Nitric oxide donors for cervical ripening in first-trimester surgical abortion.

BACKGROUND: Cervical priming before first-trimester surgical abortion is recommended in certain groups of women. Nitric oxide (NO) donors induce cervical ripening without uterine contractions, but the efficacy and side effects are of concern. OBJECTIVES: To evaluate NO donors for cervical ripening before first-trimester surgical abortion, in terms of efficacy, side effects, and reduction of complications. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and POPLINE. We also searched reference lists of retrieved papers. We contacted experts in the field for information on both published and unpublished trials. SELECTION CRITERIA: Randomised controlled trials comparing NO donors alone or in combination with other methods for cervical ripening in first-trimester surgical abortion. DATA COLLECTION AND ANALYSIS: Two review authors independently selected and extracted the data onto a data extraction form. We processed the data using Review Manager (RevMan 5) software. MAIN RESULTS: We included 9 studies involving 766 participants. There were no serious complications (infection requiring antibiotic treatment, blood transfusion, complications requiring unintended operation, cervical injury, uterine perforation, death or serious morbidity) in the included trials.NO donors were more effective in cervical ripening when compared with placebo or no treatment. Baseline cervical dilatation before the procedure was higher in NO donors group (mean difference (MD) 0.30, 95% confidence interval (CI) 0.01 to 0.58) The cumulative force required to dilate the cervix to 8 mm (MD -4.29, 95% CI -9.92 to 1.35), headache (risk ratio (RR) 1.73, 95% CI 0.86 to 3.46), abdominal pain (RR 0.87, 95% CI 0.50 to 1.50), or patient satisfaction (RR 0.95, 95% CI 0.84 to 1.07) were not different. More nausea and vomiting occurred in the women who received a NO donor (RR 2.62, 95% CI 1.07 to 6.45).NO donors were inferior to prostaglandins for cervical ripening. The cumulative force required to dilate the cervix to 8 mm to 9 mm was higher (MD 13.12, 95% CI 9.72 to 16.52), and baseline cervical dilatation was less (MD -0.73, 95% CI -1.01 to -0.45) in the NO donor group. However, the probability of dilation greater than 8 mm at three hours was higher in the NO donor group (RR 6.67, 95% CI 2.21 to 20.09). Side effects including headache (RR 5.13, 95% CI 3.29 to 8.00), palpitation (RR 3.43, 95% CI 1.64 to 7.15), dizziness (RR 3.29, 95% CI 1.46 to 7.41), and intraoperative blood loss (MD 33.59 ml, 95% CI 24.50 to 42.67) were also higher. However, abdominal pain (RR 0.33, 95% CI 0.25 to 0.44) and vaginal bleeding (RR 0.14, 95% CI 0.07 to 0.27) were less in the NO donor group. No difference for nausea/vomiting in both groups(RR 1.17, 95% CI 0.94 to 1.46). Patient satisfaction was not different.One trial compared a NO donor with a NO donor plus prostaglandin. The cumulative force required to dilate the cervix to 8 mm was higher (MD 14.50, 95% CI 0.50 to 28.50) in the NO donor group. There was no difference in headache (RR 0.88, 95% CI 0.38 to 2.00), abdominal pain (RR 0.14, 95% CI 0.02 to 1.07), or intraoperative blood loss (MD -50, 95% CI -164.19 to 64.19). AUTHORS' CONCLUSIONS: NO donors are superior to placebo or no treatment, but inferior to prostaglandins for first-trimester cervical ripening, and associated with more side effects.

A new role for monocytes in modulating myometrial inflammation during human labor.

Here we fully characterize the cytokine profile of laboring human myometrium using Luminex analysis of 48 cytokine proteins, and stereologically quantified infiltration of monocytes and neutrophils into the myometrium. We hypothesized that monocytes can regulate their accumulation in the myometrium by disruption of proinflammatory cytokines to prevent an uncontrolled inflammatory response after labor onset. We isolated primary human myometrial cells (HMCs) from term, nonlaboring myometrial biopsies. Confluent HMCs were cocultured directly with human monocytic (THP-1) or lymphocytic (U937) cells, and with the same cells spatially separated by a membrane insert. After 72 h, HMCs and THP-1 were harvested separately, and RNA was extracted and analyzed by quantitative PCR. Coculture supernatants were collected and analyzed by Luminex assay and ELISA. We found that the laboring human myometrium produces significantly higher amounts of interleukin (IL) 6, IL9, IL18, IL1RA, CCL2, CCL7, CXCL8, CSF3, and tumor necrosis factor alpha, which coincides with the influx of immune cells. The direct contact or presence of THP-1 monocytes (but not U937 cells) significantly decreased CCL2 protein levels and increased IL1RA protein levels secreted by HMCs. This time-dependent decrease of CCL2 was greater with increasing number of monocytes being in direct contact with HMCs. We suggest a novel mechanism by which monocytes are first recruited to the myometrium by multiple cytokines and contribute to the physiologic inflammation of labor. After completing transmigration, activated monocytes disrupt locally established CCL2 gradients (possible by CCR2-mediated consumption) to limit their accumulation in the uterus. This mechanism may serve as a negative feedback loop to control the local inflammation and promote a return to homeostasis.

Prenatal diagnosis and pathology of laryngeal atresia in congenital high airway obstruction syndrome.

Congenital high airway obstruction syndrome is a rare but life-threatening condition. Therefore, prenatal diagnosis is important. The obstruction can be due to laryngeal/tracheal atresia or external compression. While a differential diagnosis with congenital cystic adenomatoid malformation (CCAM) type III may be difficult, it is still possible with ultrasonography. In this study, we report a case of bilateral echogenic lungs with hydrops fetalis. After the prenatal diagnosis of laryngeal atresia, the couple opted to have an elective termination of pregnancy performed at 20 weeks of gestation. The diagnosis was confirmed by a complete pathological examination.

Inhibin-A levels between 14 and 20 weeks of gestation in Thai women.

AIM: To construct a normal value for inhibin-A concentrations at 14-20 weeks of gestation for a Thai population. MATERIAL AND METHODS: Inhibin-A concentrations from pregnant women without Down's syndrome at 14-20(+6) weeks of gestation were measured. Maternal serum inhibin-A levels were analyzed according to the gestational age. RESULTS: Serum specimens from 727 Thai women were analyzed. Inhibin-A levels decreased from 14 to 17(+4) weeks and then gradually rose thereafter, giving a U-shape pattern. CONCLUSION: The data of inhibin-A concentration at 14-20 weeks of gestation for normal Thai pregnant women fitted well with quadratic regression.

Nitric oxide donors for cervical ripening in first-trimester surgical abortion.

BACKGROUND: Cervical priming before first-trimester surgical abortion is recommended in certain groups of women. Nitric oxide (NO) donors induce cervical ripening without uterine contractions, but the efficacy and side effects are of concern. OBJECTIVES: To evaluate efficacy, side effects and complications of NO donors for cervical ripening before first-trimester surgical abortion. SEARCH METHODS: We searched the Cochrane Controlled Trials Register, MEDLINE, EMBASE and POPLINE. We also searched reference lists of retrieved papers. We contacted experts in the field for information on both published and unpublished trials. SELECTION CRITERIA: Randomised controlled trials comparing NO donors alone or in combination with other methods for cervical ripening in first-trimester surgical abortion. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected and extracted the data onto a data extraction form. We processed the data using Review Manager (RevMan5) software. MAIN RESULTS: We included nine studies involving 766 participants. There were no serious complications (infection requiring antibiotic treatment, blood transfusion, complications requiring unintended operation, cervical injury, uterine perforation, death or serious morbidity) in the trials included.NO donors were more effective in cervical ripening comparing with placebo or no treatment. Baseline cervical dilatation before the procedure was higher in NO donors group (mean difference 0.30, 95% CI 0.01, 0.58) The cumulative force required to dilate the cervix to 8 mm (mean difference -4.29, 95% CI -9.92, 1.35), headache (RR 1.73, 95% CI 0.86, 3.46), abdominal pain (RR 0.87, 95% CI 0.50, 1.50) or patient satisfaction (RR 0.95, 95% CI 0.84, 1.07) were not different. More nausea and vomiting occurred in the women who received a NO donor (RR 2.62, 95% CI 1.07, 6.45).NO donors were inferior to prostaglandins for cervical ripening. The cumulative force required to dilate the cervix to 8-9 mm was higher (mean difference 13.12, 95% CI 9.72, 16.52) and baseline cervical dilatation was less (mean difference -0.73, 95% CI -1.01, -0.45) in the NO donor group. Side effects including headache (RR 5.13, 95% CI 3.29, 8.00), palpitation (RR 3.43, 95% CI 1.64, 7.15), dizziness (RR 3.29, 95% CI 1.46, 7.41) and intraoperative blood loss (mean difference 33.59 ml, 95% CI 24.50, 42.67) were also higher. However, abdominal pain (RR 0.33, 95% CI 0.25, 0.44) and vaginal bleeding (RR 0.14, 95% CI 0.07, 0.27) was less in the NO donor group. Patient satisfaction was not different.One trial compared a NO donor with a NO donor plus prostaglandin. The cumulative force required to dilate the cervix to 8 mm was higher (mean difference 14.50, 95% CI 0.50, 28.50) in the NO donor group. There was no difference in headache (RR 0.88, 95% CI 0.38, 2.00), abdominal pain (RR 0.14, 95% CI 0.02, 1.07) or intraoperative blood loss (mean difference -50, 95% CI -164.19, 64.19). AUTHORS' CONCLUSIONS: NO donors are superior to placebo or no treatment, but inferior to prostaglandins for first-trimester cervical ripening, and associated with more side effects.

Effect of isosorbide mononitrate for cervical ripening before surgical termination of pregnancy in the first trimester.

OBJECTIVE: To evaluate the efficacy of isosorbide mononitrate (IMN) for cervical ripening prior to first trimester surgical termination of pregnancy. METHODS: A prospective, double-blind, randomized, placebo-controlled trial. Women scheduled for surgical termination of a nonviable fetus before 12 weeks of gestation from October 2008 to June 2009 were enrolled and randomly assigned to receive either 20 mg vaginally of IMN (n=24) or a placebo (n=24) 4 hours before suction evacuation. Cervical dilation before evacuation was assessed with 10-mm Hegar dilators followed by smaller sizes that were measured until the instrument passed freely through the internal os. Cervical dilation, adverse effects, termination complications, and patient satisfaction were the main outcomes. RESULTS: Mean cervical dilation was not significantly different between the IMN and placebo groups (6.29+/-0.99 mm vs 5.71+/-1.04 mm; P=0.05). Mean operative time did not differ between the groups (16+/-0.07 min vs 18+/-0.06 min; P=0.55), nor did patient satisfaction measured by visual analogue scale (7.04+/-1.68 vs 6.54+/-1.22; P=0.24). CONCLUSION: IMN was comparable to placebo in terms of efficacy and patient satisfaction for cervical priming prior to first-trimester termination of pregnancy.

Nitric oxide donors for cervical ripening in first-trimester surgical abortion.

BACKGROUND: Cervical priming before first-trimester surgical abortion is recommended in certain groups of women. Nitric oxide (NO) donors induce cervical ripening without uterine contractions, but the efficacy and side effects are of concern. OBJECTIVES: To evaluate efficacy, side effects and complications of NO donors for cervical ripening before first-trimester surgical abortion. SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register, MEDLINE, EMBASE and Popline. We also searched reference lists of retrieved papers. We contacted experts in the field for information on both published and unpublished trials. SELECTION CRITERIA: Randomised controlled trials comparing NO donors alone or in combination with other methods for cervical ripening in first-trimester surgical abortion. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected and extracted the data onto a data extraction form. We processed the data using Review Manager (RevMan5) software. MAIN RESULTS: We included eight studies involving 718 participants. There were no serious complications (infection requiring antibiotic treatment, blood transfusion, complications requiring unintended operation, cervical injury, uterine perforation, death or serious morbidity) in the trials included.NO donors were ineffective in cervical ripening comparing with placebo or no treatment. The cumulative force required to dilate the cervix to 8 mm (mean difference -4.29, 95% CI -9.92, 1.35), baseline cervical dilatation before the procedure (mean difference 0.21, 95% CI -0.12, 0.53), headache (RR 1.73, 95% CI 0.86, 3.46), abdominal pain (RR 0.87, 95% CI 0.51, 1.50) or patient satisfaction (RR 0.95, 95% CI 0.84, 1.07) were not different. More nausea and vomiting occurred in the women who received a NO donor (RR 2.62, 95% CI 1.07, 6.75).NO donors were inferior to prostaglandins for cervical ripening. The cumulative force required to dilate the cervix to 8-9 mm was higher (mean difference 13.12, 95% CI 9.72, 16.52) and baseline cervical dilatation was less (mean difference -0.73, 95% CI -1.01, -0. 45) in the NO donor group. Side effects including headache (RR 5.13, 95% CI 3.29, 8.00), palpitation (RR 3.43, 95% CI 1.64, 7.15), dizziness (RR 3.29, 95% CI 1.46, 7.41) and intraoperative blood loss (mean difference 33.59 ml, 95% CI 24.50, 42.67) were also higher. However, abdominal pain (RR 0.33, 95% CI 0.25, 0.44) and vaginal bleeding (RR 0.14, 95% CI 0.07, 0.27) was less in the NO donor group. Patient satisfaction was not different.One trial compared a NO donor with a NO donor plus prostaglandin. The cumulative force required to dilate the cervix to 8 mm was higher (mean difference 14.50, 95% CI 0.50, 28.50) in the NO donor group. There was no difference in headache (RR 0.88, 95% CI 0.38, 2.00), abdominal pain (RR 0.14, 95% CI 0.02, 1.07) or intraoperative blood loss (mean difference -50, 95% CI -164.19, 64.19). AUTHORS' CONCLUSIONS: NO donors are inferior to prostaglandins for first-trimester cervical ripening, and associated with more side effects. NO donors are comparable to placebo and no treatment for cervical ripening.

A comparison of the efficacy of sublingual and oral misoprostol 400 microgram in the management of early pregnancy failure: a randomized controlled trial.

OBJECTIVE: To compare repeated doses of sublingual with oral misoprostol in the medical management of early pregnancy failure. MATERIAL AND METHOD: One hundred and thirty eight women with a period of gestation less than 20 week calculated by her last menstrual period and less than 12 weeks by size were sequentially allocated to two groups to receive either 400 microg of misoprostol orally or sublingually every 4 hours until termination of pregnancy was completed. RESULTS: There is no difference in the mean induction to abortion interval. Fever and chill were more common in sublingual group compared with oral group. The other adverse effects were similar and included nausea, vomiting, diarrhea, abdominal pain, and headache. CONCLUSION: Sublingual misoprostol is as effective as oral route. Most adverse effects are similar in both groups except fever was more common in sublingual group.

Ion channels: new targets for the next generation of tocolytics agents.

Ion channels are interesting molecules since they mediate not only uterine contraction but also uterine relaxation. We have examined the expression, function, and correlation between the large conductance calcium-activated potassium (BKCa) channel, beta2 adrenoceptor (AR), and long-lasting (L) type calcium (Ca2+) channel. These are the main channels and receptor that are involved in the uterine contraction/ relaxation process. Our evidence has shown that BKCa channel is closely correlated with beta2 AR in mediating uterine relaxation. Both proteins are situated in close proximity on the plasma membrane of human myometrium and are downregulated approximately 50% after the onset of labor. Interestingly, L type Ca2+ channel, which involves in the contraction pathway, seems to be in the same compartmentation as BKCa channel/ beta2 AR macromolecular complex. Further studies are now being conducted to identify the signaling complex components that could potentially be a target for new tocolytic agents.

A randomised controlled trial of 6 and 12 hourly administration of vaginal misoprostol for second trimester pregnancy termination.

OBJECTIVE: To compare the effectiveness of vaginal misoprostol administered 6 or 12 hourly for second trimester pregnancy termination. DESIGN: A randomised controlled trial. SETTING: University teaching hospital. SAMPLE: Two hundred and seventy-nine pregnant women at gestations between 14 and 26 weeks undergoing pregnancy termination. METHODS: Women were randomised to receive 600-microg misoprostol tablets vaginally either every 6 hours or every 12 hours until abortion occurred. MAIN OUTCOME MEASURES: Induction-abortion interval, success rate within 24 and 48 hours and adverse effects. RESULTS: There was no significant difference in the median induction to abortion interval 6 hours (16 hours) and 12 hours (16 hours; P= 0.80). The total dose of misoprostol was higher in the 6-hour group (1800 vs 1200 microg). The cumulative abortion rates within 24 hours were 74% and 67% and within 48 hours 94% and 92%, in the 6- and 12-hour groups, respectively. Fever was more common in the 6-hour group (53%) versus the 12-hour group (31%; P < 0.001). The incidence of nausea, vomiting, diarrhoea, severe bleeding and abdominal pain were similar. CONCLUSIONS: Misoprostol (600 microg) administered at 12-hour intervals was associated with fewer adverse effects and was as effective as a 6-hour interval.

Progesterone enhances the tocolytic effect of ritodrine in isolated pregnant human myometrium.

OBJECTIVE: To evaluate the effect of natural progesterone on the relaxant effect of ritodrine on pregnant human oxytocin-induced myometrial contractility. STUDY DESIGN: Isometric tension recordings were performed under physiologic conditions on isolated myometrial strips taken from low-risk term pregnant women undergoing elective cesarean section. Cumulative effects of natural progesterone (10 (-11) to 10 (-5) mol/L) on oxytocin-induced myometrial contractility were evaluated. Contractile activity following ritodrine exposure was also investigated in myometrium pretreated with natural progesterone. RESULTS: Natural progesterone alone exerted a concentration-dependent relaxant effect on myometrial contractions. The concentration-response curve for ritodrine from natural progesterone pretreated myometrium was shifted to the left with a significant reduction ( P < .01) of 50% of the maximal response, contraction amplitude ( P < .05), and frequency ( P < .05). However, there was no significant difference in the mean maximal inhibition achieved ( P = .95). CONCLUSION: Natural progesterone increased the relaxant effect of ritodrine by reducing 50% of the maximal response, amplitude, and frequency of myometrial contraction, most likely through nongenomic actions. These results suggest that natural progesterone may be beneficial for preventing preterm birth in a low-risk population.

Contribution of coupling between human myometrial beta2-adrenoreceptor and the BK(Ca) channel to uterine quiescence.

The beta(2)-adrenergic receptor (beta(2)-AR) and the large-conductance Ca(2+)-activated K(+) (BK(Ca)) channel have been shown, separately, to be involved in mediating uterine relaxation. Our recent studies reveal that the levels of both beta(2)-AR and BK(Ca) channel proteins in pregnant human myometrium decrease by approximately 50% after the onset of labor. We present direct evidence in support of a structural and functional association between the beta(2)-AR and the BK(Ca) channel in pregnant human myometrium. Localization of both proteins is predominantly plasmalemmal, with 60% of beta(2)-AR colocalizing with the BK(Ca) channel. Coimmunoprecipitation studies indicate that BK(Ca) and beta(2)-AR are structurally linked by direct protein-protein interactions. Functional correlation was confirmed by experiments of human myometrial contractility in which the BK(Ca) channel blocker, paxilline, significantly antagonized the relaxant effect of the beta(2)-AR agonist ritodrine. These novel findings provide an insight into the coupling between the beta(2)-AR and BK(Ca) channel and may have utility in the application of this signaling cascade for therapeutic potential in the management of preterm labor.

Reduced expression of immunoreactive beta2-adrenergic receptor protein in human myometrium with labor.

A considerable body of evidence exists suggesting that the beta(2)-adrenergic receptor (beta(2)-AR) mediates uterine relaxation. However, little information exists on the localization, distribution, or expression of beta(2)-ARs in the human myometrium during the nonpregnant to labor transition. We have used immunochemical methods to investigate beta(2)-AR localization and expression in the nonpregnant, term pregnant, and term parturient uterus. Myometrial biopsies were obtained from 1) nonpregnant, menstruating women undergoing hysterectomy; 2) singleton term pregnant women undergoing elective cesarean section before the onset of labor; or 3) singleton term pregnant women undergoing emergency cesarean section after spontaneous labor. Tissues were processed for immunohistochemistry, immunofluorescence, and Western blotting and a primary polyclonal antibody specific to the human beta(2)-AR to identify immunoreactive myometrial beta(2)-AR. Protein levels were subsequently quantified by densitometry relative to rat brain protein. Immunohistochemistry and immunofluorescence demonstrated the presence of beta(2)-AR predominantly at the plasma membrane and also in the cytosol of myometrial cells. A 2-fold decrease in protein levels of the beta(2)-AR was apparent in the myometrium of labor compared with that of nonpregnant and pregnant nonlaboring women (P < 0.05). These results demonstrate that down-regulation of beta(2)-AR protein with labor may constitute a contributory mechanism by which uterine quiescence is removed at term.

Postterm with favorable cervix: is induction necessary?

OBJECTIVE: To study the cesarean rate between expectant management and immediate induction in the otherwise uncomplicated postterm pregnancy with favorable cervix. STUDY DESIGN: A total of 249 women with uncomplicated pregnancies at 41 weeks plus 3 days (290 days) with favorable cervix (Bishop score > or =6) were randomized to either expectant management (n=125) or immediate induction of labor (n=124). The women in the induction group were sent to labor ward for induction by artificial rupture of membranes (ARM) and/or oxytocin infusion. The women with expectant management had nonstress test (NST) and amniotic fluid index (AFI) performed once a week and twice a week after 43 weeks of gestation until spontaneous labor. RESULTS: The cesarean rate was not different between expectant management and immediate induction (21.6% versus 26.6%; P=0.36). Ninety-five percent of the expectant group delivered within 1 week after enrollment, and all of them delivered within 9 days after randomization. Maternal and fetal complications in both groups were not different. There was also no difference in the mean birth weight (P=0.24) and the frequency of macrosomia (birth weight > or = 4000 g) between the two groups (P=0.23). CONCLUSION: Cesarean section rate between expectant management and immediate induction in the otherwise uncomplicated postterm pregnancy with favorable cervix was not different. Due to the very low adverse perinatal outcome, both expectant management and immediate induction are acceptable.