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 »  Abstract
 » Introduction
 » Methods
 » Results
 » Discussion
 » Conclusion
 »  References
 »  Article Tables

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 Table of Contents    
RESEARCH ARTICLE
Year : 2018  |  Volume : 50  |  Issue : 5  |  Page : 260-265
 

A comparative randomized study on effect of vaginally administered glyceryl trinitrate placebo on cervical ripening prior to induction of labor in overdue pregnancies


1 Deparment of Gynecology and Obstetrics, Süleymaniye Education and Research Hospital, Istanbul, Turkey
2 Deparment of Gynecology and Obstetrics, Istanbul Aydin University, Istanbul, Turkey
3 Department of Nursing, Faculty of Health Science, Bandirma Onyedi Eylül University, Balikesir, Turkey

Date of Submission21-May-2018
Date of Acceptance16-Oct-2018
Date of Web Publication14-Dec-2018

Correspondence Address:
Dr. Yilda Arzu Aba
Bandirma Onyedi Eylül University, Health Science Faculty Balikesir, Bandırma
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijp.IJP_182_18

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 » Abstract 


OBJECTIVE: The aim of this study is to examine the effectiveness and adverse effects of local glyceryl trinitrate (GTN) application during labor compared with a placebo group.
METHODS: The study consisted of 70 pregnant women with overdue pregnancies who presented to the hospital for labor induction between January 2009 and January 2011 in the Obstetrics Clinic of Istanbul Süleymaniye Gynecology and Obstetrics Education and Training Hospital. Vaginal suppositories-containing GTN (36/70) or placebo (34/70) was administered to the participants in a randomized fashion. The placebo and GTN involving vaginal ovules used in the study were prepared in the Pharmacy Department of Istanbul University Faculty of Pharmacy. Maternal effects during labor, rates of normal vaginal and C/S deliveries, the interval between the initial medication and delivery, and amount of total oxytocin used were compared between the GTN and placebo groups.
RESULTS: There were no significant differences between the GTN and placebo groups regarding bishop scores, the interval between medication and delivery, delivery types, indications for cesarean section, and complications including hyperstimulation, tachysystole, uterine rupture, placental abruption, and uterine atony (P > 0.05).
CONCLUSION: Our results revealed that there were no differences between GTN and placebo regarding their effect on cervical ripening in overdue pregnant women.


Keywords: Glyceryl trinitrate, nitric oxide donor, overdue pregnancy


How to cite this article:
Dülger Ö, Sik BA, Aba YA. A comparative randomized study on effect of vaginally administered glyceryl trinitrate placebo on cervical ripening prior to induction of labor in overdue pregnancies. Indian J Pharmacol 2018;50:260-5

How to cite this URL:
Dülger Ö, Sik BA, Aba YA. A comparative randomized study on effect of vaginally administered glyceryl trinitrate placebo on cervical ripening prior to induction of labor in overdue pregnancies. Indian J Pharmacol [serial online] 2018 [cited 2019 Jan 17];50:260-5. Available from: http://www.ijp-online.com/text.asp?2018/50/5/260/247531





 » Introduction Top


Induction of labor is recommended in cases where the continuation of pregnancy poses a threat to the mother and the fetus. Approximately 20%–30% of all pregnancies undergo labor induction.[1],[2] Labor induction uses mechanical or pharmacologic methods to stimulate regular uterine contractions, to speed up cervical dilatation, and to initiate labor before its spontaneous onset.[3] If spontaneous labor does not start after the completion of 41 gestational weeks, several medical methods can be used to induce labor.[4],[5] The management and treatment of postterm pregnancies depend on fetal well-being and cervical maturation state.[6] When cervical maturation is not sufficient, the induction of labor is difficult and takes a long time. Therefore, cervical ripening is an important prerequisite to the successful induction of labor.[7],[8] The ideal cervical ripening agent should not cause uterine contractions or uterine hypertonus, should not require fetal monitoring and should have minimal maternal and fetal adverse effects. Although prostaglandins (PGs) are often used for cervical ripening, they are known to cause uterine contractions due to their stimulatory effects on the myometrium.[9] The human cervix can produce nitric oxide, which is proposed to be the final metabolic mediator of cervical maturation at the end of the maturation cascade before the initiation of labor.[9] Nitric oxide donors drive the release of nitric oxide in vivo, and due to their minimal adverse effects, they have drawn much attention for their use in cervical ripening. Animal studies have shown that free radical nitric oxide is a mediator that plays a role in cervical ripening.[10]

In the current study, we locally administered glyceryl trinitrate (GTN), a nitric oxide donor, in the form of vaginal suppositories in overdue (>40 weeks) and postterm (>42 weeks) pregnancies for cervical ripening. Further, we aimed to examine the effectiveness and adverse effects of GTN application observed during labor compared with a placebo group.

Till date, the efficacy of GTN has generally been identified through comparison with PGs in studies. The results of the studies showed that although GTN was more reliable compared with PGs, GTN was less efficient. The difference and uniqueness of our study from previous studies are that the efficacy of the administration of GTN alone was compared with placebo in overdue pregnancies whose delivery action had not yet started.


 » Methods Top


The study consisted of 70 pregnant women with overdue pregnancies who presented to the hospital for labor induction between January 2009 and January 2011 in the Obstetrics Clinic of Istanbul Süleymaniye Gynecology and Obstetrics Education and Training Hospital. The study was conducted in the Perinatology Unit, and delivery room of Istanbul Süleymaniye Gynecology and Obstetrics Education and Training Hospital after approval of the board of the hospital education, planning, and ethics committee were granted (Decision Date/No: November 06, 2008). The patients evaluated in the scope of the study were included after they signed informed consent forms.

The inclusion criteria for the study were as follows: (1) Detection of overdue pregnancy (postterm) in accordance with the calculation of the last menstrual period and with ultrasonographic measurements performed in the early period (2) Detection of no signs of fetal distress in nonstress testing (NST), (3) No signs of active birth action, (4) No signs of cervical opening and cervical effacement in the vaginal digital examination, and (5) Detection of no regular uterine contractions.

The exclusion criteria were as follows: (1) Bishop score >6; (2) Initiated birth; (3) Early membrane rupture; (4) Fetal malpresentation; (5) Multiple pregnancy; (6) Fetal Doppler flow disorders; (7) History of past uterine surgery; (8) Preeclampsia and eclampsia; (9) Large baby on ultrasonographic measurements (>4000 g); and (10) Placenta previa and placental location anomalies.

The placebo and GTN involving vaginal ovules used in the study were prepared in the Pharmacy Department of Istanbul University Faculty of Pharmacy. The selected “ovule excipient” in the preparation of the ovules was Witepsol S 55 (Hüls AG; Germany), and the “hot melting” technique was used as the preparation technique. The placebo ovules were melted in a Witepsol S 55 water bath, and the melted mass was poured into ovule casing strips at 38°C ± 2°C. The ovules were kept until they reached room temperature, and each cooled mass was separately wrapped with aluminum foil after they were removed from the strips. Ten placebo ovules were weighed, and the mean ovule weight was 2.814 ± 0.015 g. The GTN involving ovules were melted in a Witepsol S 55 water bath with measuring with the reference of mean 1 ovule weight. The active ingredient, which was calculated to involve 500 mcg in each ovule, was added to the melted mass at 38°C ± 2°C. The system was constantly mixed on a magnetic mixer during the inclusion process. The homogeneous mass was poured into the ovule casing strips. The ovules were kept until they reached room temperature, and each cooled mass was separately wrapped with aluminum foil after they were removed from the strips. The placebo and GTN involving ovules were stored at +4°C in a hospital refrigerator wrapped in aluminum foil ready for use.

The women included in our study were divided into two groups in accordance with our randomization table. The medical treatment and the vaginal examinations all through the labor period were performed by a single physician. The bimanual examination was performed for the pregnant women on examination seats. Five hundred mcg GTN or placebo involving vaginal ovules were placed into the posterior fornix of the pregnant women who had no cervical dilatation and effacement in the bimanual examination. The vital signs (body temperature, heart rate, and blood pressure) of the pregnant women were measured every 15 min for 1 h. In addition, continuous fetal heart rate monitoring was performed for 1 h. Abnormal symptoms such as headache, palpitation, and chest pain, and symptoms of pregnancy such as uterine contractions were constantly questioned.

Vaginal examinations were performed by the senior specialist of obstetrics who was responsible for the medication at 3, 6, and 12 h after the first dose to learn about the cervical opening and effacement. No second dose of medication was administered to women with a Bishop score >6 at h 6,[11],[12],[13] and the patients were spontaneously monitored for 1 h by performing vaginal amniotomy to the fetal amnional membrane. Delivery induction was initiated in accordance with the “active management” protocol[13] to patients who were detected to have progressed in cervical dilatation <1 cm/h in the bimanual examination. Delivery induction was not initiated in patients in whom a progress >1 cm/h cervical dilatation was detected. The second dose of GTN was administered, and Bishop scores were evaluated for 24 h in to women who were detected to have Bishop scores <6. Delivery induction was initiated in accordance with the “active management” protocol[13] by performing vaginal amniotomy to the fetal amnional membrane to the patients when the Bishop score was >6. Delivery induction was initiated in accordance with the “active management” protocol in patients who were detected to have no change in the score after 24 h.

In accordance with the “active management” protocol, 5 units of oxytocin was infused in 500 cc 5% dextrose. The infusion dose was administered with the initiation dose of 6 mL U/min, and with 3 mL U/min increases every 30 min. The maximum dose was identified as 30 mL U/min.

The initiated delivery action was defined as 3 cm and larger cervical dilatation opening, with 60% and higher cervical effacement. Unresponsive induction was defined as no initiation of active labor action despite adequate oxytocin stimulation after at least 6 h. Regular uterus contractions were identified as the three contractions reaching to at 80 Montevideo units in 10 min on an NST device. Uterine hyperstimulation was defined as the detection more than 6 contractions reaching 80 Montevideo units in 10 min on the NST device in addition to fetal heart anomalies. Uterine tachysystole was evaluated as the presence of more than 6 uterine contractions reaching 80 Montevideo units in 10 min with no fetal heart anomalies.

Cesarean section was performed with obstetric indications such as no progression of cervical dilatation, no lowering of the level of head, persistent fetal heart disorders, and unresponsive induction. Neonate condition, Apgar scores at min 1 and 5, and neonatal morbidity and mortality were evaluated.

Maternal effects during labor, rates of normal vaginal and C/S deliveries, the interval between the initial medication and delivery, and amount of total oxytocin used were compared between the GTN and placebo groups.

Data analysis

For data analysis, the Statistical Package for the Social Sciences Ver. 16.0 software (SPSS, Inc., Chicago, IL, USA) was used. The Kolmogorov–Smirnov test was used to examine the normal distribution of variables, and the Chi-square and Fisher's exact tests were used to compare the distribution of sociodemographic and clinical variables within the two groups. The independent sample t-test was used to examine the differences between the two groups. A test of hypothesis with P < 0.05 was considered statistically significant.


 » Results Top


According to the computer-generated randomization table, 34 pregnant women received placebo, and 36 pregnant women received GTN vaginal suppositories.

The demographic properties of the groups are presented in [Table 1].
Table 1: Maternal demographic properties

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The Bishop scores recorded before medication and at the 3rd, 6th, and 12th h following medication were similar in both groups [Table 2].
Table 2: Distribution of bishop scores

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The interval between medication and delivery was an average of 15.33 h in the GTN group and 18.06 h in the placebo group; this was not significantly different [Table 3].
Table 3: Treatment outcomes and delivery types

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Thirty-one (86.1%) women from the GTN group and 26 (76.5%) women from the placebo group gave birth via the vaginal route. In the GTN group, C/S was performed in four patients due to fetal distress and in 1 patient due to nonprogressive labor. In the placebo group, C/S was performed in 3 patients due to nonprogressive labor, in 2 patients due to induction failure, and in 3 patients due to fetal distress. Vacuum application was performed in 1 (2.8%) patient from the GTN group due to a prolonged second stage of labor. The groups were similar in terms of delivery types (P > 0.05) [Table 3].

Regarding complications, uterine hyperstimulation, uterine rupture, and placental detachment were not observed in any of the participants. However, tachysystole was observed in 4 (11.1%) patients in the GTN group and 1 (2.9%) patient in the placebo group. In the GTN group, postpartum bleeding was observed in 1 patient due to retained placenta and in 1 patient due to the genital laceration. In the placebo group, postpartum bleeding was observed in 1 patient due to retained placenta, in 1 patient due to genital laceration, and in 1 patient due to uterine atony related to fetal macrosomia. There was no significant difference in terms of bleeding due to atony between the groups (P > 0.05) [Table 4].
Table 4: Distribution of complications

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 » Discussion Top


When labor induction is necessary in postterm pregnant women, various agents are used to ripen the cervix, and PG analogs are the best known among these. The effectiveness of PG analogs in cervical ripening has been demonstrated in many studies; however, their adverse effects limit their use.[14],[15] Recent research has focused on discovering agents that can prepare the cervix for induction of labor without initiating uterine contractions. To this end, nitric oxide donors have garnered much attention.

In one study by Chanrachakul et al., 54 pregnant women at term received vaginal tablets containing 500 mcg GTN as an NO donor, and 56 pregnant women at term received vaginal tablets containing 3 mg prostaglandin E2 (PGE2). Both drugs were administered at 6-h intervals, and the participants were given a maximum of two doses. The mean gestational week of the participating women was 40.0 ± 1.4 weeks in the GTN group and 39.6 ± 1.7 weeks in the PGE2 group, which was not statistically significant. Uterine tachysystole, which can cause fetal heart rate anomalies in fetuses under in utero stress, was observed in 5 (9%) women who received PGE2, but in none who received GTN (P < 0.05). They observed no hyperstimulation in either group.[16] In the current study, the mean gestational age was 41.1 ± 4.17 weeks in the GTN group and 40.6 ± 3.71 weeks in the placebo group. The number of overdue days was significantly different between the groups (P < 0.008). We observed no hyperstimulation in either group; however, 1 (2.9%) woman from the placebo group and 4 (11.1%) women from the GTN group developed tachysystole. We believe that tachysystole was observed at a higher rate in the GTN group because the women in that group had a more advanced gestational age, which may result in higher uterine oxytocin receptor concentrations.

Furthermore in the study by Chanrachakul et al., the authors noted that GTN was effective in ripening the cervix; however, they reported that Bishop scores at the 12th h were higher in the PGE2 group. This finding is supported by the fact that nitric oxide exerts its effects through the modulation of collagen and extracellular matrix structures, and softens the cervix without causing uterine contractions.[16] In the current study, we observed no differences in Bishop scores between the groups.

Chanrachakul et al. also noted that GTN was not as effective as PGE2 for the induction of labor because the latent phase, time until delivery and all stages of labor were longer in women who received GTN. The total amount of oxytocin used was also significantly higher in the GTN group compared with the PGE2 group.[16] In the present study, the average time from medication until delivery was 15.33 ± 6.69 h in the GTN group and 18.06 ± 10.43 h in the placebo group. Following medication, all labor stages in our study were shorter in the GTN group. In their study, Chanrachakul et al. reported that C/S was performed in 35.2% of women in the GTN group and in 35.7% of women in the PGE2 group, and the most frequent indication for C/S was nonprogressive labor. In our study, the C/S rate was 13.9% in the GTN group and 23.5% in the placebo group. The most frequent indication for C/S in the current study was also nonprogressive labor; induction failure was observed in 2 women (5.9%) from the placebo group.

Although it may be expected that the myometrial relaxing effect of nitric oxide may lead to postpartum atony, we observed no significant increase in the frequency of postpartum bleeding with GTN administration. Chanrachakul et al. also reported no increase in the incidence of postpartum bleeding.[16]

In one randomized, double-blind, placebo-controlled study, Yazdizadeh et al. assigned 90 primiparous pregnant women with Bishop scores ≤5 into two groups and administered 40 mg isosorbide mononitrate (IMN) and placebo vaginal tablets at 0 and 12 h. They investigated the effect of IMN on cervical ripening and labor induction, and found that the IMN group had significantly higher Bishop scores (4.92 vs. 4.03, P = 0.001), lower induction times (350 vs. 446 min, P = 0.03), lower intervals until the active phase (387.6 vs. 520.4 min, P = 0.03) and shorter intervals between medication and delivery (33.9 vs 36.2 h, P = 0.03) than the placebo group.[17] In another double-blind, randomized, controlled study, Bullarbo et al. administered a single dose (40 mg) of IM and placebo tablets to the posterior vaginal fornix of 200 pregnant women whose gestational ages were beyond 42 weeks and compared adverse effects, C/S indications, and Bishop scores. They found no significant differences between the groups regarding Bishop scores, and they attributed this result to giving only a single dose of IMN.[18] Likewise, in the current study, we also found no difference in Bishop scores between the groups.

In one study, nitric oxide donor metabolites were examined in the cervical fluids of 208 women with term and overdue (>294 days) pregnancies, using an assay with a detection limit of 3.8 micromol/L. Nitric oxide metabolites in cervical fluid were less often detectable in women going beyond term (60%) than in those delivering at term (87%) (P = 0.001). In addition, the initiation of active labor and labor stages were noted to be markedly prolonged in the overdue group (P < 0.01). The authors stated that reduced cervical nitric oxide release might contribute to prolonged pregnancy.[19] In our study, we observed that GTN administered to overdue pregnant women had no effect on the duration of labor when compared with the placebo group.

In another study, Chanrachakul et al. administered IMN and misoprostol for cervical ripening in 107 women with term pregnancies and compared their adverse effects. They observed remarkably less uterine tachysystole (0 vs. 19.2%, P < 0.01) and hyperstimulation (0 vs. 15.4%, P < 0.01) in the IMN group. The interval between medication and vaginal delivery was longer in the IMN group (25.6 ± 6.1 vs. 14 ± 6.9 h, P < 0.01); however, they reported no difference in C/S rates.[20] The higher incidence of hyperstimulation and tachysystole with misoprostol, a PG E1 analog, limits the use of this group of drugs. In the current study, we found no differences between the groups regarding adverse effects.

In their randomized, controlled study, Agarwal et al. administered 40 mg IMN as a nitric oxide donor and placebo tablets to the vaginal fornix of 200 women with overdue pregnancies who were followed up in an outpatient setting. They compared Bishop scores, time until delivery, and fetal and maternal adverse effects. The authors reported a significant difference in the 24th h Bishop score, and significantly lower amounts of oxytocin were used in the IMN group.[21] Furthermore, they observed no maternal or fetal adverse effects in the IMN group. The authors proposed that IMN was safe and effective for cervical ripening when self-administered at home by women with overdue pregnancies. In our study, we found no differences between the groups regarding the 3rd, 6th, and 12th h Bishop scores. The groups also showed no significant differences regarding time until delivery, interval between medication and amniotomy, interval between medication and initiation of oxytocin, and interval between medication and active phase of labor. In a 2014 randomized and placebo-controlled study, Krishnamurthy et al. administered 40 mg IMN and placebo vaginal tablets to 100 pregnant women. Although the 12th and 24th h Bishop scores, interval between medication and delivery, and oxytocin requirement were lower in the IMN group, the differences were not statistically significant. They reported no maternal or fetal adverse effects in the IMN group. To summarize, similar to our results, Krishnamurthy et al. found no difference between the IMN and placebo groups regarding their effects on cervical ripening.[22]


 » Conclusion Top


GTN is a safe drug to use, but we did not find it to be more efficient than placebo to justify its clinical use as a cervical ripening agent. Further studies are required where the efficacy of nitric oxide donors for cervical ripening using different formulations, doses, and in combination with other ripening agents may be evaluated.

Financial support and sponsorship

The financial support of this work has been covered by the authors.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

1.
Haq AN, Ahsan S, Sher Z. Induction of labour in postdates pregnant women. J Coll Physicians Surg Pak 2012;22:644-7.  Back to cited text no. 1
    
2.
Tam T, Conte M, Schuler H, Malang S, Roque M. Delivery outcomes in women undergoing elective labor induction at term. Arch Gynecol Obstet 2013;287:407-11.  Back to cited text no. 2
    
3.
Daskalakis G, Zacharakis D, Simou M, Pappa P, Detorakis S, Mesogitis S, et al. Induction of labor versus expectant management for pregnancies beyond 41 weeks. J Matern Fetal Neonatal Med 2014;27:173-6.  Back to cited text no. 3
    
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Elhassan M, Mirghani OA, Adam I. Intravaginal misoprostol vs. dinoprostone as cervical ripening and labor-inducing agents. Int J Gynaecol Obstet 2004;85:285-6.  Back to cited text no. 4
    
5.
Collins PW. Misoprostol: Discovery, development, and clinical applications. Med Res Rev 1990;10:149-72.  Back to cited text no. 5
    
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Chazan B, Niemiec KT, Filipp E. Postterm pregnancy – Importance of this problem in modern obstetrics. Ginekol Pol 1996;67:148-56.  Back to cited text no. 6
    
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Hawkins JS, Wing DA. Current pharmacotherapy options for labor induction. Expert Opin Pharmacother 2012;13:2005-14.  Back to cited text no. 7
    
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Yount SM, Lassiter N. The pharmacology of prostaglandins for induction of labor. J Midwifery Womens Health 2013;58:133-44.  Back to cited text no. 8
    
9.
Edwards RK, Richards DS. Preinduction cervical assessment. Clin Obstet Gynecol 2000;43:440-6.  Back to cited text no. 9
    
10.
Thomson AJ, Lunan CB, Ledingham M, Howat RC, Cameron IT, Greer IA, et al. Randomised trial of nitric oxide donor versus prostaglandin for cervical ripening before first-trimester termination of pregnancy. Lancet 1998;352:1093-6.  Back to cited text no. 10
    
11.
Bishop EH. Pelvic scoring for elective induction. Obstet Gynecol 1964;24:266-8.  Back to cited text no. 11
    
12.
ACOG technical bulletin. Dystocia and the augmentation of labor. Number 218 – December 1995 (replaces no 137, December 1989, and no 157, July 1991). American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet 1996;53:73-80.  Back to cited text no. 12
    
13.
Bishop EH. Elective induction of labor. Obstet Gynecol 1955;5:519-27.  Back to cited text no. 13
    
14.
Keirse MJ. Prostaglandins in preinduction cervical ripening. Meta-analysis of worldwide clinical experience. J Reprod Med 1993;38:89-100.  Back to cited text no. 14
    
15.
Sanchez-Ramos L, Peterson DE, Delke I, Gaudier FL, Kaunitz AM. Labor induction with prostaglandin E1 misoprostol compared with dinoprostone vaginal insert: A randomized trial. Obstet Gynecol 1998;91:401-5.  Back to cited text no. 15
    
16.
Chanrachakul B, Herabutya Y, Punyavachira P. Randomized comparison of glyceryl trinitrate and prostaglandin E2 for cervical ripening at term. Obstet Gynecol 2000;96:549-53.  Back to cited text no. 16
    
17.
Yazdizadeh H, Abedi P, Najar S, Angali KA. The impact of isosorbide mononitrate on cervical ripening and labor induction in primiparous women with term pregnancy: A double-blind, randomized, controlled trial. Iran J Nurs Midwifery Res 2013;18:246-50.  Back to cited text no. 17
    
18.
Bullarbo M, Orrskog ME, Andersch B, Granström L, Norström A, Ekerhovd E, et al. Outpatient vaginal administration of the nitric oxide donor isosorbide mononitrate for cervical ripening and labor induction postterm: A randomized controlled study. Am J Obstet Gynecol 2007;196:50.e1-5.  Back to cited text no. 18
    
19.
Väisänen-Tommiska M, Nuutila M, Ylikorkala O. Cervical nitric oxide release in women postterm. Obstet Gynecol 2004;103:657-62.  Back to cited text no. 19
    
20.
Chanrachakul B, Herabutya Y, Punyavachira P. Randomized trial of isosorbide mononitrate versus misoprostol for cervical ripening at term. Int J Gynaecol Obstet 2002;78:139-45.  Back to cited text no. 20
    
21.
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;118:205-9.  Back to cited text no. 21
    
22.
Krishnamurthy R, Pallavee P, Ghose S. Evaluation of isosorbide mononitrate for preinduction of cervical ripening: A randomized placebo-controlled trial. J Family Reprod Health 2015;9:75-81.  Back to cited text no. 22
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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