Dhivya Kanagasabhai

Muthuramu Poovathi

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148International Journal of Scientifi c Study | March 2016 | Vol 3 | Issue 12
Effect of Vaginal Administration of Nitric Oxide 
Donor Isosorbide Mononitrate on Cervical Ripening 
Before Induction in Term Pregnancy: A Randomized 
Controlled Study
Muthuramu Poovathi1, Dhivya Kanagasabhai2
1Professor, Department of Obstetrics and Gynecology, Thanjavur Medical College, Thanjavur, Tamil Nadu, India, 2Assistant Professor, 
Department of Obstetrics and Gynecology, Thanjavur Medical College, Thanjavur, Tamil Nadu, India.
onset of  labor. In the case of  ripened cervix, the most 
common methods of  labor induction are oxytocin infusion 
and/or amniotomy. In unripened cervix, it is wise to use 
local medical or other mechanical methods to achieve 
ripening. The most common medical agents used for 
ripening of  cervix are prostaglandin (PG) administered 
intracervically or vaginally. Thus, PG kept via these routes 
are associated with side effects like hyperstimulation. 
Hyperstimulation is registered in 5% of  women treated 
with PG, moreover, treatment is not always effective and it 
has to be repeated. Hence, many cases of  failed induction 
have been reported with PGE2. Therefore, it is necessary 
to fi nd an alternative drug that is the more effective and it 
should not be associated with hyperstimulation. One such 
drug is NO donors, ISMN.
NO, a free radical synthesized endogenously in human 
uterine cervix.1 Studies were performed by Ledingham 
INTRODUCTION
Most exciting events in women’s life are labor. Many steps 
are involved normally in a normal course of  labor. Labor 
usually follows a normal pattern and result in delivering a 
healthy child to the mother and to the world. This study is 
mainly focused on the effects of  nitric oxide (NO) donor 
isosorbide mononitrate (ISMN) for cervical ripening in 
term pregnancy. Induction of  labor is necessary in situation, 
where it could be hazardous to wait for the spontaneous 
Original  Article
Abstract
Introduction: Nitric oxide donors have been shown to cause cervical ripening. The aim of this study was to investigate whether 
sustained-release isosorbide mononitrate (ISMN-SR) 60 mg administered vaginally is effective for preinduction cervical ripening 
in term pregnancy and any effect on mother and fetus.
Materials and Methods: A single-blinded study was conducted in Raja Mirasudar Hospital, Thanjavur for a period of 12-month. 
This study was conducted in 200 patients with uncomplicated singleton pregnancies at term. These patients were randomly 
allocated to receive either ISMN-SR 60 mg (n = 100) or vitamin C 100 mg (n = 100) vaginally. Modifi ed Bishop’s Score was 
evaluated after 24 h in each group.
Results: At the commencement of the study, there were no differences between mean ages, Bishop score of the two groups. 
In the ISMN-SR group, there was a signifi cantly higher increase in the mean modifi ed Bishop score (2.466 vs. 0.561) P < 0.05 
after 24 h. Percentage of those requiring additional ripening agent found to be lower in the study group (56.7%) compared to 
control group (91.7%). Cesarean section rates were similar in both groups.
Conclusion: ISMN-SR administered vaginally in effective for pre-induction cervical ripening.
Key words: Cervical ripening, Labor, Nitric oxide, Term pregnancy
Access this article online
www.ijss-sn.com
Month of Submission : 01-2016
Month of Peer Review : 02-2016
Month of Acceptance : 03-2016
Month of Publishing : 03-2016
Corresponding author: Dr. Muthuramu Poovathi, Department of Obstetrics and Gynaecology, Thanjavur Medical College, Thanjavur, 
Tamil Nadu, India. Phone: +91-9047486668. E-mail: drmpoovathi@gmail.com
DOI: 10.17354/ijss/2016/139
Poovathi and Kanagasabhai: Effect of Vaginal Administration of NO2 Donor Isosorbide Mononitrate on Cervical Ripening
149 International Journal of Scientifi c Study | March 2016 | Vol 3 | Issue 12
et al., 2000; Vaisanen-Tommiska et al., 2003 shown that it 
has been up regulated at term pregnancy. Hence, NO was 
believed to play a major role as ripening agent (Chwalisz, 
1997; 1998).2,3 Many studies on vaginally administered NO 
donor have shown ripening effects of  this drug (Thomson 
et al., 1997,).4,5 Current study aims to give role of  NO donor, 
ISMN on cervical ripening and labor induction.
Drugs commonly used in hospital settings such as PGE2 and 
E1 (PGE1) were effective for cervical ripening. However, the 
high incidence rates of  myometrial hyperstimulation, uterine 
tachysystole and fetal distress associated with their use.
ISMN, an NO donor had been shown to induce ripening 
of  cervix NO found to be the fi nal mediator of  cervical 
ripening. NO donor inhibit uterine contractions and 
promote uterine blood fl ow. It acts by altering cervical 
collagen tissue.
NO play a major role in regulating many factors in the 
infl ammatory process of  cervical ripening. There are three 
major isoforms of  NO synthases (NOS). All these three 
major isoforms of  NOS are present in human uterine 
cervix (Bao et al., 2001, Tschugguel et al., 1999).2 Moreover 
inducible NOS have been found in epithelial cells and 
stromal spindle cells (Tschugguel et al. 1999)2 and it has also 
been demonstrated by immunostainin g in the uterine cervix 
at term (Ekerhovd et al., 2000). Many studies have shown 
that inducible enzymes have been upregulated in human 
uterine cervix during delivery.2 Metabolites of  oxides of  
nitrogen in the cervical fl uid are increased at term compared 
to preterm. Inducible NOS isoform can be induced by 
cytokines, tumor necrosis factor α, interferon λ or endotoxins 
in a calcium-independent manner. NO may exert its effect 
through stimulation of  endogenous PG synthesis through 
cyclooxygenase stimulation3 or through stimulation of  at 
least one matrix metalloproteinase (MMP), MMP-1 .6
During late pregnancy, there is an alteration in 
glycosaminoglycan composition of  the cervix, which 
plays an important role in ripening process. Amount of  
hyaluronic acid that is present in the cervix is increased 
at term. Together these changes bring an alteration in the 
binding affi nity to collagen thus altering the tissue hydration 
and cervical extensibility (Rechberger et al., 1996).
NO suppresses the synthesis of  proteoglycan (Hauselmann 
et al., 1998). NO promote apoptosis that has been 
demonstrated in smooth muscle cells (Romero et al., 
1990) and fi broblasts (Leppert, 1998) during cervical 
ripening. Several lines of  evidence from studies of  other 
tissue suggest that this process is stimulated by NO 
(Nicotera et al., 1997).7 Finally, cervix is constituted by 
only 10-15% of  smooth muscle cells, the role of  which 
has been studied to some extent only. Relaxing effects of  
cervical smooth muscle following administration of  NO 
donors have been demonstrated in vitro in cervical tissue 
specimens from term women.
Taken together, NO found to be the fi nal mediator of  
cervical ripening. The present study was performed to 
evaluate the safety and effectiveness of  ISMN treatment 
for cervical ripening.
MATERIALS AND METHODS
A randomized prospective placebo-controlled study was 
conducted in Raja Mirasudar Hospital, Thanjavur during 
the period of  August 2014-August 2105. Institutional 
Ethical Committee approval was obtained.
The participants all had a singleton pregnancy, with 
gestational age >40 weeks, uncomplicated pregnancy and 
intact membranes.
Exclusion criteria were antepartum hemorrhage, 
previous uterine incision, fetal malpresentation, ruptured 
membranes, preeclampsia, intrauterine growth restriction, 
oligohydramnios, heart disease, diabetes, patient with H/O 
headache, palpitation, and hypotension.
Informed consent was obtained from the women. Patients 
were randomly allocated to one of  the two study groups. 
Induction is necessary, since the progression of  pregnancy 
after 40 weeks, increases the risk of  adverse outcomes 
such as meconium passage, chorioamnionitis, macrosomia, 
intrauterine death, and need for caesarean delivery.
Baseline Bishop’s Score was recorded. The participants 
were given either ISMN 60 mg, 2 tablets administered 
12 h apart into posterior fornix of  the vagina or vitamin 
C 100 mg 2 tablets as placebo.
If  Bishop score 6 or higher, labor was induced by oxytocin. 
In participants, whose Bishop score <6 after second dose, 
0.5 mg PGE2 gel instilled intracervically. Treatment with 
PGE2 gel repeated after 6 h, only once, if  cervical did not 
occur and was followed by oxytocin infusion.
The second dose of  ISMN repeated only after evaluation of  
blood pressure, pulse rate, fetal heart rate, and verifi cation 
of  symptoms such as a headache.
Primary outcome variable was Bishop Score of  baseline 
and 12 h after the second dose, duration of  labor, whether 
delivered vaginally or by caesarean section. Other maternal 
outcome variables were presence or absence of  tachycardia, 
hypotension, headache, and palpitation.
Poovathi and Kanagasabhai: Effect of Vaginal Administration of NO2 Donor Isosorbide Mononitrate on Cervical Ripening
150International Journal of Scientifi c Study | March 2016 | Vol 3 | Issue 12
Fetal outcome variables were Apgar score at 1 and 5 min and 
whether neonatal intensive care unit admission necessary 
or not. Secondary outcome variable was operative delivery 
rates and complications such as uterine hyperstimulation, 
meconium stained amniotic fl uid, tachysystole, and post-
partum hemorrhage.
The data, from our study, were collected compiled and 
statistically analyzed using SPSS statistics, software 
version 20. A statistical test used for analysis were t-test and 
Chi-square test. P < 0.05 was taken as signifi cant.
RESULTS
A total of  200 women were randomized.
• 100 to the study group
• 100 to the control group.
Comparisons of  Bishop score, PGE2 oxytocin usage, labor 
duration between study and control group. All the results 
are depicted in tabular form. (Tables 1-6).
DISCUSSION
In obstetrics and gynecology, NO donor has been used 
for the treatment of  preterm labor. NO donor has been 
shown to induce cervical ripening without causing uterine 
contraction by rearrangements of  cervical collagen tissue 
and ground substance. In contrast to PG, they also inhibit 
uterine contraction and promote uterine blood fl ow.
ISMN is a slow releasing NO donor. Levels of  NO 
metabolites in the cervix are known to be increased at term.
A signifi cant improvement in Bishop score was noted in 
study group after second dose of  ISMN. Similar results 
were reported in earlier studies by Rameez et al., 2007,8 
Hana et al., 2010, Bullarbo et al., 2007,9 Agarwal et al., 2012,10 
Helal et al., 2004.
The need for additional ripening agent PGE2 was found to 
be lesser in the study group (56.7% vs. 91.67%). This was in 
agreement with study by Agarwal et al., 2012, Bollapragada 
et al., 2009 and Bullarbo et al., 2007.9
The requirement for oxytocin was found to be lesser in the 
study group compared to control group (56.7% vs. 71.7%). 
However, the differences were not statistically signifi cant. 
On contrary study by Eddama et al., 2009,11 Habib et al., 
2008 show oxytocin requirement found to be lesser in 
ISMN group and was statistically signifi cant.
Duration of  labor was found to be signifi cantly lesser in 
study compared with that of  the control group. This was 
Table 1: Demographic characteristics of the study 
participants
Characteristics Study group 
(n=100)
Control group 
(n=100)
P value
Age (years) 23.78±1.757 23.67±1.820 >0.05
Gestational age (week) 3.62±1.075 3.68±1.172 >0.05
Parity (%)
Primigravida 53.5 55 >0.05
II Gravida 30 26.7 >0.05
III Gravida 16.7 18.3 >0.05
Table 2: Demographic characteristics of the study 
and control groups were comparable
Variable Study 
group
Control 
group
P value
Baseline Bishop score 1.80±0.879 1.82±0.39 >0.05
Post intervention Bishop score 4.87±2.466 2.08±0.561 <0.05
PGE2 used (%) 56.7 91.7 <0.05
PGE2 not used (%) 43.3 8.3 <0.05
Oxytocin (%)
Used 56.7 71.7 >0.05
Not used 43.3 28.3 >0.05
PGE2: Prostaglandin E2
Table 3: Comparison of mode of delivery between 
study and control group
Variable n=100 (%) P value
Study group Control group
Vaginal delivery 65 53.3 >0.05
Outlet forceps 10 15 >0.05
Vacuum delivery 3.3 0 >0.05
LSCS 21.7 31.7 >0.05
LSCS: Lower segment Cesarian section
Table 4: Adverse maternal side effects
Effect n=60 (%) P value
Study group Control group
Palpitation 16.7 0 <0.05
Headache 65 1.7 <0.05
Table 5: Comparison of labor complication
Variable Study group (%) Control group (%) P value
Hyper stimulation 0 5 >0.05
PPH 1.7 3.3 >0.05
PPH: Postpartum hemorrhage
Table 6: Fetal variables
Meconium
With PGE2 13.3% 15% >0.05
Without PGE2 1.7% 5%
Total 15% 20%
Non-reactive CTG
With PGE2 3.3% 11.7% >0.05
Without PGE2 - -
Total 3.3% 11.7%
PGE2: Prostaglandin E2
Poovathi and Kanagasabhai: Effect of Vaginal Administration of NO2 Donor Isosorbide Mononitrate on Cervical Ripening
151 International Journal of Scientifi c Study | March 2016 | Vol 3 | Issue 12
in agreement with study, Agarwal et al., 2012, Helal et al., 
2004, Habib et al., 2008.
The common side effects were palpitation and headache. In 
the present study, percentage of  study group and control 
group reporting palpitation found to be 16.7% and 0% 
(P < 0.05).
Agarwal et al., 201210 found that in his study percentage of  
those experiencing palpitation in study group as 18% and 
none in control group. This result was in agreement with 
the present study.
Habib et al., 200812 in his study reported that those 
experiencing palpitation in ISMN group found to be 
13.73% and none in control group. P = 0.02 is statistically 
signifi cant. This result was in agreement with this study. 
In the present study, no cases of  tachysystole and 
hyperstimulation have been found in ISMN group.
This study confi rmed that vaginally administered ISMN 
neither induced tachysystole nor hyperstimulation.
No abnormal fetal heart tracings were noted in women 
after ISMN treatment.
Use of  ISMN by vaginal route helps in improving Bishop 
score and reduces the duration of  labor. It has no effect 
on the hemodynamic state of  the mother. In constrict to 
the other cervical ripening agents, NO donor administered 
vaginally had the advantage of  the absence of  uterine 
contraction. Hence, it removed the main reasons that 
women were monitored during the induction of  cervical 
ripening.
NO donors suitable agents for preinduction cervical 
ripening. The absence of  contraction had obviated the 
need for fetal monitoring.
ACKNOWLEDGMENTS
I gratefully acknowledge and express my sincere thanks 
to our Dean, Thanjavur Medical College and hospital, 
Thanjavur, for allowing me to do this study and utilizing 
the Institutional facilities. I would also like to thank all 
the medical and paramedical staffs who have helped me 
complete this study.
Special thanks to all the patients who willingly cooperated 
and participated in this study. I would like to thank all my 
colleagues and friends who have been a constant source 
of  encouragement to me.
CONCLUSION
The use of  ISMN by the vaginal route as ripening agent 
before induction of  labor at term helps in improving 
Bishop score and reduces the duration of  labor. It has no 
effect on the hemodynamic state of  the mother and fetus. 
In contrast to the other cervical ripening agents, NO donor, 
administered vaginally, has the advantage of  absence of  
uterine contractions. Hence, it removes the main reason 
that women are monitored during the induction of  
cervical ripening. Hence, NO donors are suitable agents 
for pre-induction cervical ripening at term. The absence 
of  contraction has obviated the need for fetal monitoring 
such agent could be given on as outpatient basis.
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How to cite this article: Poovathi M, Kanagasabhai D. Effect of Vaginal Administration of Nitric Oxide Donor Isosorbide Mononitrate on 
Cervical Ripening Before Induction in Term Pregnancy: A Randomized Controlled Study. Int J Sci Stud 2016;3(12):148-151.
Source of Support: Nil, Confl ict of Interest: None declared.


Effect of Vaginal Administration of Nitric Oxide Donor Isosorbide Mononitrate on Cervical Ripening Before Induction in Term Pregnancy: A Randomized Controlled Study

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Effect of Vaginal Administration of Nitric Oxide Donor Isosorbide Mononitrate on Cervical Ripening Before Induction in Term Pregnancy: A Randomized Controlled Study

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