Infection-induced thrombin production: a potential novel mechanism for preterm premature rupture of membranes (PPROM).

BACKGROUND: Preterm premature rupture of membranes is a leading contributor to maternal and neonatal morbidity and death. Epidemiologic and experimental studies have demonstrated that thrombin causes fetal membrane weakening and subsequently preterm premature rupture of membranes. Although blood is suspected to be the likely source of thrombin in fetal membranes and amniotic fluid of patients with preterm premature rupture of membranes, this has not been proved. Ureaplasma parvum is emerging as a pathogen involved in prematurity, which includes preterm premature rupture of membranes; however, until now, prothrombin production that has been induced directly by bacteria in fetal membranes has not been described. OBJECTIVE: This study was designed to investigate whether Ureaplasma parvum exposure can induce prothrombin production in fetal membranes cells. STUDY DESIGN: Primary fetal membrane cells (amnion epithelial, chorion trophoblast, and decidua stromal) or full-thickness fetal membrane tissue explants from elective, term, uncomplicated cesarean deliveries were harvested. Cells or tissue explants were infected with live Ureaplasma parvum (1×105, 1×106 or 1×107 colony-forming units per milliliter) or lipopolysaccharide (Escherichia coli J5, L-5014; Sigma Chemical Company, St. Louis, MO; 100 ng/mL or 1000 ng/mL) for 24 hours. Tissue explants were fixed for immunohistochemistry staining of thrombin/prothrombin. Fetal membrane cells were fixed for confocal immunofluorescent staining of the biomarkers of fetal membrane cell types and thrombin/prothrombin. Protein and messenger RNA were harvested from the cells and tissue explants for Western blot or quantitative reverse transcription polymerase chain reaction to quantify thrombin/prothrombin protein or messenger RNA production, respectively. Data are presented as mean values ± standard errors of mean. Data were analyzed using 1-way analysis of variance with post hoc Dunnett's test. RESULTS: Prothrombin production and localization were confirmed by Western blot and immunostainings in all primary fetal membrane cells and tissue explants. Immunofluorescence observations revealed a perinuclear localization of prothrombin in amnion epithelial cells. Localization of prothrombin in chorion and decidua cells was perinuclear and cytoplasmic. Prothrombin messenger RNA and protein expression in fetal membranes were increased significantly by Ureaplasma parvum, but not lipopolysaccharide, treatments in a dose-dependent manner. Specifically, Ureaplasma parvum at a dose of 1×107 colony-forming units/mL significantly increased both prothrombin messenger RNA (fold changes in amnion: 4.1±1.9; chorion: 5.7±4.2; decidua: 10.0±5.4; fetal membrane: 9.2±3.0) and protein expression (fold changes in amnion: 138.0±44.0; chorion: 139.6±15.1; decidua: 56.9±29.1; fetal membrane: 133.1±40.0) compared with untreated control subjects. Ureaplasma parvum at a dose of 1×106 colony-forming units/mL significantly up-regulated prothrombin protein expression in chorion cells (fold change: 54.9±5.3) and prothrombin messenger RNA expression in decidua cells (fold change: 4.4±1.9). CONCLUSION: Our results demonstrate that prothrombin can be produced directly by fetal membrane amnion, chorion, and decidua cells. Further, prothrombin production can be stimulated by Ureaplasma parvum exposure in fetal membranes. These findings represent a potential novel underlying mechanism of Ureaplasma parvum-induced rupture of fetal membranes.

A randomized trial of phenylephrine infusion versus bolus dosing for nausea and vomiting during Cesarean delivery in obese women.

PURPOSE: Hypotension is common after spinal anesthesia for Cesarean delivery. It is associated with nausea, vomiting, and fetal acidosis. Previous research on phenylephrine excluded obese subjects. We compared the incidence of intraoperative nausea and vomiting (IONV) in obese patients who received a prophylactic phenylephrine infusion vs those who received bolus dosing for the treatment of spinal-induced hypotension. METHODS: In this multicentre, double-blinded randomized controlled trial, 160 obese women undergoing elective Cesarean delivery under spinal anesthesia were randomized to receive a prophylactic phenylephrine infusion initiated at 50 µg·min-1 (and titrated according to a predefined algorithm) or 100 µg phenylephrine boluses to treat hypotension. Maternal systolic blood pressure was maintained within 20% of baseline. The primary study outcome was the incidence of IONV. RESULTS: Intraoperative nausea and vomiting were significantly reduced in the infusion group compared to the bolus group (46% vs 75%, respectively; relative risk [RR], 0.61; 95% confidence interval [CI], 0.47 to 0.80; P < 0.001). This was associated with significantly reduced need for intraoperative rescue antiemetics (26% vs 42%, respectively; RR, 0.62; 95% CI, 0.40 to 0.97; P = 0.04), but no difference in the incidence of vomiting. Postoperative vomiting at two hours was reduced in the infusion group (11% vs 25%; RR, 0.44; 95% CI, 0.21 to 0.90; P = 0.02);however, there were no differences in the incidence or severity of postoperative nausea, need for rescue antiemetics at two hours and 24 hr, or the incidence of postoperative vomiting at 24 hr. CONCLUSION: In obese women undergoing Cesarean delivery with spinal anesthesia, prophylactic phenylephrine infusion was associated with less intraoperative nausea, less need for rescue antiemetics, and reduced early postoperative vomiting. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT01481740). Registered 22 July 2011.

The Oxytocin Product Correlates with Total Oxytocin Received during Labor: A Research Methods Study.

OBJECTIVE: Total dose of oxytocin received during labor is an important variable in studies of human labor but is difficult to calculate. We sought to identify a surrogate measure for total dose of oxytocin received. STUDY DESIGN: For each subject receiving oxytocin during labor, the oxytocin total dose received in labor was calculated as the area under the curve. Maximal oxytocin infusion rate, total duration of oxytocin infusion, and the product of both, defined as the oxytocin product, were then each correlated with the total dose of oxytocin received using the Pearson's correlation coefficient. RESULTS: Oxytocin dosing data were available from 402 women at Duke and 6,907 women from Pithagore6. The two variables alone, or combined as the oxytocin product, demonstrated a high correlation with the oxytocin total dose (r > 0.7), with the oxytocin product demonstrating the highest (r > 0.9). This was true whether labor was induced or augmented and whether delivery was vaginal or cesarean. CONCLUSION: The oxytocin product, composed of two easily obtained variables, demonstrated a very high correlation with total oxytocin dose received in labor and represents a simple and accurate surrogate for total dose of oxytocin received during labor. The oxytocin product can be used in clinical studies in which oxytocin dose is an important variable.

The Effect of Progestins on Tumor Necrosis Factor α-Induced Matrix Metalloproteinase-9 Activity and Gene Expression in Human Primary Amnion and Chorion Cells In Vitro.

BACKGROUND: Current treatment modalities for preventing preterm premature rupture of membranes are limited, but progestins may play a role. Tumor necrosis factor α (TNFα) enhances matrix metalloproteinase-9 (MMP-9) gene expression and activity in fetal membranes, contributing to membrane weakening and rupture. We previously demonstrated that progestins attenuate TNFα-induced MMP-9 activity in a cytotrophoblast cell line. However, whether they have a similar effect in primary amnion and chorion cells of fetal membranes is unknown. In this study, we evaluated the effect of progestins on basal and TNFα-induced MMP-9 activity and gene expression in primary chorion and amnion cells harvested from the fetal membranes of term nonlaboring patients. METHODS: Primary amnion and chorion cells were isolated from fetal membranes obtained from term uncomplicated nonlaboring patients following elective cesarean delivery (n = 11). Confluent primary amnion and chorion cell cultures were both pretreated with vehicle (control), progesterone (P4), 17α-hydroxyprogesterone caproate (17P), or medroxyprogesterone acetate (MPA) at 10 M concentration for 6 hours followed by stimulation with TNFα at 10 ng/mL for an additional 24 hours. Cell cultures pretreated with the vehicle only served as the unstimulated control and the vehicle stimulated with TNFα served as the stimulated control. Both controls were assigned a value of 100 units. Cell culture medium was harvested for MMP-9 enzymatic activity quantification using gelatin zymography. Total RNA was extracted for quantifying MMP-9 gene expression using real-time quantitative PCR. Basal MMP-9 activity and gene expression data were normalized to the unstimulated control. TNFα-stimulated MMP-9 activity and gene expression were normalized to the stimulated control. The primary outcome was the effect of progestins on TNFα-induced MMP-9 enzymatic activity in term human primary amnion and chorion cells in vitro. Secondary outcomes included the effect of progestin therapy on TNFα-induced MMP-9 gene expression and on basal MMP-9 activity and gene expression in primary amnion and chorion cells in vitro. RESULTS: Primary cells were harvested from 11 patients. Compared with the unstimulated control, TNFα increased MMP-9 activity (P = 0.005 versus control in primary amnion cells and P < 0.001 versus control in primary chorion cells) and MMP-9 gene expression (P = 0.030 versus control in primary amnion cells, P < 0.001 versus control in primary chorion cells). Compared with the unstimulated controls, MPA, but not P4 or 17P, reduced basal MMP-9 activity [mean difference (95% CI) -49.6 (-81.9, -17.3) units, P = 0.001] and gene expression [mean difference (95% CI) -53.4 (-105.9, -0.9) units, P = 0.045] in primary amnion cells. Compared with the stimulated control, MPA also reduced TNFα-induced MMP-9 activity [mean difference (95% CI) -69.0 (-91.8, -46.3) units, P < 0.001] and gene expression [mean difference (95% CI) -86.0 (-120.7, -51.3) units, P < 0.001] in primary amnion cells. Progestin pretreatment had no significant effect on basal or TNFα-induced MMP-9 activity and gene expression in primary chorion cells. CONCLUSIONS: The inhibitory effect of MPA on both basal and TNFα-induced MMP-9 activity and gene expression in primary amnion cells demonstrate a possible mechanism by which progestins may prevent fetal membrane weakening leading to preterm premature rupture of membranes.

Anesthetic management and outcomes of parturients with dilated cardiomyopathy in an academic centre.

PURPOSE: This study examines the peripartum anesthetic management and outcomes of women with dilated cardiomyopathy in a large university medical centre over a seven-year period. PRINCIPAL FINDINGS: Twenty-five women were included in this series, 18 with a new diagnosis of cardiomyopathy and seven with a history of cardiomyopathy. Sixteen patients (64%) identified themselves as African American, seven (28%) were Caucasian, and two patients (8%) were Hispanic. The median (range) gestational age at the time of a new diagnosis of cardiomyopathy was 29 (7-38) weeks. Eight women (32%) had New York Heart Association class III/IV symptoms at the time of delivery or in the immediate postpartum period. A multidisciplinary team of obstetricians, anesthesiologists, cardiologists, and pediatricians were involved in the care of these women. The median (range) gestational age at the time of delivery was 33.5 (30-40) weeks. There were nine vaginal deliveries and 15 operative deliveries. One patient had fetal loss at 19 weeks gestation. Twelve women had labour induced with an intravenous infusion of oxytocin at a rate of 0.001-0.02 IU·min(-1). An oxytocin infusion at a variable rate with a maximum dose of 0.05 IU·min(-1) was administered after vaginal delivery to maintain uterine tone. Epidural analgesia was initiated prior to induction of labour or in the latent phase of labour. Seven Cesarean deliveries were performed under combined spinal-epidural anesthesia, five were performed under epidural anesthesia, and three women had general anesthesia. Oxytocin was administered via an intravenous infusion at a rate of 0.05-0.2 IU·min(-1) after operative delivery. One patient had a cardiac arrest on induction of general anesthesia and was successfully resuscitated. There were no maternal or neonatal deaths. Ten women were followed up at our institution and at six months postpartum; 50% of these patients were still symptomatic. CONCLUSION: We report favourable outcomes in 25 pregnant women with dilated cardiomyopathy who were managed by a multidisciplinary team.

Intermittent epidural bolus compared with continuous epidural infusions for labor analgesia: a systematic review and meta-analysis.

BACKGROUND: The current standard labor epidural analgesic regimens consist of a local anesthetic in combination with an opioid delivered via continuous epidural infusion (CEI). With CEI local anesthetic, doses may be large with resulting profound motor blockade potentially affecting the incidence of instrumental deliveries. In this systematic review of randomized controlled trials (RCTs), we compared the effect of intermittent epidural bolus (IEB) to standard CEI dosing with or without patient-controlled epidural analgesia on patient satisfaction, the need for manual anesthesia interventions, labor progression, and mode of delivery in healthy women receiving labor epidural analgesia. METHODS: A systematic review of RCTs that compared CEI with IEB for labor analgesia was performed. The articles were evaluated for validity, and data were extracted by the authors and summarized using odds ratios (ORs), mean differences (MDs), and 95% confidence intervals (CIs). RESULTS: Nine RCTs were included in this systematic review. Three hundred forty-four subjects received CEI, whereas 350 subjects received IEB labor analgesia. All 9 studies were deemed to be low risk of bias. There was no statistical difference detected between IEB and CEI in the rate of cesarean delivery (OR, 0.87; 95% CI, 0.56-1.35), duration of labor (MD, -17 minutes; 95% CI, -42 to 7), or the need for anesthetic intervention (OR, 0.56; 95% CI, 0.29-1.06). IEB did result in a small but statistically significant reduction in local anesthetic usage (MD, -1.2 mg bupivacaine equivalent per hour; 95% CI, -2.2 to -0.3). Maternal satisfaction score (100-mm visual analog scale) was higher with IEB (MD, 7.0 mm; 95% CI, 6.2-7.8). CONCLUSIONS: IEB is an appealing concept; current evidence suggests IEB slightly reduces local anesthetic usage and improves maternal satisfaction. Given the wide CIs of the pooled results for many outcomes, definite conclusions cannot be drawn for those outcomes, but there is also a potential that IEB improves instrumental delivery rate and need of anesthesia interventions. More study is required to conceptualize the ideal IEB regimen and investigate its effect on labor analgesia and obstetric outcomes.

A retrospective assessment of the incidence of respiratory depression after neuraxial morphine administration for postcesarean delivery analgesia.

Respiratory depression can occur after neuraxial morphine administration. In the obstetric population, there are little data on respiratory depression after neuraxial morphine administration in women undergoing cesarean delivery. In this single-center, retrospective study in 5036 obstetric patients (mean body mass index = 34 kg/m) who underwent cesarean delivery and received neuraxial morphine, we did not identify any instances of respiratory depression requiring naloxone administration or rapid response team involvement. Therefore, the upper 95% confidence limit for respiratory depression in our study is 0.07% (1 event per 1429 cases).

Duration of exposure to epidural anesthesia at delivery, DNA methylation in umbilical cord blood and their association with offspring asthma in Non-Hispanic Black women.

Epidural anesthesia is an effective pain relief modality, widely used for labor analgesia. Childhood asthma is one of the commonest chronic medical illnesses in the USA which places a significant burden on the health-care system. We recently demonstrated a negative association between the duration of epidural anesthesia and the development of childhood asthma; however, the underlying molecular mechanisms still remain unclear. In this study of 127 mother-child pairs comprised of 75 Non-Hispanic Black (NHB) and 52 Non-Hispanic White (NHW) from the Newborn Epigenetic Study, we tested the hypothesis that umbilical cord blood DNA methylation mediates the association between the duration of exposure to epidural anesthesia at delivery and the development of childhood asthma and whether this differed by race/ethnicity. In the mother-child pairs of NHB ancestry, the duration of exposure to epidural anesthesia was associated with a marginally lower risk of asthma (odds ratio = 0.88, 95% confidence interval = 0.76-1.01) for each 1-h increase in exposure to epidural anesthesia. Of the 20 CpGs in the NHB population showing the strongest mediation effect, 50% demonstrated an average mediation proportion of 52%, with directional consistency of direct and indirect effects. These top 20 CpGs mapped to 21 genes enriched for pathways engaged in antigen processing, antigen presentation, protein ubiquitination and regulatory networks related to the Major Histocompatibility Complex (MHC) class I complex and Nuclear Factor Kappa-B (NFkB) complex. Our findings suggest that DNA methylation in immune-related pathways contributes to the effects of the duration of exposure to epidural anesthesia on childhood asthma risk in NHB offspring.

Dexamethasone for the prophylaxis of postoperative nausea and vomiting associated with neuraxial morphine administration: a systematic review and meta-analysis.

BACKGROUND: We performed a systematic review to assess the efficacy of dexamethasone in reducing postoperative nausea, vomiting (PONV), pruritus, and enhancing postoperative analgesia in patients receiving neuraxial anesthesia with neuraxial morphine. METHODS: We searched Medline (1966-2011), the Cochrane Central Register of Controlled Trials, EMBASE, and Web of Science for all randomized controlled trials comparing dexamethasone with placebo for the prevention of PONV and/or pruritus in patients receiving neuraxial morphine as part of a neuraxial anesthetic technique. Data were extracted independently by the authors on the incidence of PONV, pruritus, pain scores at 4 and 24 hours, and use of rescue antiemetics, antipruritics, and analgesics. RESULTS: Eight randomized controlled trials (4 cesarean deliveries, 4 total abdominal hysterectomies) were included. From these trials, 768 patients were analyzed with 473 receiving dexamethasone and 295 receiving placebo. The doses of dexamethasone investigated ranged from 2.5 to 10 mg. Dexamethasone reduced the incidence of postoperative nausea (relative risk, RR [95% confidence interval, CI] = 0.57 [0.45, 0.72]), vomiting (RR [95% CI] = 0.56 [0.43, 0.72]), and the use of rescue antiemetic therapy (RR [95% CI] = 0.47 [0.36, 0.61]) compared with placebo. There was no evidence of dose responsiveness with respect to its antiemetic effect. Dexamethasone also reduced 24-hour visual analog pain scores (measured on an 11-point scale [0-10]) (mean difference [95% CI] = -0.30 [-0.46, -0.13]) and the use of rescue analgesics (RR [95% CI] = 0.72 [0.52, 0.98]). Dexamethasone did not reduce the incidence of pruritus (RR [95% CI] = 0.98 [0.84, 1.15]). Examination of the funnel plots and Egger's test revealed evidence of publication bias in the primary outcomes. CONCLUSION: Dexamethasone is an effective antiemetic for patients receiving neuraxial morphine for cesarean delivery and abdominal hysterectomy. In addition, the doses used for antiemetic prophylaxis enhanced postoperative analgesia compared with placebo. However, dexamethasone was not effective for the prophylaxis against neuraxial morphine-induced pruritus.

Analgesic and antiemetic needs following minimally invasive vs open staging for endometrial cancer.

OBJECTIVE: We sought to assess perioperative outcomes of minimally invasive vs open endometrial cancer staging procedures. STUDY DESIGN: A total of 181 consecutive patients underwent open or minimally invasive hysterectomy with or without lymphadenectomy. Perioperative outcomes, analgesic, and antiemetic use were compared. RESULTS: In all, 97 and 84 women underwent open and minimally invasive staging procedures, respectively. In the open staging group, median anesthesia time was shorter (197 vs 288 minutes; P < .0001), but recovery room stay (168 vs 140 minutes; P = .01) and hospital stay (4 vs 1 day; P < .0001) were longer. Median narcotic (13 vs 43 mg morphine equivalents; P < .0001) and antiemetic (43% vs 25%; P = .01) use were lower for minimally invasive surgery in the first 24 hours postoperatively. Median estimated blood loss was lower for minimally invasive procedures (100 vs 300 mL; P < .0001). CONCLUSION: Minimally invasive staging for endometrial cancer is associated with lower use of narcotics and antiemetics, and shorter hospital stay compared to open procedures.

Dexamethasone as an Analgesic Adjunct for Postcesarean Delivery Pain: A Randomized Controlled Trial.

OBJECTIVES: Dexamethasone has been shown to have analgesic properties in the general surgical population. However, the analgesic effects for women that undergo cesarean deliveries under spinal anesthesia remain unclear and may be related to the timing of dexamethasone administration. We hypothesized that intravenous dexamethasone administered before skin incision would significantly reduce postoperative opioid consumption at 24 h after cesarean delivery under spinal anesthesia with intrathecal morphine. METHODS: Women undergoing elective cesarean deliveries under spinal anesthesia were randomly assigned to receive 8 mg of intravenous dexamethasone or placebo prior to skin incision. Both groups received a standardized spinal anesthetic and multimodal postoperative analgesic regime. The primary outcome was cumulative opioid consumption at 24 h. Secondary outcomes included cumulative opioid consumption at 48 h, time to first analgesic request, and pain scores at rest and on movement at 2, 24, and 48 h. RESULTS: 47 patients were analyzed-23 subjects that received dexamethasone and 24 subjects that received placebo. There was no difference in the median (Q1, Q3) cumulative opioid consumption in the first 24 hours following cesarean delivery between the dexamethasone group {15 (7.5, 20.0) mg} and the placebo group {13.75 (2.5, 31.25) mg} (P=0.740). There were no differences between the groups in cumulative opioid consumption at 48 h, time to first analgesic request, and pain scores. CONCLUSIONS: Intravenous dexamethasone 8 mg administered prior to skin incision did not reduce the opioid consumption of women that underwent cesarean deliveries under spinal anesthesia with intrathecal morphine and multimodal postoperative analgesic regimen.

Associations between maternal obesity, gestational cytokine levels and child obesity in the NEST cohort.

BACKGROUND: Although maternal systemic inflammation is hypothesized to link maternal pre-pregnancy obesity to offspring metabolic dysfunction, patient empirical data are limited. OBJECTIVES: In this study, we hypothesized that pre-pregnancy obesity alters systemic chemo/cytokines concentrations in pregnancy, and this alteration contributes to obesity in children. METHODS: In a multi-ethnic cohort of 361 mother-child pairs, we measured prenatal concentrations of plasma TNF-α, IL-6, IL-8, IL-1ß, IL-4, IFN-γ, IL-12 p70 subunit, and IL-17A using a multiplex ELISA and examined associations of pre-pregnancy obesity on maternal chemo/cytokine levels, and associations of these cytokine levels with offspring body mass index z score (BMI-z) at age 2-6 years using linear regression. RESULTS: After adjusting for maternal smoking, ethnicity, age, and education, pre-pregnancy obesity was associated with increased concentrations of TNF-α (P = .026) and IFN-γ (P = .06). While we found no evidence for associations between TNF-α concentrations and offspring BMI-z, increased IFN-γ concentrations were associated with decreased BMI-z (P = .0002), primarily in Whites (P = .0011). In addition, increased maternal IL-17A concentrations were associated with increased BMI-z in offspring (P = .0005) with stronger associations in African Americans (P = .0042) than Whites (P = .24). CONCLUSIONS: Data from this study are consistent with maternal obesity-related inflammation during pregnancy, increasing the risk of childhood obesity in an ethnic-specific manner.

A double-blind, placebo-controlled trial of four fixed rate infusion regimens of phenylephrine for hemodynamic support during spinal anesthesia for cesarean delivery.

BACKGROUND: The administration of prophylactic phenylephrine infusions in combination with fluid cohydration significantly reduces the incidence of hypotension in women having cesarean delivery under spinal anesthesia. The ideal dosing regimen for this purpose is not known. In this study, we investigated the dose of phenylephrine that, when administered as a prophylactic fixed rate infusion, is associated with the least interventions needed to maintain maternal systolic blood pressure (SBP) within 20% of baseline. METHODS: Women undergoing elective cesarean delivery were randomly allocated to receive placebo or prophylactic phenylephrine infusion at 25, 50, 75, or 100 µg/min immediately after spinal anesthesia in combination with a 2-L fluid coload. Maternal SBP was maintained within the target range using a predetermined algorithm. The number of physician interventions, hemodynamic performance, intraoperative nausea and vomiting, and umbilical cord blood gases were compared among the groups. RESULTS: One hundred one patients were included in the analysis. There were no differences between the placebo and phenylephrine groups in the number of interventions needed to maintain maternal SBP within the target range. Doses of phenylephrine of 25 and 50 µg/min were associated with significantly fewer interventions when compared with 100 µg/min (P = 0.004 vs 50 µg/min, P = 0.02 vs 25 µg/min). Predelivery hypotension was more frequent in the control group compared with all phenylephrine groups. Phenylephrine 75 and 100 µg/min groups were associated with a significantly higher incidence of predelivery hypertension compared with control (P < 0.001 vs 75 µg/min and 100 µg/min). There was a trend toward an increase in median magnitude of deviations of SBP above or below baseline (P = 0.006), and the bias of SBP to be above baseline (P < 0.001) with increasing rates of phenylephrine infusion. There were no differences in the incidence and severity of intraoperative nausea and vomiting and umbilical cord blood gases among the groups. CONCLUSIONS: The use of prophylactic fixed rate phenylephrine infusions did not significantly reduce the number of physician interventions needed to maintain maternal predelivery SBP within 20% of baseline compared with placebo. However, prophylactic phenylephrine infusions reduced the incidence and severity of maternal predelivery hypotension. Phenylephrine 25 and 50 µg/min administered as a prophylactic fixed rate infusion provided greater maternal hemodynamic stability than phenylephrine 75 and 100 µg/min. Prophylactic fixed rate infusions may have limited application in clinical practice, and future studies assessing the accuracy of hemodynamic control with variable rate phenylephrine infusions are needed.

Progestins Inhibit Interleukin-1ß-Induced Matrix Metalloproteinase 1 and Interleukin 8 Expression via the Glucocorticoid Receptor in Primary Human Amnion Mesenchymal Cells.

Preterm premature rupture of membranes is a leading cause of preterm births. Cytokine induced matrix metalloproteinase1 and interleukin 8 production from amnion mesenchymal cells may contribute to fetal membrane weakening and rupture. Progestins inhibit inflammation induced fetal membrane weakening but their effect on the inflammatory response of amnion mesenchymal cells is unknown. This study was designed to determine the role of progesterone receptor membrane component 1 and the glucocorticoid receptor in mediating the effects of progestins on interleukin-1ß induced matrix metalloproteinase 1 and interleukin-8 expression in human amnion mesenchymal cells. Primary amnion mesenchymal cells harvested from human fetal membranes were passaged once and treated with vehicle, progesterone or medroxyprogesterone acetate at 10-6 M for 1 h followed by stimulation with interleukin-1ß at 1 ng/ml for 24 h. Medroxyprogesterone acetate but not progesterone inhibited interleukin-1ß-induced interlukin-8 and matrix metalloproteinase 1 mRNA expression. In subsequent dose response studies, medroxyprogesterone acetate, but not progesterone, at doses of 10-6-10-8 M inhibited interleukin-1ß induced interleukin-8 and matrix metalloproteinase 1 mRNA expression. We further demonstrated that inhibition of glucocorticoid receptor expression, but not progesterone receptor membrane component 1 knockdown with small interfering RNA transfection, resulted in a reversal in medroxyprogesterone acetate's (10-7 M) inhibition of interleukin-1ß- induced matrix metalloproteinase 1 mRNA expression and interleukin-8 mRNA expression and protein expression. Our findings demonstrate that medroxyprogesterone acetate exerts its anti-inflammatory effect primarily through the glucocorticoid receptor in human amnion mesenchymal cells. Modulation of glucocorticoid receptor signaling pathways maybe a useful therapeutic strategy for preventing inflammation induced fetal membrane weakening leading to preterm premature rupture of membranes.

Functional Genomics of Healthy and Pathological Fetal Membranes.

Premature preterm rupture of membranes (PPROM), rupture of fetal membranes before 37 weeks of gestation, is the leading identifiable cause of spontaneous preterm births. Often there is no obvious cause that is identified in a patient who presents with PPROM. Identifying the upstream molecular events that lead to fetal membrane weakening presents potentially actionable mechanisms which could lead to the identification of at-risk patients and to the development of new therapeutic interventions. Functional genomic studies have transformed understanding of the role of gene regulation in diverse cells and tissues involved health and disease. Here, we review the results of those studies in the context of fetal membranes. We will highlight relevant results from major coordinated functional genomics efforts and from targeted studies focused on individual cell or tissue models. Studies comparing gene expression and DNA methylation between healthy and pathological fetal membranes have found differential regulation between labor and quiescent tissue as well as in preterm births, preeclampsia, and recurrent pregnancy loss. Whole genome and exome sequencing studies have identified common and rare fetal variants associated with preterm births. However, few fetal membrane tissue studies have modeled the response to stimuli relevant to pregnancy. Fetal membranes are readily adaptable to cell culture and relevant cellular phenotypes are readily observable. For these reasons, this is now an unrealized opportunity for genomic studies isolating the effect of cell signaling cascades and mapping the fetal membrane responses that lead to PPROM and other pregnancy complications.

Serotonin receptor antagonists for the prevention and treatment of pruritus, nausea, and vomiting in women undergoing cesarean delivery with intrathecal morphine: a systematic review and meta-analysis.

BACKGROUND: We performed a systematic review to determine the overall efficacy of serotonin (5-HT3) receptor antagonists for the prevention and treatment of pruritus, nausea, and vomiting in women receiving spinal anesthesia with intrathecal morphine for cesarean delivery. METHODS: Reports of randomized, controlled trials that compared prophylaxis or treatment of pruritus and/or nausea, and vomiting using one of the 5-HT3 receptor antagonists or placebo in women undergoing cesarean delivery were reviewed. The articles were scored for validity and data were extracted by the authors independently and summarized using relative risks (RR) with 95% confidence intervals (CI). RESULTS: Nine randomized, controlled trials were included in the systematic review. The nine trials had a total of 1152 patients enrolled; 539 received 5-HT3 receptor antagonists, 413 received placebo, and 200 received other antiemetics and were not included in the analysis. The incidence of pruritus was not reduced with 5-HT3 receptor antagonists prophylaxis compared with placebo (80.7% vs 85.8%, RR [95% CI] = 0.94 [0.81-1.09]). However, their use reduced the incidence of severe pruritus and the need for treatment of pruritus (number-needed-to-treat = 12 and 15, respectively). Their use for the treatment of established pruritus showed improved efficacy compared with placebo with a number-needed-to-treat of three. There was a significant reduction in the incidence of postoperative nausea (22.0% vs 33.6%, RR [95% CI] = 0.75[0.58-0.96]) and vomiting (7.7% vs 16.8%, RR [95% CI] = 0.49 [0.30-0.81]), and the need for postoperative rescue antiemetic treatment with the use of 5-HT(3) receptor antagonists when compared with placebo (9% vs 23%, RR [95% CI] = 0.38 [0.21-0.68]). CONCLUSIONS: Although prophylactic 5-HT(3) receptor antagonists were ineffective in reducing the incidence of pruritus, they significantly reduced the severity and the need for treatment of pruritus, the incidence of postoperative nausea and vomiting, and the need for rescue antiemetic therapy in parturients who received intrathecal morphine for cesarean delivery. They were also effective for the treatment of established pruritus. Although more studies are warranted, the current data suggest that the routine prophylactic use of those drugs should be considered in this patient population.

Roles of Progesterone Receptor Membrane Component 1 in Oxidative Stress-Induced Aging in Chorion Cells.

INTRODUCTION: Oxidative stress-mediated fetal membrane cell aging is activated prematurely in preterm premature rupture of membranes (PPROMs). The mechanism of this phenomenon is largely understudied. Progesterone receptor membrane component 1 (PGRMC1) has been recognized as a potential protective component for maintaining fetal membrane integrity and healthy pregnancies. We aimed to investigate the effects of oxidative stress (represented by hydrogen peroxide [H2O2]) on fetal membrane and chorion cell senescence, p38 mitogen-activated protein kinase (MAPK) phosphorylation, and sirtuin 3 (SIRT3) and to examine the roles of PGRMC1 in these effects. METHODS: Following serum starvation for 24 hours, full-thickness fetal membrane explants and primary chorion cells were treated with H2O2 at 100, 300, and 500 µM for 24 hours. Cells were fixed for cell senescence-associated ß-galactosidase assay. Cell lysates were harvested for quantitive reverse transcription polymerase chain reaction to quantify SIRT3 messenger RNA. Cell lysates were harvested for Western blot to semi-quantify SIRT3 protein and p38 MAPK phosphorylation levels, respectively. To examine the role of PGRMC1, primary chorion cells underwent the same treatment mentioned above following PGRMC1 knockdown using validated PGRMC1-specific small-interfering RNA. RESULTS: Hydrogen peroxide significantly induced cell senescence and p38 MAPK phosphorylation, and it significantly decreased SIRT3 expression in full-thickness fetal membrane explants and chorion cells. These effects were enhanced by PGRMC1 knockdown. DISCUSSION: This study further demonstrated that oxidative stress-induced cell aging is one of the mechanisms of PPROM and PGRMC1 acts as a protective element for maintaining fetal membrane integrity by inhibiting oxidative stress-induced chorion cell aging.

Progestins Inhibit Tumor Necrosis Factor α-Induced Matrix Metalloproteinase 9 Activity via the Glucocorticoid Receptor in Primary Amnion Epithelial Cells.

Progestins have been recommended for preterm birth prevention in high-risk women; however, their mechanism of action still remains an area of debate. Medroxyprogesterone acetate (MPA) has previously been shown to significantly inhibit tumor necrosis factor α (TNFα)-induced matrix metalloproteinase 9 (MMP9) messenger RNA (mRNA) expression and activity in primary amnion epithelial cells, a process that may lead to preterm premature rupture of membranes. A mechanism that explains MPA's inhibition of TNFα-induced MMP9 mRNA expression and activity in primary amnion epithelial cells is unclear since these cells lack the classic nuclear progesterone receptor but express a membrane-associated progesterone receptor-progesterone receptor membrane component 1 (PGRMC1) along with the glucocorticoid receptor (GR). Primary amnion epithelial cells harvested from healthy term pregnant women at cesarean section were treated with PGRMC1 (to knockdown PGRMC1 expression), GR (to knockdown GR expression), or control small interfering RNA (siRNA; 10 nm) for 72 hours, pretreated with ethanol or MPA (10-6 M) for 6 hours, and then stimulated with or without TNFα 10 ng/mL for 24 hours. Real-time quantitative polymerase chain reaction and gelatin zymography were used to quantify MMP9 mRNA expression and activity, respectively. Experimental groups were compared using 1-way analysis of variance. Both TNFα-induced MMP9 mRNA expression and activity were significantly inhibited by pretreatment with MPA; however, only the inhibition of TNFα-induced MMP9 activity was partially reversed with PGRMC1 siRNA. However, GR siRNA reversed both the inhibition of TNFα-induced MMP9 mRNA expression and activity by MPA. This study demonstrates that MPA mediates its anti-inflammatory effects primarily through GR and partially through PGRMC1 in primary amnion epithelial cells.

P6 stimulation for the prevention of nausea and vomiting associated with cesarean delivery under neuraxial anesthesia: a systematic review of randomized controlled trials.

BACKGROUND: A number of studies investigated the use of P6 stimulation for the prevention of intraoperative and postoperative nausea and vomiting (IONV and PONV) in women having cesarean delivery under neuraxial anesthesia. We performed a systematic review to determine the overall efficacy of these techniques in preventing IONV and PONV in this patient population. METHODS: We performed a literature search of all randomized controlled trials (1966-2007) that compared different methods of P6 stimulation with placebo in women having cesarean delivery under neuraxial anesthesia. Data were extracted on the primary outcomes including the incidence of nausea, vomiting, and the need for rescue antiemetic therapy, both intraoperatively and postoperatively. RESULTS: Six studies involving 649 patients were included in this review. Five studies reported on intraoperative outcomes. Of these, two studies reported a significant reduction in the incidence of intraoperative nausea with P6 stimulation, and one study reported a significant reduction in rescue antiemetic requirement. However, none of the studies reported any differences between the treatment and control groups with respect to vomiting. Four studies reported postoperative outcomes. Of these, one study reported a significant reduction in postoperative nausea, two studies reported a significant reduction in postoperative vomiting, and one study reported a significant reduction in the need for postoperative rescue antiemetic therapy. CONCLUSIONS: While some studies showed a benefit of P6 stimulation, this finding was not consistent. The presence of heterogeneity and inconsistent results among the included trials prevents any definitive conclusions on the efficacy of P6 stimulation in reducing IONV and PONV associated with cesarean delivery performed under neuraxial anesthesia.