NITROGLYCERINE SKIN PATCH VS PLACEBO PATCH FOR ENHANCING CERVICAL RIPENING IN LABOR INDUCTION: A RANDOMIZED CONTROLLED TRIAL
Phase: PHASE2
Conditions: Induction of Labor Affected Fetus / Newborn
Sponsor: Ain Shams Maternity Hospital

 
 
NITROGLYCERINE SKIN PATCH VS 
PLACEBO PATCH FOR ENHANCING 
CERVICAL RIPENING IN LABOR INDUCTION: 
A RANDOMIZED CONTROLLED TRIAL 
 
Protocol of a Thesis 
Submitted for partial fulfillment of Master’s Degree 
in Obstetrics & Gynecology  
by 
 
Peter Nagy Aziz Hanna 
M.B.B.Ch, Ain Shams University (2009) 
Resident of Ob/Gyn at El-Mabara Hospital, Assiut Governate 
 
Supervised by:  
Prof. Dr. Abdel-Megeeed Ismail Abdel-Megeed 
Professor of Obstetrics and Gynecology, Ain Shams University 
 
Dr. Ahmed Sherif Abd El-Hamid 
Lecturer of Obstetrics and Gynecology, Ain Shams University 
 
Faculty of Medicine 
Ain Shams University 
2017 

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Introduction: 
      Nitrous oxide donors are widely used in clinical practice for many 
medical conditions. Nitrous oxide (NO) is known to have a secondary 
messenger role in signal transduction process for many cellular functions. NO 
signal transduction pathway is mediated by another secondary messenger, 
cGMP, through activation of guanyl cyclase which in turn participate in a 
cellular process. For instance, NO is produced by the endothelial cell layer of 
blood vessels causing relaxation of the blood vessel smooth muscles and 
causes vasodilation (endothelial derived relaxing factor, EDRF) (Ignarro, 
1990). The same mechanism may cause relaxation of other smooth muscles 
in the body. In the obstetrics and gynecology field it is approved for tocolysis 
in cases of risk of preterm labor (Green-top guidelines, 2011). 
NO is expected to have a role in the remodeling process that occur in 
the cervix prior to onset of labor. During the cervical ripening process, 
chemical and physical changes to the collagen composition of the cervix are 
required to make the cervix more soft and distensible for effacement and 
dilation during normal delivery (Liu et al., 2014). There is an increasing 
evidence that there is a rise in the activity of inducible NO synthase (iNOS) 

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in the cervix before the onset of labor which may have a role in the ripening 
process ( Tschugguel et al., 1999). 
Many studies have been held out to establish the efficacy of the 
NO donors in promoting cervical ripening and labor induction. Many 
patients who need termination of pregnancy may benefit its use as a 
safe and affordable method. Nevertheless, there is so much debate 
regarding their ability to have such effect. Some studies concluded 
that NO donors guarantee a safe method for outpatient induction of 
labor (Bullarbo et al., 2007). Other studies disagreed that they have 
any considerable action at all. They concluded that NO donors do not 
appear to be a useful tool in the process of induction of labor 
(Collingham et al., 2010 ). 
There is an increasing rate of deliveries by caesarean section in 
Egypt lately (DHS, 2014). One of the major causes that makes the 
obstetrician favors delivery by caesarean section is fear of failure or 
complications of induction of labor. Many preparations used in 
induction of labor have been associated with fetal and maternal 
compromise. While in developed countries, labor induction is widely 

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practiced; for example it accounts for 20% of pregnancies in the UK. 
Therefore, the search of a safer and reliable method of induction is 
still ongoing (NHS Maternity statistics, 2015). 
A Cochrane systemic review in 2011 considered 19 trial studies 
to compare the efficacy of NO donors in labor induction with other 
agents. It concluded that NO donors do not appear to be more useful 
than other agents. It suggested that more studies are required to 
examine how NO donors may work alongside established induction 
of labor protocols, especially those based in outpatient settings (Kelly 
et al., 2011). 
 
 
 
 
 
 

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Aim and Objectives: 
Aim: This study aims to establish the efficacy of nitroglycerine skin patch as a NO 
donor in addition to dinoprostone for induction of labor. 
Objectives: The primary outcome of the study is to compare the changes 
occurring to the cervix through the progression in the Bishop’s score 
between NO donor (nitroglycerine patch) vs placebo; in combination with 
a well-established method of induction (Dinoprostone). 
The secondary objective of the study is to observe and report possible fetal 
and maternal side effects that may be associated. This will establish the 
safety and tolerability of NO donors. 
Research Question:                                                                                                 
Does the usage of Nitroglycerine skin patch enhance cervical ripening and 
facilitate induction of labor by Dinoprostone? 
Research Hypothesis : 
Null hypothesis: Nitroglycerine skin patch does not cause advantage for ripening of 
the cervix nor facilitate the process of labor induction. 
Alternative hypothesis : Nitroglycerine skin patch has favorable effect in 
enhancing cervical ripening and the outcome of induction of labor.

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Methodology: 
This study will be a double-blinded randomized controlled trial and will be 
conducted in Ain Shams University Maternity Hospital. It will include 100 
pregnant women at term who will be indicated for induction of labor. 
Sample Size Justification: 
The study was calculated using STATA® version 11 program, setting the 
type-1 error at 0.5 and the power (1-β) at 0.8. Sample size is correlated to 
former studies in induction of labor (Collingham et al., 2010). Calculation 
according to these values produced a minimal sample size of 45 cases in 
each group. 
Alpha error= 0.05  (two sides)  
Power of study= 0.8 
Based on favorable outcome of cervix (p1= 41%, p2=81%) with ratio of 
intervention group to control group 1:1. 
Inclusion criteria are: 
(1) Singleton living full-term fetus. 
(2) Cephalic presentation, 
(3) Bishop score less than 5, 
(4) Assuring fetal monitoring, 
(5) The mother does not have PROM, 

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The exclusion criteria are; 
(1) Expected fetal anomaly (eg. by ultrasound), 
(2) Abnormal presentation, 
(3) Multiple pregnancy, 
(4) Non assuring fetal CTG, 
(5) Fetus more than 90th percentile of expected weight, 
(6) Previous maternal obstructed labor or previous cesarean section, 
(7) Maternal obstetric or medical complication, 
(8) Structural anomaly of the uterus 
Any woman with other general or obstetric risk will be excluded. The 
women that fulfill these criteria will be admitted to the hospital for 
induction of labor. 
 
Assessment: 
The women who fulfill the inclusion criteria will undergo a thorough 
assessment and evaluation as follow: 
1- History: personal, medical and detailed obstetric history. Previous 
history of obstetric or medical complication with pregnancy and 
expectance of recurrence should be considered. 

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2- General examination: for vital signs and cardiopulmonary diseases. 
General signs of other complications (eg. anemia with pregnancy) 
should be taken in consideration. 
3- Obstetric examination: fundal level and pelvic grip for assessment of 
fetal size and lie. Vaginal exam will be done to assess the 
presentation and scoring the cervix according to Bishop’s score: 
(Table):Bishop score for cervical assessment(Williams Obstetrics, 23rd ed) 
 
Method: 
After approval of Ethics Committee of Scientific Research, the 
women under the study will be informed about the study plan and possible 

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benefits and adverse effects. After having an informed consent, they will 
be randomized into two groups receive either nitroglycerine skin patch 
(Nitroderm TTS® 5mg, Novartis) or a placebo patch. 
Group A: will receive nitroglycerine skin patch at time of admission 
plus 
induction 
with 
dinoprostone 
3mg 
(Dinoglandin® 
3gm, 
Rotabiogen) / 8 hours vaginal tablet into the posterior fornix of the 
vagina. 
Group B: will receive placebo patch at time of admission plus 
induction with dinoprostone 3mg (Dinoglandin® 3gm, Rotabiogen)/ 
8 hours into the posterior vaginal fornix. 
Allocation and Concealment: 
Both 
nitroglycerine 
and 
placebo 
patches 
will 
be 
randomized 
according to a sequence of random numbers generated by computer. They 
will be enclosed in opaque, sealed, easy opening envelopes. Each envelope 
contains either a nitroglycerine skin patch or a placebo patch. Opening the 
envelope at the moment the mother enters the labor ward for induction of 
labor. The intervention and control groups and the investigator will be 
blinded about which patch the women will be assigned to. 
 
 

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Randomization and Administration: 
Both placebo and Nitroderm TTS® patches will be identical in 
appearance. They are randomly numbered and delivered to the residents in 
the admission ward. The resident obstetrician is asked to deliver the patch 
to the mother to apply it on the upper chest. 
At the same time, dinoprostone (as Dinoglandin E2® Rotabiogen 
3mg vaginal tablet) will be administered into the posterior fornix of the 
vagina after soaking it with gel. Another dose will be given after 8 hours 
according to Ain Shams University Hospital protocol for labor induction. 
Neither the mother nor the obstetrician would know which patch is given. 
 
Evaluation of the effect: 
Assessment of the cervix will be done at the second dose and after 
12 and 24 hours through the changes and progression of the Bishop’s 
score. A blank table of Bishop’s score will be delivered to the examiner 
who will be asked to fill the table according to the cervical state. The table 
will be filled twice for every patient. Data will be collected at the end of 
the study for final assessment of the results. 
 
 

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Management and Monitoring: 
If the case managed to initiate labor, reevaluation of the mother and 
the fetus will be carried out. And the mother will be monitored according 
to routine management via the partogram. 
If there is a progression in the Bishop’s with no onset of labor, 
induction will be initiated by amniotomy. Provided that the liquor is clear, 
oxytocin intravenous drip will be initiated. If the liquor is meconium 
stained, thorough fetal monitoring will take place. Persistent abnormal 
fetal CTG or deeply stained liquor will be referred to theater for cesarean 
section. 
The fetus will be monitored by the cardiotocography. The mother will be 
evaluated by the vital signs and other signs of headache, palpitation, 
dizziness, GI upset ….etc. 
 
 

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Data presentation and Statistical Methods: 
Data will be collected, tabulated, then analyzed using PC using Statistical 
package for Social Science (SPSS 15.0.1 for windows; SPSS Inc, Chicago, IL, 
2001). 
Normally distributed numerical data will be presented as mean and 
SD, and skewed data as median and interquartile range. Qualitative data 
will be presented as number and percentage. 
Comparison between the means will be done by paired t test for 
independent samples. Skewed data will be compared using the Mann-
Whitney test. Categorical data will be compared using the chi-squared test 
for qualitative data comparison. 
A p-value <0.05 will be considered statistically significant.  
Both groups will be compared regarding: 
 Time from the start of labor induction to vaginal delivery 
 Time from start of drug administration to the earliest uterine contraction 
 Progression of Bishop’s score 
 Duration of the first, second and third stages of labor 
 Whether they eventually need to have a cesarean section or not. 
 Incidence 
of 
maternal 
complications, 
namely; 
headache, 
nausea, 
postpartum hemorrhage,  
 Neonatal outcome through Apgar score at 1 and 5 minutes after 
delivery.  

 
 
References: 
 Bullarbo M, Orrskog ME, Andersch B, et al, Outpatient vaginal 
administration of the nitric oxide donor isosorbide mononitrate for cervical 
ripening and labor induction postterm: A randomized controlled study. 
AJOG, 2007; 196: 50.e1-50.e5 
 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(1):121-126. 
 DHS, Demographic and Health Survey in Egypt: report DM65: 3-4. 
 Green-top Guidelines No. 1B, “Preterm labor tocolytic drugs”. 
RCOG, 2011. 
 Ignarro L, Nitric oxide. A novel signal transduction mechanism for 
transcellular communication. Hypertension, 1990; 16:477-483 
 Kelly AJ, Munson C, Minden L. Nitric oxide donors for cervical ripening 
and induction of labor. Cochrane Database Systematic Review; 15 June, 
2011; (6): CD006901. doi: 10.1002/14651858.CD006901.pub2.  
 Liu A,Lang J, Luhang M, Chen W et al. Efficacy and safety of 
intravaginal misoprostol versus intracervical dinoprostone for labor 
induction at term: A systematic review and meta-analysis. Journal of 
Obstetrics and Gynecology Research 2014 Apr; 40(4):897-906. 
 NHS Maternity Statistics, England-2014-15:  
https://www.gov.uk/government/statistics/announcements/nhs-maternity-statistics-england-2014-15 
 Tschugguel W, Schneeberger C, Lass H, et al.; Human cervical ripening 
is associated with an increase in cervical inducible nitric oxide synthase 
expression. Biology of Reproduction, June 1999; vol.60 no.6 : 1367-1372 
 Williams Obstetrics 23rd Edition, Labor Induction; 500-510