in both developed and developing countries. In the UK, for example, 60% of adults are overweight and 25% are obese. Obesity is associated with many pathological complications including respiratory, cardiovascular and endocrine, but it also affects fertility and is associated with many reproductive complications. This has led us and others to investigate links between women with high BMI, pregnancy outcome and uterine function. These studies in turn have led investigators to ask how obesity can have such an impact on reproduction and, as part of this, to consider the role of the adipokines released from adipose tissues. Our focus in this short review is on adipokines and myometrial activity, and for completeness we overview their effects on other smooth muscles. To date four adipokines (leptin, visfatin, apelin and ghrelin) have been investigated and all affect myometrial contractility, but some more potently than others. We consider the possible mechanisms involved in how adipokines may modify uterine contractility, and discuss the potential impact on labor and delivery.

Measurement of maternal cerebral tissue hemoglobin on near-infrared time-resolved spectroscopy in the peripartum period.

AIM: To measure cerebral tissue hemoglobin in uncomplicated and complicated pregnant women during the peripartum period. METHODS: Time-resolved spectroscopy (TRS-20) can measure absolute concentration of oxygenated, deoxygenated, and total tissue hemoglobin based on the transit time of individual photons. Therefore, we used TRS-20 to measured tissue hemoglobin in the hemi-prefrontal lobes of normotensive pregnant women with (n = 51) or without (n = 19) epidural anesthesia, hypertensive pregnant women with pre-eclampsia (n = 10), a pregnant woman with acute onset of hypertension soon after delivery, and a hypertensive woman after hemorrhagic stroke in delivery. RESULTS: Cyclic labor concomitant with intra-abdominal pressure caused synergistic elevation in cerebral tissue hemoglobin. In contrast, epidural anesthesia reduced the amplitude of the cyclic increase of cerebral tissue hemoglobin in normotensive pregnant women. Hypertension in labor due to pre-eclampsia increased the amplitude of synergistic elevation of cerebral tissue hemoglobin caused by cyclic labor and intra-abdominal pressure. A prolonged high basal level of cerebral tissue hemoglobin was observed in a case of acute onset of hypertension soon after delivery. A decrease in cerebral tissue hemoglobin in the hemi-prefrontal lobe was observed in a woman 2 h after the onset of hemorrhagic stroke in labor. CONCLUSIONS: TRS-20 can detect specific changes in maternal cerebral tissue hemoglobin level in response to physiological and pathophysiological changes in delivery. Thus, it represents a promising new conventional tool for maternal cerebral monitoring in the peripartum period.

HMGB1 promotes a p38MAPK associated non-infectious inflammatory response pathway in human fetal membranes.

OBJECTIVE: Spontaneous preterm birth (PTB) and preterm prelabor rupture of membranes (pPROM) are major pregnancy complications often associated with a fetal inflammatory response. Biomolecular markers of this fetal inflammatory response to both infectious and non-infectious risk factors and their contribution to PTB and pPROM mechanism are still unclear. This study examined fetal membrane production, activation and mechanistic properties of high mobility group box 1 (HMGB1) as a contributor of the non-infectious fetal inflammatory response. MATERIALS AND METHODS: HMGB1 transcripts and active HMGB1 were profiled in fetal membranes and amniotic fluids collected from PTB and normal term birth. In vitro, normal term not in labor fetal membranes were exposed to lipopolysaccharide (LPS) and water soluble cigarette smoke extract (CSE). HMGB1-transcripts and its protein concentrations were documented by RT-PCR and ELISA. Recombinant HMGB1 treated membranes and media were subjected to RT-PCR for HMGB1 receptors, mitogen activated protein kinase pathway analysis, cytokine levels, and Western blot for p38MAPK. RESULTS: HMGB1 expression and its active forms were higher in PTB and pPROM than normal term membranes and amniotic fluid samples. Both LPS and CSE enhanced HMGB1 expression and release in vitro. Fetal membrane exposure to HMGB1 resulted in increased expression of TLR2 and 4 and dose-dependent activation of p38MAPK-mediated inflammation. CONCLUSIONS: HMGB1 increase by fetal membrane cells in response to either oxidative stress or infection can provide a positive feedback loop generating non-infectious inflammatory activation. Activation of p38MAPK by HMGB1 promotes development of the senescence phenotype and senescence associated sterile inflammation. HMGB1 activity is an important regulator of the fetal inflammatory response regardless of infection.

Neuregulin 1-induced AKT and ERK phosphorylation in patients with fragile X syndrome (FXS) and intellectual disability associated with obstetric complications.

Animal models of fragile X syndrome (FXS) suggest the impairment of the intracellular AKT messenger system, which is activated by neuregulin 1 (NRG1), a key regulator of neurodevelopment. We investigated NRG1-induced activation of the AKT and extracellular signal-regulated kinase (ERK) systems by the measurement of the phosphorylated AKT/ERK to total AKT/ERK ratio in peripheral B lymphoblasts of patients with FXS, IQ-matched controls with intellectual disability (obstetric complications, preterm birth, perinatal hypoxia, and low birth weight), and typically developed healthy participants. Results revealed that patients with FXS displayed decreased AKT but normal ERK activation after the administration of NRG1. IQ-matched controls with intellectual disability displayed intact AKT/ERK activation. In conclusion, FXS, but not intellectual disability associated with obstetric complications, is associated with decreased NRG1-induced AKT phosphorylation.

Amniotic fluid insulin and C-peptide as predictive markers for fetal macrosomia, birth injuries, and delivery complications?

BACKGROUND: Gestational diabetes mellitus (GDM) occurs in 3-5% of all pregnancies. GDM increases both maternal and fetal risks, causes fetal macrosomia, and hence increases the rates of caesarean sections and delivery complications such as shoulder dystocia. An early predictive marker and consequent early treatment could be beneficial, so amniotic fluid insulin and C-peptide have been examined in several studies. Increased amniotic fluid insulin in early amniocentesis between the 14th and 20th gestational week predicted a later GDM. A potential direct association with fetal macrosomia remains to be determined. MATERIAL AND METHODS: This retrospective study investigated amniotic fluid insulin/C-peptide from amniocenteses between 14 and 20 weeks of gestation in correlation with fetal birth weight, type of delivery, and complications. To focus on effects of fetal hyperinsulinism apart from therapeutic confounders, we included patients who did not participate in GDM screening. Insulin and C-peptide were measured in 144 samples of frozen amniotic fluid. Birth weight, type of delivery, complications, and birth injuries were noted. RESULTS: Birth weights ranged from 760 g to 4410 g with a mean weight of 3424 g at an average of 40 weeks gestation. The mean amniotic fluid insulin was 4.36 U/ml and the mean C-peptide concentration was 0.076 ng/ml. There was no correlation between amniotic fluid insulin or C peptide and birth weight, type of delivery, complications, and birth injuries. CONCLUSIONS: Amniotic fluid insulin and C-peptide are unsuitable as predictive marker for fetal macrosomia, type of delivery, complications, or birth injuries.

Women with high BMI: should they be managed differently due to antagonising action of leptin in labour?

Leptin - a protein hormone is synthesised in the adipose tissue in humans. Its level therefore should be directly proportional to the amount of adipose tissue in the body. There is evidence that leptin may be responsible for various complications in obese and morbidly obese women in labour by its effect on the myometrium causing uterine smooth muscle relaxation (causes less Ca(2+) flux in myometrium). By doing this, we believe it opposes oxytocin effect on the myometrium which in fact promotes uterine smooth muscle contractions (causes more Ca(2+) flux in myometrium). The opposing action of these two hormone may contribute to the dysfunctional labour process, prolonged first stage of labour, increase in operative vaginal delivery in second stage of labour and increase in caesarean section rate both in first and second stage of labour in obese women. Also, there is increased incidence of postdated pregnancy, induction of labour and atonic postpartum haemorrhage in obese and morbidly obese women. Does this mean labour should be managed differently in women with high BMI?

[Interest of lactate micro-dosage in scalp and umbilical cord in cases of abnormal fetal heart rate during labor. Prospective study on 162 patients]. / Place du microdosage des lactates au scalp et au cordon devant des anomalies du rythme cardiaque fœtal pendant le travail. Étude prospective sur 162 patientes.

OBJECTIVE: To compare the interest of lactate microanalysis with pH measurement (Gold Standard procedure) in cord blood and fetal scalp blood samples for the assessment of abnormal fetal heart rate (FHR) during labour. STUDY DESIGN: A prospective observational study conducted from July 1st 2007 till March 31st 2008 on 162 patients with abnormal FHR during labour. RESULTS: Sampling failure for scalp lactate was less than 1 % compared to a failure of 10.5 % for scalp pH (P<0.001). There was a good correlation between pH and lactates in fetal scalp blood samples and in cord blood samples, between lactate in the last fetal scalp sample and in cord blood. When there was umbilical acidosis (pH≤7.15 or lactate≥5mmol/L), Apgar score at 5 minutes was significantly lower than when there was no acidosis (4.66±3.59 versus 8.35±2.73 for pH ; 6.6±3.77 versus 8.45±2.58 for lactate). The specificity of the lactate in the umbilical cord artery (≥5 mmol/laws) was 76.4 % for predicting an Apgar score at 5 minutes less than 7 ; 79.7 % for predicting the need for immediate neonatal care ; 77.3 % for predicting an hospital stay in neonatal unit. These figures were generally worse but close to those found for a threshold value of umbilical artery pH≤7.15. CONCLUSION: The values of lactate in cord blood and fetal scalp blood samples were comparable to pH values (Gold standard procedure). This method is easy to perform and is an attractive alternative to pH for monitoring fetal asphyxia. It is our opinion that the combination of the two methods is of interest.

Peripartal hormonal changes in Alpine goats: a comparison between physiological and pathological parturition.

In this study, 31 pregnant Alpine does were used to investigate the peripartal plasma profiles of progesterone, estradiol-17ß, 15-ketodihydro-PGF(2α) and cortisol, assessing differences between goats with physiological and pathological parturition. The goats were observed around the time of parturition; all peripartum abnormalities were recorded, and veterinary assistance was provided if necessary. Blood samples were collected every 12 h from 7 days before to 7 days after delivery, and plasma used for hormonal analysis by radioimmunoassay. Two animals died during the study, and their data were excluded from the study. Of the remaining 29 animals, 23 goats had a spontaneous and physiological delivery, while six goats showed pathological parturition, including dystocia and retained placenta. The 65 alive kids were viable at birth and at 7 days of age. The results concerning the hormonal concentrations in the normal parturition confirm and define more precisely the patterns already described in the goat, while the comparison between physiological and pathological parturition has never been previously reported in this species. Highest peripartum levels of cortisol were found in the pathological group at delivery (30.6 vs 15.9 ng/ml) (p<0.01) and 12 h later (26.2 vs 11.1 ng/ml) (p<0.05); the greater cortisol concentrations found in goats with dystocia and retained placenta could suggest a higher level of stress. No significant differences between the two groups were found with respect to the circulating values of the other hormones, but the individual variability and the small number of goats enrolled in the pathological delivery group could have masked possible differences.

Labour analgesia and the baby: good news is no news.

When investigating different methods of maternal pain relief in labour, neonatal outcome has not always been at the forefront, or else maternal changes, such as haemodynamics, fever, length of labour, need for oxytocin or type of delivery, are taken as surrogates for neonatal outcome. It is essential to examine the actual baby and to appreciate that labour pain itself has adverse consequences for the baby. For systemic analgesia, pethidine has been most extensively studied and compared with neuraxial analgesia. It depresses fetal muscular activity, aortic blood flow, short-term heart rate variability and oxygen saturation. In the newborn it exacerbates acidosis, depresses Apgar scores, respiration, neurobehavioural score, muscle tone and suckling. Alternatives have few advantages, remifentanil being the most promising. Neuraxial analgesia is associated with better Apgar scores and variable neurobehavioural changes. Neonatal acid-base status is not only better with epidural than with systemic opioid analgesia, it is also better than with no analgesia. The effect on breast feeding has yet to be established, though it is certainly no worse than that of systemic opioid analgesia. Variations in neuraxial technique have little impact on the newborn. Widespread ignorance of the benefit to the newborn of neuraxial labour analgesia in the UK among non-anaesthetists needs to be combated.

Maternal and fetal oxidative stress and intrapartum term fever.

OBJECTIVE: The association between maternal chorioamnionitis and fetal oxidative stress has not been well established. STUDY DESIGN: A nested case control study was performed within a prospective cohort of term nulliparous women: 20 cases (intrapartum fever of >100.4 degrees F) and 20 afebrile controls. Oxidative stress was assessed using ThioGlo-1 (TG-1; Calbiochem, San Diego, CA) fluorescent sulfhydryl detection. Median levels (+/- interquartile range) of protein-thiol sulfhydryls were compared. RESULTS: In early labor, maternal oxidative stress (lower protein sulfhydryls) was significantly higher in those women who subsequently had intrapartum fever develop (79.87 +/- 22.88 vs 127.73 +/- 43.79 counts/second per microg protein; P < .001). In contrast, cord serum sulfhydryls were not different between groups (75.77 +/- 14.00 vs 75.04 +/- 17.83 counts/second per microg protein; P = .99) CONCLUSION: Our data suggest that the term human fetus is protected from maternal oxidative stress associated with intrapartum fever. However, maternal oxidative status in early labor is associated with subsequent intrapartum fever. Optimal fetal neuroprotection will require a more precise knowledge of pathogenic mechanisms.

Effect of different degrees of glucose intolerance on maternal and perinatal outcomes.

OBJECTIVE: To evaluate the effect of markedly elevated 50-g glucose loading test (GLT) (>or=200 mg/dL) and equivocal 100-g GLT (one abnormal value) results on maternal and perinatal outcomes. METHODS: Retrospective analysis of 2029 singleton pregnancies screened for gestational diabetes mellitus (GDM). Maternal and perinatal outcomes in five different groups with different degrees of glucose intolerance were compared. First group consisted of patients with normal 50-g test, second group was formed by patients with abnormal 50-g glucose test but a normal 100-g test. Third group included patients with one abnormal value after 100-g test. Patients in the fourth group were diagnosed to have GDM after an abnormal 100-g test. Patients in the fifth group had a value >or=200 mg/dL after 50-g test and were diagnosed to have GDM. RESULTS: Macrosomia and large for gestational age incidence were highest in the group with one elevated glucose tolerance test (GTT) value. Hospitalisation rates, hypoglycemia, hyperbilirubinemia and polycythemia were more common in neonates born to mothers with one elevated GTT value and to mothers with a GLT > 200 mg/dL. CONCLUSION: Adverse maternal and perinatal outcomes in patients with one elevated GTT value and in patients with a GLT value > 200 mg/dL warrant close glucose monitoring and treatment in these groups even in the absence of a diagnostic abnormal GTT.

[Some biochemical parameters in the placenta in discoordinated and powerless labors].

A number of biochemical parameters (total nitrites and nitrates (NO(x)), cyclic guanosine monophosphate (cGMP), nitrotyrosine, medium-weight molecules (MCM) in the placenta were determined in women with gestosis during discoordinated and powerless labor. Thirty placentas (10 placentas from parturients after discoordinated labor, 10 from those after powerless labor, 10 placentas as a control group) were examined. Changes in the parameters under study were found to result in the development of nitroxide and oxidant stresses and endotoxicosis. The biochemical parameters should be considered as placental criteria for the differential diagnosis of labor anomalies in gestosis, such as powerless and discoordinated labors.

Delayed parturition and altered myometrial progesterone receptor isoform A expression in mice null for Krüppel-like factor 9.

Preterm and delayed labor conditions are devastating health problems with currently unknown etiologies. We previously showed that the transcription factor Krüppel-like factor 9 (KLF9) influences the expression and/or transcriptional activity of receptors for estrogen and progesterone in endometrial cells in vivo and in vitro. Given that estrogen and progesterone differentially regulate uterine myometrial contractility during gestation, we hypothesized that lack of KLF9 could compromise myometrial function, leading to defects in parturition. To test this, we used mice null for Klf9 to evaluate gestation length, response to the progesterone receptor (PGR) antagonist RU486, expression levels of steroid receptor proteins, nuclear receptor coactivator and contractility-associated genes, and nuclear factor-kappaB (NF-kappaB) DNA binding activity in myometrium near term. Klf9 knockout (KO) mice exhibited delayed parturition by 1-2 days relative to wild-type (WT) counterparts, in the absence of fetal genotype contribution and differences in serum estrogen and progesterone levels. Knockout mice near term were refractory to the abortive action of RU486, and they displayed aberrant myometrial expression patterns of nuclear PGR-A and NF-kappaB p65/RELA relative to WT mice. Myometrial expression levels of nuclear estrogen receptor-alpha did not differ, whereas those for Oxtr and Crebbp mRNAs were lower, in KO versus WT mice. Results indicate that KLF9 contributes to the regulation of PGR-associated components in the myometrium necessary for timely onset of parturition in mice. The present study highlights the potential utility of Klf9 null mice to investigate the pathophysiology of parturition defects involving PGR signaling.

Prolonged labour associated with lower expression of syndecan 3 and connexin 43 in human uterine tissue.

BACKGROUND: Prolonged labour is associated with greater morbidity and mortality for mother and child. Connexin 43 is a major myometrial gap junction protein found in human myometrium. Syndecan 3 seems to prevail in the human uterus among heparan sulphate proteoglycans, showing the most significant increase during labour. The aims of the present study were to investigate syndecan 3 and connexin 43 mRNA expressions and protein distributions in human uterine tissue during normal and prolonged labour. METHODS: Uterine isthmic biopsies were collected from non-pregnant (n = 7), term pregnant women not in labour (n = 14), in normal labour (n = 7) and in prolonged labour (n = 7). mRNA levels of syndecan 3 and connexin 43 were determined by real time RT-PCR. The localization and expression were demonstrated by immunohistochemistry and confocal microscopy. RESULTS: In women with prolonged labour, the mRNA expressions of syndecan 3 and Connexin 43 were considerably lower than the expression level at normal labour (p < 0.05). In term-pregnant tissue, the expression of syndecan 3 and connexin 43 did not differ significantly compared to non-pregnant and normal labour. The immunoreactivity of syndecan 3 was strong at normal labour, in contrast to prolonged labour, where both a weaker expression and an irregular distribution were detected. The immunoreactivity of connexin 43 increased until term and further stronger staining occurred at normal labour. At prolonged labour, the immunoreactivity was weaker and more unevenly distributed. At labour, a co-localization of syndecan 3 and connexin 43 could be demonstrated in the smooth muscle by confocal microscopy. CONCLUSION: The high expression of syndecan 3 and connexin 43 and their co-localization to the smooth muscle bundles during normal labour, together with the significant reduction in prolonged labour, may indicate a role for these proteins in the co-ordination of myometrial contractility.