|Year : 2013 | Volume
| Issue : 4 | Page : 310-317
A comparison of isosorbide mononitrate, misoprostol, and combination therapy for preinduction cervical ripening at term: a randomized controlled trial
Ahmed T Soliman
Department of Obstetrics and Gynecology, Faculty of Medicine, Tanta University, Tanta, Egypt
|Date of Web Publication||1-Feb-2014|
Ahmed T Soliman
Department of Obstetrics and Gynecology, Faculty of Medicine, Tanta University, Tanta
The purpose of this study was to compare the efficacy, safety, and acceptability of isosorbide mononitrate (IMN), misoprostol, and combination therapy for cervical ripening before induction of labor at term.
Patients and methods
A prospective, double-blind, placebo-controlled, randomized clinical trial was carried out on 196 term and post-term nulliparous women with unfavorable cervices who were assigned randomly to receive either 40 mg of IMN (n = 65), 50 ΅g of misoprostol (n = 65), or both of them (n = 66) in the posterior vaginal fornix. Changes in the Bishop score and cervical length, progress, and outcomes of labor and adverse effects were assessed.
Combination therapy was more effective than IMN or misoprostol alone. Successful induction (vaginal delivery within 24 h of initiation of cervical ripening) was significantly higher in the misoprostol (60%) and the combination therapy (62.1%) groups compared with the IMN (27.7%) group (P < 0.0001). The mean duration (h) from treatment initiation to delivery was greater for IMN (26.7 7.5) than for misoprostol (16.5 6.7) and combination therapy (14.8 6.2) groups (P < 0.0001). Oxytocin was needed more in the IMN group (93.8%) than in the misoprostol (21.5%) and combination therapy (25.8%) groups (P < 0.0001). IMN was safer and more acceptable than misoprostol and combination therapy. The cesarean rate was not significantly different among groups, but the major indications were different: dystocia (54.5%) in the IMN group versus a persistent nonreassuring fetal heart rate pattern (57.9%) in the misoprostol and (47.6%) the combination therapy groups (P = 0.01).
Combination therapy was more effective than either IMN or misoprostol alone for preinduction cervical ripening at term. However, IMN was safer, well tolerated, and more acceptable.
Keywords: Cervical ripening, isosorbide mononitrate, labor induction, misoprostol, nitric oxide, term pregnancy
|How to cite this article:|
Soliman AT. A comparison of isosorbide mononitrate, misoprostol, and combination therapy for preinduction cervical ripening at term: a randomized controlled trial. Tanta Med J 2013;41:310-7
|How to cite this URL:|
Soliman AT. A comparison of isosorbide mononitrate, misoprostol, and combination therapy for preinduction cervical ripening at term: a randomized controlled trial. Tanta Med J [serial online] 2013 [cited 2017 Oct 18];41:310-7. Available from: http://www.tdj.eg.net/text.asp?2013/41/4/310/126184
| Introduction|| |
The induction of labor is frequently indicated for a variety of obstetric, medical, and social conditions  . Approximately 20% of pregnant women have their labor induced in the UK and the USA each year  . Although there is no ideal predictor of successful induction of labor, cervical status is now accepted as the most useful characteristic  .
Cervical ripening, clinically diagnosed by softening, effacement, and dilatation of the uterine cervix, is commonly stimulated pharmacologically before induction of labor to reduce the risk of prolonged labor, failed induction, cesarean section, and maternal and fetal morbidity , . Prostaglandins (PGs) and their analogs of the E series are the most commonly used drugs for preinduction cervical ripening , . Although PGs are effective cervical-ripening agents, they are associated with several adverse effects, such as gastrointestinal symptoms, fever, pain, and high incidence of tachysystole, uterine hyperstimulation, and even uterine rupture , .
The ideal agent for cervical ripening would induce adequate cervical ripening with minimal adverse effects to the mother and the fetus  . An increasing body of evidence indicates a pivotal role of nitric oxide (NO) in the process of cervical ripening ,, . Many investigators have proposed that NO donors might be such agents ,, .
In clinical trials, several NO donors such as isosorbide mononitrate (IMN), glyceryl trinitrate (GTN), and sodium nitroprusside were reported to reduce the cervical resistance before uterine evacuation in patients undergoing termination of pregnancy in the first trimester , . Eppel et al.  showed in a randomized controlled study that vaginal administration of IMN in combination with gemeprost resulted in earlier second-trimester abortion compared with gemeprost alone. Studies demonstrated that the NO donors, GTN and IMN, were effective cervical-ripening agents in pregnancy at term ,, .
The purpose of this study was to compare the efficacy, safety, and acceptability of IMN, misoprostol, and combination therapy for cervical ripening before induction of labor at term.
| Patients and methods|| |
This double-blind, randomized, controlled study was conducted in the Department of Obstetrics and Gynecology, Tanta University Hospital, between April 2010 and March 2012. Before initiation of the study, approval was granted by the ethics committee of the university. All women included were fully informed of the nature and scope of the study, as well as potential side effects. Written informed consent was obtained from all participant women before recruitment.
The study population consisted of term and post-term pregnant women referred from the antenatal clinic for induction of labor for a variety of obstetric, medical, and social indications. Inclusion criteria were nulliparity, a gestational age of at least 37 completed weeks, a singleton fetus with vertex presentation, unfavorable cervices (Bishop score<6  ), intact membranes, reactive nonstress test, normal umbilical arterial Doppler indices, absence of labor, and willingness of women to participate in the study. Exclusion criteria included multiparity, multiple pregnancy, fetal malpresentation, premature rupture of fetal membranes, regular uterine contractions, major cephalopelvic disproportion, and contraindications to IMN (hypersensitivity to nitrates, hypotension, hypovolemia, cardiac disease, marked anemia, and closed-angle glaucoma) or misoprostol [active cardiorespiratory disease, placenta previa, a history of cesarean delivery or major uterine surgery, and a nonreassuring fetal heart rate (FHR) pattern].
At admittance, cardiotocography was performed to ensure that the fetal heart activity was normal. Assessment of the uterine cervix included consistency, length, dilatation, and position as well as the station of the fetal head to obtain the Bishop score  . The cervical length was also measured by transvaginal ultrasound using an ultrasound machine (an EUB 505 Hitaci co, Tokyo, Japan), with a 6.5 MHz transvaginal probe. In addition, the umbilical artery resistance index and the pulsatility index were determined by Doppler velocimetry, and maternal vital signs [pulse rate, blood pressure (BP), and temperature] were recorded.
A total of 200 women fulfilled the inclusion criteria and agreed to participate in the study. Women were assigned to one of the three treatment groups: IMN, misoprostol, or combination therapy using a computer-generated randomization table and their allocation kept in consecutively numbered, sealed, opaque envelopes. The hospital pharmacy dispensed the medication and placebo tablets and neither the doctors nor the patients knew as to what medication was being administered. After randomization, four women were excluded because of various reasons [Figure 1]. A total of 196 women were included in the final analysis as follows:
- The IMN group included 65 women who received the NO donor IMN 40 mg tablet (Mono Mak; 6 th October Pharma, Egypt) plus the placebo tablet in the posterior vaginal fornix.
- The misoprostol group included 65 women who received the PGE1 analog misoprostol 50 μg tablet (Cytotec; Searle, Paris, France) plus the placebo tablet in the posterior vaginal fornix.
- The combination therapy group included 66 women who received the IMN 40 mg tablet (Mono Mak; October Pharma) plus the misoprostol 50 μg tablet (Cytotec; Searle) in the posterior vaginal fornix.
The participants were examined regularly at 3, 6, 9, 12, and 24 h after taking the medication to evaluate the change in the Bishop score. Vital signs were monitored every 30 min. Women were asked to report to the residents and nurses when they had uterine contractions, pain, or abnormal symptoms such as headache, palpitation, dizziness, fainting, and gastrointestinal symptoms. According to the protocol, FHR and uterine activity were monitored continuously and recorded at baseline and at 3 h.
The second and third doses of medications (IMN 40 mg tablet in the first group and misoprostol 50 μg tablet in the second and third groups) were given if the Bishop score was less than 6 at 6 and 12 h; otherwise, women were sent to the labor ward for induction. Twenty-four hours after the first medication, the remaining women were sent to the labor ward. Amniotomy was carried out and oxytocin was given if adequate uterine contractions were not achieved after 2 h. If amniotomy was not feasible, oxytocin was given and followed by amniotomy later.
Indications to start oxytocin augmentation of labor were a protracted or arrested cervical dilatation for at least 2 h with inadequate uterine contractions (<200 MVU) or a patient not in the active phase of labor after three doses of the medication. An oxytocin infusion was started at 2 mU/min and increased in increments of l-2 mU/min at 15-30-min intervals as needed to achieve an adequate contraction pattern. Opiate and epidural analgesia was given on the patient's request and at the discretion of the obstetrician.
Maternal demographics, labor and delivery characteristics, adverse effects, and neonatal outcomes were examined. A favorable cervix was defined as a Bishop score of greater than 6. Active phase of labor was defined as regular uterine contractions of at least three contractions in 10 min with rapid progressive cervical dilatation beyond 3 cm and 100% effacement. Abnormal uterine contraction patterns were defined as tachysystole (six or more contractions during a 10-min period for two consecutive 10-min periods), hypertonus (single-uterine contraction with a duration of >2 min), and hyperstimulation (the presence of tachysystole or hypertonus with an associated FHR abnormality). Abnormal FHR patterns included fetal tachycardia, fetal bradycardia, late decelerations, severe variable decelerations, or loss of beat-to-beat variability , . Failed induction was defined as an inability to achieve active phase of labor despite adequate oxytocin stimulation for at least 6 h after amniotomy. Cesarean delivery was performed for obstetric indications, including failed induction, dystocia, and a persistent nonreassuring FHR pattern after resuscitation.
Primary efficacy outcomes were the cervical-ripening effect of each drug (as documented by the change in the Bishop score, the cervical length, and the time from drug application to active phase of labor) and successful labor induction (as documented by the time from drug application to delivery, the number of women in the active phase, and the number of women who delivered vaginally within 24 h of initiation of therapy). Secondary outcomes included the duration of labor stages and phases, need and dose of oxytocin augmentation, and the mode of delivery. Safety outcomes included major adverse events (abnormal FHR, abnormal uterine activity, hypotension requiring treatment, and postpartum hemorrhage as well as neonatal outcome documented by Apgar scores at 1 and 5 min, birth weight, umbilical venous pH, and the rate of admission to the neonatal ICU) and minor side effects (headache, palpitation, hot flushing, dizziness, fainting, nausea, and vomiting as well as pain and requirement of analgesia).
At the end of the study, the treatment allocation for each study number was revealed for final analysis of data.
Data were entered into a Microsoft Excel worksheet and analyzed using SPSS software version 10. Values in the present study are expressed as mean ± SD unless otherwise specified. Paired t-tests were carried out to compare pretreatment and post-treatment Bishop scores, cervical length, BP, maternal and FHR, and Doppler indices among the three groups. One-way analysis of variance tests were complaining of maternal and neonatal adverse events. P-values of less than 0.05 were considered significant.
| Results|| |
The final analysis revealed that 196 women were randomized to receive IMN (n = 65), misoprostol (n = 65), or combination therapy (n = 66). The flow and the outcome of participants through each stage of the study are shown in [Figure 1]. There were no statistically significant differences among the three study groups with respect to age, BMI, gestational age, initial Bishop score, and the indication for induction of labor as shown in [Table 1].
[Table 2] displays the response of the participants to the cervical-ripening agents. The initial Bishop score was similar among the study groups. Significant improvement was noted in the Bishop score at 6 h in all three groups (P < 0.0001). However, the mean Bishop score at 6 h was significantly higher in the combination therapy (7.1 ± 1.9) and the misoprostol (6.8 ± 2.3) groups compared with the IMN group (6.1 ± 2.1, P = 0.02). Also, the initial cervical length was comparable among the three groups. At 6 h, there was a significant shortening of the cervix in the misoprostol and the combination therapy groups (P < 0.0001), but not in the IMN group (P > 0.05). The proportion of participants requiring second and third doses of the medication was significantly higher in the IMN group (52.3 and 15.4%) compared with the misoprostol (33.8 and 4.6%) and the combination therapy (31.8 and 9.1%) groups (P = 0.005). However, the number of failed inductions was not significantly different among the treatment groups [Table 2].
Outcomes of treatment and labor dynamics are shown in [Table 3]. The time from treatment initiation to delivery (h) was significantly shorter in the combination therapy (14.8 ± 6.2) and the misoprostol (16.5 ± 6.7) groups compared with the IMN (26.7 ± 7.5) group (P < 0.0001). This difference was observed either including or excluding those women who had a cesarean delivery (P < 0.0001).
The mean durations of the first and the second stages of labor were significantly shorter in the misoprostol and the combination therapy groups compared with the IMN group (P = 0.048 and 0.02, respectively). Oxytocin was needed in 61 women (93.8%) in the IMN group compared with 14 women (21.5%) in the misoprostol and 17 women (25.8%) in the combination therapy groups (P < 0.0001).
Successful induction (vaginal delivery within 24 th hours of initiation of cervical ripening) was significantly higher in the misoprostol (60%) and the combination therapy (62.1%) groups compared with the IMN (27.7%) group (P < 0.0001). The proportion of women who required opiate analgesia in the first 24 h was significantly higher in the misoprostol (53.8%) and the combination therapy (40.9%) groups compared with the IMN (13.8%) group (P < 0.0001).
[Table 4] displays maternal and fetal safety parameters. Before initiation of therapy, women in the three study groups were comparable with respect to systolic and diastolic BPs, maternal and FHRs, and umbilical artery Doppler indices. At 3 h, women in the IMN group had significantly lower systolic (P = 0.046) and diastolic (P = 0.02) BPs and a significantly higher maternal pulse rate (P=0.04) compared with women in the misoprostol and the combination therapy groups. Moreover, the FHR increased and the umbilical artery resistance index decreased significantly at 3 h in the IMN but not in the other groups.
[Table 5] displays maternal and fetal adverse effects. The incidence of uterine tachysystole and hyperstimulation syndrome was significantly higher in the misoprostol (15.4 and 13.8%) and the combination therapy (10.6 and 7.6%) groups compared with the IMN (0 and 0%) group (P = 0.006 and 0.009), respectively. Likewise, the incidence of meconium-stained amniotic fluid and an abnormal FHR pattern was significantly higher in the misoprostol (26.2 and 20%) and the combination therapy (24.2 and 18.2%) groups compared with the IMN (9.2 and 4.6%) group (P = 0.03 and 0.02), respectively. Headache and palpitation were significantly more frequent in the IMN group, whereas abdominal/pelvic pain was significantly more frequent in the misoprostol and the combination therapy groups.
[Table 6] shows the mode of delivery and the neonatal outcome. The cesarean delivery rate was not significantly different among the study groups, but the major indications were different: dystocia (54.5%) in the IMN group versus a persistent nonreassuring FHR pattern (57.9%) in the misoprostol and (47.6%) the combination therapy groups (P = 0.01). The neonatal outcome was similar among the three study groups.
| Discussion|| |
The human uterine cervix is a unique organ composed of smooth muscle cells (10-15%) and connective tissue (85-90%). The cervical stroma consists predominantly of extracellular connective tissue, mainly type I and III collagen bundles that provide rigidity and competence of the cervix during pregnancy with little elastin  . The matrix consists of water, glycosaminoglycans, and proteoglycans as well as dermatane sulfate, hyaluronic acid, and heparin sulfate  . Cervical ripening is an active process resembling an inflammatory reaction, which involves a complex cascade of degradative enzymes accompanied by degradation and disorganization of the collagen framework, an increased water content, and rearrangement of extracellular matrix proteins and glycoproteins , . Among factors regulating cervical ripening (i.e. mechanical factors, estrogens, cytokines, neuropeptides, and other inflammatory agents), PGs are regarded to play a crucial role  NO, a free radical gas with a short half-life of 4 s, is thought to be a fundamental mediator of cervical ripening ,, . As the ideal cervical-ripening agent is one that induces cervical remodeling without stimulating uterine activity, NO donors may be such agent as they relax the myometrium while inducing cervical ripening  .
The current study demonstrates that the combination of IMN and misoprostol is more effective for cervical ripening and labor induction than either IMN or misoprostol alone and results in a shorter latent phase of labor and a shorter induction to delivery time. Our findings are reinforced with the results of a study conducted in Portugal by Nunes et al.  , who reported that the association of the NO donor GTN (500 mg/kg) with dinoprostone (2 mg) in 99 women was more effective than dinoprostone alone in 97 women for cervical ripening and labor induction at term. A limitation of their study was that they did not evaluate the cervical-ripening effect of GTN alone. This beneficial effect of combination therapy (an NO donor and a PG analog) is not unexpected and has biologic plausibility because the mechanism of action of NO donors and PGs is different ,,,,,,, and their combined use may be synergistic and lead to more effective cervical ripening  .
In contrast, Wolfier et al.  showed that vaginal application of IMN plus dinoprostone appeared to be no more effective than placebo plus dinoprostone for cervical ripening and labor induction at term  . Our data, however, differ from the latter report as we used IMN plus misoprostol followed by misoprostol alone at 6 and 12 h in the combination group. Interestingly, Ledingham et al.  failed to show any benefit of combining vaginally administered IMN with misoprostol over misoprostol alone for first-trimester pregnancy termination, suggesting a different effectivity of IMN depending on the gestational age  .
At the same time, they have an antagonistic effect in the myometrium that is stimulated by PGs and relaxed by NO donors, resulting in less frequent episodes of uterine hyperactivity  . In our study, however, combination therapy resulted in a slight but insignificant decrease in the incidence of uterine hyperactivity compared with misoprostol alone. Furthermore, we hypothesized that combining IMN with misoprostol might reduce the side effects associated with either drug alone because the smooth-muscle-relaxant properties of IMN may result in a reduced incidence of the side effects attributable to PG-associated gastrointestinal and myometrial contractions  . In our study, we found that the addition of IMN does not reduce the incidence of abdominal/pelvic pain or the need to opiate analgesia in the first 24 h. Moreover, combination therapy does not reduce the incidence of meconium-stained amniotic fluid or an abnormal FHR associated with misoprostol alone. In contrast, combination therapy reduced significantly the incidence of headache but not palpitation compared with IMN alone. Our finding, demonstrating more headache after vaginal administration of IMN, is lent support by similar results of previous studies in which headache was the most frequent side effect with NO donors ,,,,,,, . Other maternal side effects were comparable in the study groups.
The vasodilatory effects of NO donors are widely used in the treatment of angina and chronic myocardial insufficiency. The side effects of these agents include hypotension and tachycardia  . The current study demonstrates that vaginally administered IMN does affect maternal and fetal hemodynamics albeit without clinical significance. This is in agreement with the findings of Nicoll et al.  in their randomized controlled trial of IMN in the third trimester. In contrast, studies of IMN in women undergoing termination of pregnancy in the first trimester revealed no significant changes in maternal hemodynamics ,, . The most likely reason for this discrepancy is that frequent BP measurements in our study revealed subtle changes that were not apparent when BP was measured on only two occasions. Alternative explanations include differences in the pharmacokinetics of vaginally administered IMN and differences in the cardiac output and the mean arterial pressure between the first and the third trimesters of pregnancy , .
A potential concern regarding the use of NO donors is that their uterine-relaxant effect may promote increased blood loss at the time of delivery. However, the current study reveals that the incidence of postpartum hemorrhage was similar in the three study groups. This finding is supported by results of previous studies ,,, .
High cesarean section rates were observed in our study in all three groups. This might be because all participants were nulliparous women with unfavorable cervices, a group at high risk of instrumental and operative delivery, as well as inclusion of the participants with complications such as pre-eclampsia, intrauterine growth restriction, and oligohydramnios. Importantly, no difference was noted with respect to cesarean section rates among the three groups, but the major indications were different: dystocia in the IMN group versus a persistent nonreassuring FHR pattern in the misoprostol and the combination therapy groups. This is in agreement with the results of other studies ,,, . In contrast, Sanchez-Ramos and Kaunitz  published a meta-analysis on the impact of misoprostol on the cesarean delivery rate, using pooled data from 44 randomized trials. They found a lower overall cesarean delivery rate and a lower cesarean delivery rate for failed induction in the participants who received misoprostol compared with the participants who received placebo, dinoprostone, PGE2, oxytocin, or Foley catheter. There were no significant differences in the neonatal outcome with respect to Apgar scores at 1 and 5 min, birth weight, umbilical cord venous pH, and the rate of admission to the neonatal ICU among the treatment groups. This finding is reinforced by the results of previous studies [8, 20, 27, 28] .
There is increasing interest in outpatient cervical-ripening treatment with the following advantages: patient convenience, reduced workload on labor and delivery units, and reduced hospital costs ,,, . In addition, there is a wish to 'deinstitutionalize' the process of labor, and, where appropriate, to offer women the opportunity to remain as an outpatient for a longer period of time  . It is essential that such outpatient treatment is safe, effective, and, importantly, acceptable to women. As neither fetal nor maternal side effects of clinical importance were registered with the NO donor IMN in the current study, such an agent could be given for cervical ripening on an outpatient basis. Maternal enthusiasm for IMN was clearly evident because maternal satisfaction and acceptability were found to be higher in the IMN group compared with the misoprostol and the combination therapy groups. Moreover, the vast majority of women in the IMN group reported that they would recommend such a ripening agent to other women.
| Conclusion|| |
Our data suggest that vaginally administered IMN given in combination with misoprostol is a more effective method for cervical ripening and labor induction than either IMN or misoprostol monotherapy in nulliparous women at term. The ideal regimen with optimal doses and frequency of administration of combined therapy awaits further studies. Vaginally administered IMN seems to be safe and well tolerated and provides a merit in some situations, where uterine contractions are unwanted before cervical ripening as in cases of grand multiparity, scarred uterus, and in the outpatient setting. The use of this NO donor for preinduction cervical ripening at term may thus prove to be a major therapeutic advance.
| Acknowledgements|| |
Conflicts of interest
There are no conflicts of interest.
| References|| |
|1.||Chin HG (editor). On call obstetrics and gynecology 2nd ed. 2001;Philadelphia: WB Saunders Co. |
|2.||Royal College of Obstetricians and Gynecologists Induction of labour. National Evidence-based Clinical Guidelines 2001;London, UK: RCOG Press. |
|3.||Watson WJ, Stevens D, Welter S, Day D. Factors predicting successful labor induction. Obstet Gynecol 1996; 88:990-992. |
|4.||American College of Obstetricians and Gynecologists Induction and augmentation. Technical Bulletin No. 217 1995;Washington, DC: ACOG. |
|5.||Kierse M Prostaglandins in preinduction cervical ripening: meta-analysis of worldwide clinical experience. J Reprod Med 1993; 38:89-100. |
|6.||Keirse M Any prostaglandin/any route for cervical ripening. 1995; Oxford, UK: Cochrane Collaboration. |
|7.||Maymon R, Shulman A, Pomerans M, Holtzinger M, Haimovich L, Bahary C. Uterine rupture at term pregnancy with the use of intracervical prostaglandin E2 gel for induction of labor. Am J Obstet Gynecol 1991,165:368-370. |
|8.||Herabutya Y, O-Prasertsawat P, Pokpirom J. A comparison of intravaginal misoprostol and intracervical prostaglandin E2 gel for ripening of unfavorable cervix and labor induction. J Obstet Gynaecol Res 1997; 23:369-374. |
|9.||Steiner A, Creasy R. Methods of cervical priming. Clin Obstet Gynecol 1983; 26:37-46. |
|10.||Chwalisz K, Shao-Qing S, Garfield RE, Bier HM. Cervical ripening in guinea-pigs after a local application of nitric oxide. Hum Reprod 1997; 12:2093-2101. |
|11.||Tschugguel W, Schneeberger C, Lass H, Stonek F, Zaghlula MB, Czerwenka K, et al. Human cervical ripening is associated with an increase in cervical inducible nitric oxide synthase expression. Biol Reprod 1999; 60:1367-1372. |
|12.||Vaisanen-Tommiska M. Nitric oxide in human uterine cervix: role in cervical ripening [thesis]. Finland: University of Helsinki; 2006. |
|13.||Norman J, Thomson A, Greer I. Cervical ripening after nitric oxide. Hum Reprod 1998; 13:251-252. |
|14.||Ekerhovd E, Branstrom M, Norstrom A. Nitric oxide synthases in the human cervix at term pregnancy and effects of nitric oxide on cervical smooth muscle contractility. Am J Obstet Gynecol 2000; 183:610-616. |
|15.||Chanrachakul B, Herabutya Y, Punyavachira P. Potential efficacy of nitric oxide for cervical ripening in pregnancy at term. Int J Gynaecol Obstet 2000; 71:217-219. |
|16.||Thomson A, Lunan C, Ledingham M, Howat R, et al. Randomized trial of nitric oxide versus prostaglandin for cervical ripening before first trimester termination of pregnancy. Lancet 1998; 352:1093-1096. |
|17.||Facchinetti F, Piccinini F, Volpe A. Chemical ripening of the cervix with intracervical application of sodium nitroprusside: a randomized controlled trial. Hum Reprod 2000; 15:2224-2227. |
|18.||Eppel W, Facchinetti F, Schleussner E, Pizzi C, Gruber DM, Schneider B. Second trimester abortion using isosorbide mononitrate in addition to gemeprost compared with gemeprost alone: a double-blind, randomized, placebo-controlled multicenter trial. Am J Obstet Gynecol 2005; 192:856-861. |
|19.||Ekerhovd E, Bullarbo M, Andersch B, Norstrom A. Vaginal administration of the nitric oxide donor isosorbide mononitrate for cervical ripening at term: a randomized controlled study. Am J Obstet Gynecol 2003; 189:1692-1697. |
|20.||Osman I, Mackenzie F, Norrie J, Murray HM, Greer IA, Norman JE. The ′PRIM′ study: a randomized comparison of prostaglandin E2 gel with the nitric oxide donor isosorbide mononitrate for cervical ripening before the induction of labor at term. Am J Obstet Gynecol 2006; 194:1012-1021. |
|21.||Bishop EM Pelvic scoring for elective induction. Obstet Gynecol 1964;24:266-268. |
|22.||Leppert PC. Anatomy and physiology of cervical ripening. Clin Obstet Gynecol 1995; 38:267-279. |
|23.||Kelly RW. Inflammatory mediators and cervical ripening. J Reprod Immunol 2002; 57:217-224. |
|24.||Leppert PC. Proliferation and apoptosis of fibroblasts and smooth muscle cells in rat uterine cervix throughout gestation and the effect of the antiprogesterone onapristone. Am J Obstet Gynecol 1998; 178:713-725. |
|25.||Maul H, Longo M, Saade GR, Garfield RE. Nitric oxide and its role during pregnancy: from ovulation to delivery. Curr Pharm Des 2003; 9:359-380. |
|26.||Thomson J, Burnett C, Cameron A, Cameron H, Cameron IT, Greer IA, Norman JE. Nitric oxide donors induce ripening of the human uterine cervix. Br J Obstet Gynaecol 1997; 104:1054-1057. |
|27.||Nunes FP, Campos AP, Pedroso SR, Leite CF, et al. Intravaginal glyceryl trinitrate and dinoprostone for cervical ripening and induction of labor. Am J Obstet Gynecol 2006; 194:1022-1026. |
|28.||Wölfler MM, Facchinetti F, Venturini P, Huber A, Helmer H, Husslein P, Tschugguel. Induction of labor at term using isosorbide mononitrate simultaneously with dinoprostone compared to dinoprostone treatment alone: a randomized, controlled trial. Am J Obstet Gynecol 2006; 195:1617-1622. |
|29.||Biondi C, Pavan B, Lunghi L, Vesci F. The role and modulation of the oxidative balance in pregnancy. Curr Pharm Des 2005; 11:2075-2089. |
|30.||Ledingham MA, Thomson AJ, Lunan CB, Norman JE. A comparison of isosorbide mononitrate, misoprostol and combination therapy for first trimester preoperative cervical ripening: a randomized, controlled trial. BJOG 2001; 108:276-280. |
|31.||Norman JF, Thong KJ, Baird DT. Uterine contractility and induction of abortion in early pregnancy by misoprostol and mifepristone. Lancet 1991; 338:1233-1236. |
|32.||Davis KL, Martin E, Turko IV, Murad F. Novel effects of nitric oxide. Annu Rev Pharmacol Toxicol 2001; 41:203-236. |
|33.||Nicoll AE, Mackenzie F, Greer IA, Norman JE. Vaginal application of the nitric oxide donor isosorbide mononitrate for preinduction cervical ripening: a randomized controlled trial to determine effects on maternal and fetal hemodynamics. Am J Obstet Gynecol 2001; 184:958-964. |
|34.||Collingham JP, Fuh KC, Caughey AB, Pullen KM, Lyell DJ, El-Sayed YY. Oral misoprostol and vaginal isosorbide mononitrate for labor induction: a randomized controlled trial. Obstet Gynecol 2010; 116:121-126. |
|35.||Sanchez-Ramos L, Kaunitz AM. Misoprostol for cervical ripening and labor induction: a systematic review of the literature, Clin Obstet Gynecol 2000; 43:475-488. |
|36.||Abdellah MS, Hussien M, Aboalhassan A. Intravaginal administration of isosorbide mononitrate and misoprostol for cervical ripening and induction of labour: a randomized controlled trial. Arch Gynecol Obstet 2011; 284:25-30. |
|37.||Agarwal K, Batra A, Batra A, Dabral A, Aggarwal A. Evaluation of isosorbide mononitrate for cervical ripening prior to induction of labor for postdated pregnancy in an outpatient setting. Int J Gynaecol Obstet 2012; 118:205-209. |
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]