Induction, labor length and mode of delivery: the impact on preeclampsia-related adverse maternal outcomes.

OBJECTIVE: The objectives were to evaluate whether induction, specifically prolonged labor, was associated with adverse maternal outcomes related to preeclampsia with severe features (PEC-S) and whether cesarean affected the rate. STUDY DESIGN: This was a retrospective cohort study of women with PEC-S ⩾34 weeks who were diagnosed either before planned cesarean or before induction/latent labor. The primary outcome was a composite adverse maternal outcome related to PEC-S. RESULTS: The final cohort comprised 193 women (n=172 with labor and n=21 with planned cesarean). The prevalence of the outcome was 15.5%. Women exposed to labor did not have a higher rate compared with planned cesarean (16.3% vs 9.5%, P=0.4). Adjusting for confounders, women with a cesarean after prolonged labor had a 10-fold higher adverse outcome risk compared with women with a planned cesarean (adjusted odds ratio (aOR) 9.7 (1.2 to 78.6), P=0.03) or with a vaginal delivery <24 h (aOR 9.7 (1.4 to 67.4), P=0.02). CONCLUSION: Prolonged labor and cesarean in labor were both associated with an increase in our outcome.

Rethinking IUGR in preeclampsia: dependent or independent of maternal hypertension?

OBJECTIVE: Chronic hypertension (CHTN) is a risk factor for both intrauterine growth restriction (IUGR) as well as preeclampsia. This study was performed to: (1) describe the prevalence of IUGR in women with preeclampsia (with and without CHTN) compared with controls, (2) investigate the relationship between preeclampsia and maternal CHTN with IUGR, and (3) investigate the relationship between IUGR and severity of preeclampsia. STUDY DESIGN: A case-control study was performed. Cases were patients identified with preeclampsia. Controls were patients presenting for delivery at term (>or=37 weeks). IUGR prevalence by case-control status, or severity of disease was evaluated using Pearson chi(2) tests. Multivariable logistic regression was used to control for confounders. RESULT: In all, 430 cases and 568 controls were studied. Preeclamptic women have a 2.7 (CI (1.94 to 3.86)) and 4.3 (CI (2.58 to 7.17)) times increased odds of having a fetus with IUGR at <10 and <5% compared with controls in adjusted analyses. There was a significant interaction between CHTN and IUGR. Therefore, in women without CHTN, women with PEC had increased odds of IUGR, whereas in women with CHTN, there was no difference in odds of IUGR in women with or without preeclampsia. Within the cases, severe preeclampsia was associated with IUGR<10% (AOR=1.82 (1.11 to 2.97)) but not IUGR<5% (AOR=1.6 (0.85 to 2.86)). CONCLUSION: Preeclampsia is independently associated with the development of IUGR. As suggested earlier, women with CHTN do not have the highest prevalence of IUGR, suggesting disparate pathways by which IUGR develops in women with superimposed preeclampsia compared with preeclampsia alone.

The role of thrombin in preterm parturition.

OBJECTIVE: Previous reports from our laboratory have shown that thrombin is a potent uterotonic agonist; those studies have suggested a role for thrombin during parturition, especially with regard to intrauterine bleeding. Thrombin activation can be quantified in peripheral blood by measurement of thrombin-antithrombin III (TAT) complex levels. This study sought to determine whether thrombin activation, as measured by thrombin-antithrombin III levels, is associated with premature labor. STUDY DESIGN: Thrombin-antithrombin III levels were measured in patients and control subjects with preterm labor. Quantitative TAT levels were determined by use of an enzyme-linked immunoassay with a working range from 0 to 60 ng/mL. All patients were monitored for pregnancy outcome. Receiver operating curve analysis was performed to determine the optimal TAT cutoff values. Further statistical analyses with one-way ANOVA, the chi2 test, or the Fisher exact test were performed to determine statistical significance (P <.05). RESULTS: Patients admitted with preterm labor who were subsequently delivered within 3 weeks had significantly higher mean TAT levels (7.80 +/- 2.86 ng/mL; P <.05) than control subjects (5.77 +/- 1.43 mL) or patients with preterm labor who were not delivered within 3 weeks of presentation with preterm labor (5.57 +/- 1.69 ng/mL; P <.05). Given a diagnosis of preterm labor, a TAT level of 8.0 ng/mL had a positive predictive value of 80% for delivery within 3 weeks of enrollment. CONCLUSIONS: This study showed that TAT levels are elevated in patients with preterm labor who are destined to deliver before term. These results suggest that preterm labor resulting in premature delivery is associated with the activation of thrombin. Future studies will further elucidate the role of thrombin in preterm parturition and confirm whether tests for thrombin activation can accurately identify those patients destined for preterm delivery.

Thrombin-stimulated uterine contractions in the pregnant and nonpregnant rat.

OBJECTIVE: Thrombin generated during the active clotting of blood appears to be a potent uterotonic agonist; however, the mechanism underlying this effect on uterine smooth muscle is not well understood. We performed studies to confirm the uterotonic effects of thrombin and to determine whether prostaglandin production plays a role during the uterotonic effects of thrombin or clotting blood. METHODS: Uterine contraction studies were performed using adult nonpregnant and near-term pregnant rats. The in vitro isometric contraction studies used uterine strips pretreated with indomethacin or vehicle (ethanol), which were then stimulated with thrombin. For the in vivo contraction studies, rats were pretreated with intraperitoneal injections of indomethacin or vehicle (ethanol) then stimulated by intraluminal injection of fresh rat blood or thrombin into the uterus. The contraction data were acquired using isometric force transducers, were computer digitized, normalized for spontaneous activity, and statistically analyzed. Prostaglandin (PG) F2alpha was measured using an enzyme-linked immunoassay. RESULTS: The in vitro contraction studies demonstrated that both thrombin and actively clotting blood produce a significant increase in the frequency and intensity of uterine contractions. Thrombin stimulation was associated with a 54% increase in PGF2alpha concentration in vitro; indomethacin (1 microM) pretreatment completely inhibited that increase in PGF2alpha production. Despite the suppression of PGF2alpha production, pretreatment with indomethacin had no inhibitory effect on thrombin-stimulated contractile activity. In vivo contraction studies further confirmed that indomethacin (2 mg/kg) pretreatment had no effect on blood- or thrombin-stimulated contractile activity. CONCLUSIONS: We confirmed that thrombin and thrombin produced by actively clotting blood had a robust uterotonic effect in the rat and that prostaglandin production did not play a significant role in thrombin-stimulated contractions.

Effects of thrombin on myometrial contractions in vitro and in vivo.

OBJECTIVE: A previous report from our laboratory demonstrated that thrombin stimulates myometrial contractions by activating the phosphatidylinositol signaling pathway in a dose-dependent fashion. The studies described in this report sought to determine whether thrombin and blood stimulate myometrial contractions both in vivo and in vitro and whether these uterotonic effects could be suppressed or prevented with thrombin inhibitors. STUDY DESIGN: In vitro contraction studies were performed with proestrus and estrus rat myometrial tissue. In vivo contraction studies were performed with nonpregnant and timed-pregnant Sprague-Dawley rats. RESULTS: Pretreatment of thrombin with hirudin suppressed the uterotonic effects of thrombin in vitro. Fresh whole blood stimulated myometrial contractions in a dose-dependent fashion in vitro, and thrombin inhibitors decreased the myometrial response seen with blood alone. Thrombin increased the frequency, intensity, and tone of myometrial contractions in vivo in a dose-related manner. In pregnant animals increasing doses of whole blood increased the frequency and tone of myometrial contractions. In both pregnant and nonpregnant animals whole blood significantly stimulated myometrial contractions, whereas heparinization of the blood significantly suppressed this in vivo uterotonic effect. CONCLUSION: Thrombin is a potent uterotonic agent both in vitro and in vivo; furthermore, the uterotonic effects of blood appeared to be related to thrombin production during coagulation. These studies provide a possible mechanistic explanation for the observed increase in myometrial contractions in the presence of intrauterine bleeding and may also provide an insight into preterm labor associated with vaginal bleeding.

The mechanisms underlying the stimulatory effects of thrombin on myometrial smooth muscle.

OBJECTIVE: The mechanisms underlying the stimulation of uterine contractions in the presence of intrauterine hemorrhage have not been well defined. Thrombin, a blood coagulation factor, activates membrane receptors to result in the stimulation of the phosphatidylinositol signaling pathway and the mobilization of cytosolic calcium in platelets. Our studies sought to determine whether thrombin stimulates similar events in myometrial smooth muscle. STUDY DESIGN: Cytosolic calcium imaging and in vitro contraction studies were performed with rat myometrial tissue. RESULTS: At a concentration range of 1 to 100 U/mL thrombin produced phasic myometrial contractions, which were comparable in intensity to those produced by oxytocin and prostaglandin F(2)(alpha). Thrombin-induced cytosolic calcium concentration oscillations were similar to those produced by oxytocin. Contractions stimulated by thrombin were significantly suppressed in response to inhibitors of the phosphatidylinositol signaling pathway. These studies also confirmed that membrane receptor-Gq protein coupling events play a more important role than tyrosine kinase-mediated events during thrombin stimulation of myometrial smooth muscle. CONCLUSION: Thrombin is a potent uterotonic agonist, and its effects in myometrium are mediated by intracellular signaling events comparable to those activated by classic uterotonic agents. The physiologic importance of thrombin appears to be related to its potential role in the stimulation of uterine contractions in the presence of intrauterine hemorrhage.

The effects of 2-aminoethoxydiphenyl borate, a novel inositol 1,4, 5-trisphosphate receptor modulator on myometrial contractions.

These studies were performed to evaluate the effect of 2-aminoethoxydiphenyl borate (2-APB), a novel membrane-permeable inositol 1,4,5-trisphosphate-receptor inhibitor on agonist-induced, spontaneous, and KCl-stimulated in vitro myometrial contractions. 2-APB significantly inhibited spontaneous myometrial contractions as well as phasic contractions induced by various uterotonic agonists. Confiriming its effects on intracellular calcium release, 2-APB inhibited phasic contractions in the absence of extracellular calcium. 2-APB had little effect on the tonic response to KCl stimulation, implicating its insignificant effect on voltage-gated calcium channels. The inhibitory effect of 2-APB on phasic contractions was completely reversed by washout. In summary, 2-APB effectively penetrated uterine tissue and significantly inhibited myometrial events previously shown to be mediated through activation of the PI-signaling pathway.

Induction and regulation of class II major histocompatibility complex mRNA expression in astrocytes by interferon-gamma and tumor necrosis factor-alpha.

Astrocytes can function as antigen-presenting cells (APC) upon expression of class II major histocompatibility complex (MHC) antigens, which are induced by interferon-gamma (IFN-gamma). Previous data from this laboratory had shown that the cytokine tumor necrosis factor-alpha (TNF-alpha) enhances IFN-gamma-mediated class II antigen expression on astrocytes. We have now investigated the effect of IFN-gamma and TNF-alpha on class II MHC mRNA expression in astrocytes using Northern blot analysis. Astrocytes do not constitutively express mRNA for class II MHC. Kinetic analysis of class II MHC mRNA expression in IFN-gamma-treated cells demonstrated an 8 h time lag, which was followed by an increase over the next 16 h. Optimal expression of class II mRNA was detected after a 24 h incubation with IFN-gamma. This level of expression was further enhanced by the simultaneous addition of IFN-gamma and TNF-alpha to the astrocytes, while TNF-alpha alone had no effect on class II mRNA expression. TNF-alpha does not act by increasing the stability of IFN-gamma-induced class II mRNA, indicating its action is not at that specific level of post-transcriptional control. Furthermore, astrocyte class II mRNA expression was inhibited when cycloheximide (CHX) was added together with IFN-gamma or IFN-gamma/TNF-alpha, and when CHX was added up to 4 h after treatment with IFN-gamma or IFN-gamma/TNF-alpha. These results indicate that astrocyte class II mRNA expression is mediated by newly synthesized proteins induced by IFN-gamma and/or IFN-gamma/TNF-alpha. The expression of class II antigens on astrocytes, and cytokine modulation of their expression, may be important in the initiation and perpetuation of intracerebral immune responses.