Clinical trial NCT03502915
Conditions: External Cephalic Version
Keywords: breech presentation nitrous oxide analgesia pregnancy
Sponsor: University of North Carolina, Chapel Hill
Start date: 2017-01-30; Completion date: 2019-02-14
Enrollment: 48 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study seeks to determine the effectiveness of nitrous oxide in reducing the anxiety and pain associated with external cephalic version (ECV); a maneuver to turn the fetus from breech to cephalic position.

Detailed description:
Study Procedures:

Potential subjects will be identified as they are scheduled to undergo ECV at the UNC Department of Obstetrics and Gynecology. Subjects will be enrolled in the study by one of the study investigators. Details of the study will be reviewed with potential subjects and those wishing to enroll in the study will be consented for the study by one of the study investigators. Once enrolled participants will be randomized to receive either a mixture of 50% nitrous oxide in 50% oxygen or 100% oxygen, both of which will be delivered via the Nitronox apparatus. Demographic variables will be recorded for each participant at the time they are enrolled in the study

The Nitronox apparatus will be set up to deliver either 50% nitrous oxide in 50% oxygen or 100% oxygen by an anesthesia provider covering labor and delivery who is not involved in the study. The Nitronox device will be covered to prevent participants, study investigators and obstetricians performing the procedure from knowing whether nitrous oxide is being delivered. Nitrous oxide is odorless and colorless, so in that way is indistinguishable from oxygen.

Participants will be prepared for ECV according to current protocols for ECV at UNC. IV access will be obtained and tocolytic agents will be given according to current practice and protocols. Monitoring of maternal and fetal vital signs will be done according to current protocols.

Immediately before an ECV attempt participants will breathe through the facemask of the Nitronox device for 30 seconds and will then be free to use the device ad lib during the ECV attempt. Immediately following each attempt, while fetal monitoring is occurring, the participants will be asked to rate their maximum pain score during the previous attempt. They will also be asked to rate their current level of anxiety. This process will be repeated for any further ECV attempts.

At conclusion of all ECV attempts, while fetal monitoring is occurring, the participants will be asked to rate their current level of pain, their satisfaction with the procedure and about any side effects they experienced (nausea, vomiting, dizziness, headache, other). Participants will continue to be monitored on labor and delivery as current protocol dictates, typically 30 minutes of maternal and fetal monitoring if there are no complications and fetal status is reassuring.

Following the procedure, the obstetrician who performed the procedure will be asked to rate how difficult they felt it was to perform the procedure and to rate how much they felt the analgesic provided assisted in performing the procedure. They will also be asked to indicate whether they thought the patient was in the treatment or placebo arm of the study. This will be recorded to address the adequacy of blinding.

All study variables will be assessed and recorded by one of the study investigators to ensure consistency in data collection.

Arms: arm 1: Patients will receive nitrous oxide during the version procedure. arm 2: Patients will receive placebo (100% oxygen) during the version procedure.
Interventions: intervention 1: Nitrous Oxide intervention 2: Placebo
Intervention descriptions: intervention 1: 50% nitrous oxide/50% oxygen via Nitronox delivery device intervention 2: 100% oxygen via Nitronox delivery device

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nitrous Oxide Analgesia for External Cephalic Version:  
A Randomized Control Trial 
 
Study Protocol 
 
Original Version 9/30/2016 
 
NT# NCT03502915 
 
 
 


Investigational Protocol 
 
Study title: Randomized Controlled Trial of Nitrous Oxide Analgesia in External Cephalic Version 
(ECV) 
 
Lead investigator: Kathleen A. Smith MD 
 
Co-investigators: Lacey Straube MD, Robert Strauss, MD 
 
Background and Purpose of the investigation:  
 
Breech presentation occurs in 3% of pregnancies. The Term Breech Trial in 2000 demonstrated 
that planned cesarean delivery could reduce fetal morbidity and mortality compared to planned 
breech vaginal delivery1. As a result of these findings the incidence of cesarean delivery for 
breech presentation increased. In the U.S., nearly 90% of breech deliveries are performed by 
cesarean delivery2. It is recommended to offer external cephalic version (ECV), a maneuver to 
turn the fetus from breech to cephalic position, when possible to avoid cesarean delivery2. 
Although ECV is typically a brief procedure, it is associated with a moderate amount of pain3. 
The associated pain discourages some women from pursuing ECV and limits the ability of the 
obstetrician to perform this maneuver. 
 
There is evidence that success of ECV is increased and pain is decreased when the procedure is 
performed under neuraxial anesthesia4,5. However, the use of neuraxial anesthesia for ECV 
remains controversial given the invasiveness of the procedure and associated risks. Risks may 
include maternal hypotension, post-dural puncture headache, urinary retention, pain at the 
injection site, meningitis, paresthesia, and weakness. In addition, post-procedure monitoring is 
required after a neuraxial anesthetic which may be considered excessive for this short 
procedure. At UNC, the standard of care is to offer no analgesia to the pregnant woman 
undergoing ECV. 
 
Nitrous oxide is an ideal drug for use during ECV. Nitrous oxide provides analgesia, decreases 
the perception of pain, and has an anxiolytic effect. Some women find nitrous to be a 
satisfactory and effective agent for analgesia during labor6. It has a rapid onset and offset and is 
noninvasive. Pain during ECV is of relatively short duration, less than 5 minutes, and can easily 
be anticipated3. Nitrous oxide could be easily self-administered to treat the pain associated 
with ECV in much the same manner as it is commonly used to treat the pain associated with 
strong uterine contractions during labor. For these reasons, nitrous oxide may be an 
appropriate analgesic for patients undergoing ECV. 
 
Worldwide, nitrous oxide is often used for labor analgesia and interest in nitrous oxide use 
continues to increase in the United States6. It has been estimated that nitrous oxide is used by 
approximately 50% to 75% of laboring women in the United Kingdom, and approximately 60% 
in Finland. Nitrous oxide is used and widely considered to be safe in many parts of the world 
including Canada, Australia, and New Zealand7. Use in the United States is currently estimated 


to be <1% but with rapidly increasing interest. UNC is the third academic institution in the U.S. 
to offer self-administered inhaled nitrous oxide for labor analgesia. 
 
In the context of obstetric analgesia, “nitrous oxide” refers to a half-and-half combination of 
oxygen and nitrous oxide gas, called by the trade name “Nitronox” (in the United States) and 
“Entonox” (in the United Kingdom). It is self-administered by the laboring woman using a face 
mask. It is generally administered beginning approximately 30 seconds before the onset of a 
strong contraction until the pain associated with contraction eases7. The Nitronox delivery 
system includes a demand valve which limits delivery of nitrous oxide to the inspiratory phase 
of ventilation. It also includes a scavenging system that collects expired gasses to minimize 
environmental exposure. 
 
Nitrous oxide is the only commonly used inhaled labor analgesic in modern obstetric practice 
and has a long history of safe use. This is likely related to the ease of administration, lack of 
flammability, absence of pungent odor, minimal toxicity, minimal depression of the 
cardiovascular system, lack of effect on uterine contractility, and the fact that it does not trigger 
malignant hyperthermia7. 
 
In a systematic review of available literature in 2014, Likis notes that the most common 
maternal adverse effects are unpleasant side effects that affect tolerability (e.g., nausea, 
vomiting, dizziness, and drowsiness). Some of the above listed maternal adverse effects are 
common in laboring women regardless of whether analgesia is used6. We believe 
administration of nitrous oxide for ECV to be a safe practice with a favorable risk to benefit 
ratio. Confidence in the safety of this study is bolstered by the long history of safe 
administration to women in labor. 
 
There are concerns of potential neurotoxicity of nitrous oxide, but this finding is limited to 
animal studies and only when used in combination with other anesthetics. Nitrous oxide is 
transmitted via the placenta and is rapidly eliminated by the neonate after birth once breathing 
begins. No evidence exists to suggest altered neonatal outcomes associated with the use of 
nitrous oxide alone. Apgar scores in newborns whose mothers used nitrous oxide did not differ 
significantly from those of newborns whose mothers used other labor pain management 
methods or no analgesia6. 
 
Recently published literature has provided evidence that exposure of the immature animal 
brain to anesthetics during the period of rapid synaptogenesis triggers rapid neurodegeneration 
and causes significant long-term cognitive impairment8. However, nitrous oxide, by itself at 
subanesthetic concentrations, triggers little or no neuroapoptosis in the infant rat brain9. In our 
study, nitrous oxide will be delivered at 50%, which is an analgesic or subanesthetic 
concentration. In addition, no other analgesic or anesthetic agents will be administered in 
combination with nitrous oxide.  
 
Nitrous oxide is classified as a Class C drug in pregnancy by the US FDA, “Risk cannot be ruled 
out. Either studies in animals have revealed adverse effects on the fetus (teratogenic or 


embryocidal effects or other) and there are no controlled studies in women, or studies in 
women and animals are not available. Drugs should be given only if the potential benefits 
justify the potential risk to the fetus.” As discussed above, concerns about nitrous oxide 
induced neuroapoptosis are not applicable to this study. Nitrous oxide has been used safely in 
pregnancy for greater than 100 years, and many commonly used and widely accepted drugs are 
used for analgesia and anesthesia in the parturient that are also considered Class C. The class C 
rating of nitrous oxide is likely due to the absence of large randomized controlled studies in 
women. 
 
As an example of a comparable Class C analgesic option in labor, other than an epidural, 
remifentanil has also been widely used and studied. In a meta-analysis of RCTs studying 
remifentanil for labor analgesia, remifentanil patient controlled analgesia was found to be safe 
and effective when compared with other analgesic options in labor10. In addition, remifentanil 
has been used and studied in the setting of ECV where it was found to reduce pain and increase 
patient satisfaction11. We do not routinely offer remifentanil for ECV at UNC Hospitals, but hope 
to show similar analgesic results with nitrous oxide. 
 
The potential benefits of this study include increased patient satisfaction, decreased pain, 
increased success of ECV, and decreased cesarean section rate. In addition, after completion of 
this study, nitrous oxide analgesia may become more routinely used for ECV as well as other 
painful procedures such as epidural placement, peripheral intravenous access, arterial access, 
obstetric examinations etc. If effective, this study could also help other health care providers 
with the decision to use nitrous oxide for analgesia outside of the obstetric population in the 
future. 
 
Study Design 
 
Double blind randomized controlled trial 
 
Subject Selection 
 
Participants: Pregnant women with breech presentation at 37 weeks EGA who are scheduled to 
undergo external cephalic version. 
 
Subjects eligible for study entry: 
1. Female 18yo or greater 
2. Scheduled to undergo ECV due to singleton breech presentation 
3. Not scheduled to have spinal or epidural anesthesia during the ECV procedure 
4. American Society of Anesthesiology (ASA) Physical Status 1, 2 or 3. 
5. Able to provide informed consent and adhere to study protocol 
 
A subject will not be eligible for the study if he/she meets any of the following criteria: 
1. Current or historical evidence of any clinically significant disease or condition, especially 
cardiovascular or neurological conditions that, in the opinion of the Investigator, may 


increase the risk of exposure to nitrous oxide or complicate the subject’s postprocedural 
course. 
2. Significant medical conditions or laboratory results that, in the opinion of the 
Investigator, indicate an increased vulnerability to study drugs and procedures. 
 
Study Procedures: 
 
Potential subjects will be identified as they are scheduled to undergo ECV at the UNC 
Department of Obstetrics and Gynecology. Subjects will be enrolled in the study by one of the 
study investigators. Details of the study will be reviewed with potential subjects and those 
wishing to enroll in the study will be consented for the study by one of the study investigators. 
Once enrolled participants will be randomized to receive either a mixture of 50% nitrous oxide 
in 50% oxygen or 100% oxygen, both of which will be delivered via the Nitronox apparatus. 
Demographic variables will be recorded for each participant at the time they are enrolled in the 
study (weight, BMI, age, ethnicity, gestational age, parity, placentation, breech position, hx of 
previous cesarean delivery, hx of previous ECV) 
 
The Nitronox apparatus will be set up to deliver either 50% nitrous oxide in 50% oxygen or 
100% oxygen by an anesthesia provider covering labor and delivery who is not involved in the 
study. The Nitronox device will be covered to prevent participants, study investigators and 
obstetricians performing the procedure from knowing whether nitrous oxide is being delivered. 
Nitrous oxide is odorless and colorless, so in that way is indistinguishable from oxygen.  
 
Participants will be prepared for ECV according to current protocols for ECV at UNC. IV access 
will be obtained and tocolytic agents will be given according to current practice and protocols. 
Monitoring of maternal and fetal vital signs will be done according to current protocols.  
 
Immediately before an ECV attempt participants will breathe through the facemask of the 
Nitronox device for 30 seconds and will then be free to use the device ad lib during the ECV 
attempt. Immediately following each attempt, while fetal monitoring is occurring, the 
participants will be asked to rate their maximum pain score (0-10) during the previous attempt. 
They will also be asked to rate their current level of anxiety (0-10). This process will be repeated 
for any further ECV attempts.  
 
At conclusion of all ECV attempts, while fetal monitoring is occurring, the participants will be 
asked to rate their current level of pain (0-10), their satisfaction with the procedure (0-10) and 
about any side effects they experienced (nausea, vomiting, dizziness, headache, other). 
Participants will continue to be monitored on labor and delivery as current protocol dictates, 
typically 30 minutes of maternal and fetal monitoring if there are no complications and fetal 
status is reassuring.  
 
Following the procedure, the obstetrician who performed the procedure will be asked to rate 
how difficult they felt it was to perform the procedure (1-10) and to rate how much they felt 
the analgesic provided assisted in performing the procedure (1-10). They will also be asked to 


indicate whether they thought the patient was in the treatment or placebo arm of the study. 
This will be recorded to address the adequacy of blinding.  
 
Outcomes that will be recorded following the procedure include whether the procedure was 
successful, the number of attempts performed, complications associated with the procedure 
(maternal hypotension, fetal bradycardia transient/persistent, emergent cesarean delivery, 
cord prolapse, placental abruption, other), eventual mode of delivery, indication for cesarean 
delivery if performed and analgesic/anesthetic used for delivery if any.  
 
All study variables will be assessed and recorded by one of the study investigators to ensure 
consistency in data collection. 
 
Study outcome evaluation:  
A suite of preliminary tabular and graphical investigations will be conducted prior to 
quantitative analyses to provide a thorough understanding of the data. These investigations will 
include: 
a. Descriptive statistics, with histograms and boxplots on continuous variables 
b. Frequency distributions on discrete variables 
c. Correlations among potential model predictors and covariates to reveal potential variable 
multicolinearity problems. 
 
In addition to the information compiled from the preliminary investigations described above, 
Chi-square tests of association for the outcome variables of interest and principle predictors 
will be conducted to reveal important relationships and justifications for more robust analyses. 
 
The primary outcome of the study is pain experienced during ECV. The null hypothesis of this 
outcome is that there is no difference in pain scores between patients who use a mixture of 
50% nitrous oxide and 50% oxygen during ECV (treatment group) compared to those that use 
oxygen only during ECV (placebo group). Pain scores during each ECV attempt will be recorded 
for each participant. For those participants who have more than one attempt these scores will 
be averaged to obtain a single score for the entire procedure. A student t-test will then be 
performed to evaluate the null hypothesis of no difference in pain scores between the 
treatment vs placebo groups. A difference in pain score of 2 (Scale: 0-10) is considered clinically 
significant. Based on a mean pain score difference of 2 and an average standard deviation of 2.5 
for the treatment and placebo groups, a statistical power of 80% is expected. Consideration will 
be given to categorizing the patients into “Low”, “Moderate” and “Severe” pain score 
categories along clinical guidelines to further assess the impact of analgesia on pain severity. 
Where feasible, both p-values and confidence intervals for odds ratios from logistic regression 
and/or parameter estimates from general linear modeling will be reported. 
 
Secondary outcomes of the study include patient anxiety experienced during the ECV 
procedure, pain scores following the ECV procedure, patient satisfaction with ECV procedure, 
side effects experienced and OB providers ratings of ease of procedure.  
 


We will be recording whether the ECV procedures are successful and whether any 
complications occur as a result of the ECV procedure, but given that our study is powered to 
evaluate patient pain and not these outcomes we do not expect to see any differences. 
Previous studies have shown that analgesia alone does not alter success rates of ECV, this 
includes a previous study that used nitrous oxide during ECV.  
 
Complications of ECV are very rare. Given that nitrous oxide has been demonstrated to be safe 
for labor analgesia, a similar patient population to ours, we do not anticipate that we would be 
able to detect any differences in complications in this patient population. These variables are 
being recorded for completeness.  
 
Several variables known to influence the effectiveness of ECV (BMI, age, ethnicity, gestational 
age, parity, placentation, type of breech position, amniotic fluid level, tocolytic used, history of 
prior c-section) are being recorded for each participant. We are also recording whether 
participants have previously undergone ECV with a prior pregnancy since this could influence 
their expectations of this procedure. These variables will be analyzed using chi-square or fisher 
exact test to ensure that there are no differences in these variables between the treatment and 
placebo groups.  
 
Either a general linear model or a logistic model will be employed to assess the effect of the 
main effects, interactions, and appropriate covariates on the primary outcomes of interest. 
Selected covariates and potential confounders will be included in a “forward” regression model 
and subsequently retained in the final model only if found to explain a significant amount of the 
variability in the outcome. Candidate covariates include patient anxiety during the ECV 
procedure, patient satisfaction, ECV success and history of previous ECV. 
 
All data will be recorded during one interaction with the participants and will not require 
participants to be contacted following the ECV procedure. Because of this the likelihood of 
missing data and drop out is extremely low. 
 
The only area where we might expect to have missing data is for delivery information and type 
of anesthetic used for delivery since not all patients who have an ECV at UNC actually deliver at 
UNC. However, this data is included on the data sheet only because we are curious to know 
whether involvement in the study might influence participants to try nitrous oxide for labor 
analgesia. The use of nitrous oxide for labor, while common worldwide, remains uncommon in 
the United States. Many women who present in labor have actually never heard of the use of 
nitrous oxide for labor analgesia. We also have parturients who come to UNC to deliver 
specifically because we offer nitrous oxide for labor analgesia. It would be interesting to know 
whether our contact with them through the consent process may inform them of and 
potentially lead them to consider use of nitrous oxide for labor analgesia.  
 
Power analysis:  
A power analysis to determine the sample size required to see a difference in pain score of 2 
between the groups was performed which yielded the needed sample size of 50. This analysis 


was based on pain scores from previous studies on pain during ECV in the setting of no 
analgesia as well as use of nitrous oxide or remifentanil for treatment of pain (Burgos et al, Fok 
et al, Munoz et al). 
 
Normal Distribution α=0.05 
Mean Difference 
2 
Standard Deviation 
2.4 
Total Sample Size 
50 
Number of Sides 
2 
Power 
0.823 
 
Lognormal Distribution α=0.05 
Group 1 Geometric Mean 
4.5 
Group 2 Geometric Mean 
6.5 
Coefficient of Variation 
0.45 
Total Sample Size 
50 
Number of Sides 
2 
Power 
0.843 
 
Data handling:  
At the time of enrollment in the study each participant will be assigned a unique study ID 
number. A spreadsheet that links the patient's study ID number with the patient's name and 
medical record number will be kept on a secure department server that only the investigators 
will have password protected access to. The remainder of study data will be coded and 
information regarding an individual patient will only be linked to their study ID number. Study 
ID numbers will be recorded on each data collection sheet. Data from the data collection sheets 
will then be entered into a database for analysis. In this way a coded hard copy of data for each 
participant will exist that does not include any patient names or medical record numbers, but 
will allow to ensure the integrity of the data within the database. All coded data will be entered 
into a Microsoft excel spreadsheet by one of the study investigators. This will be a password 
protected file to ensure that data cannot be manipulated by anyone other than the study 
investigators. Data analysis will be performed as described above by the study investigators 
with assistance from a consulting statistician as needed. The consulting statistician will not have 
access to any patient identifiable data, but would solely be working with the coded data. 
 
References: 
 
1. 
Hannah ME, Hannah WJ, Hewson SA, Hodnett ED, Saigal S, Willan AR. Planned 
caesarean section versus planned vaginal birth for breech presentation at term: a 
randomised multicentre trial. Term Breech Trial Collaborative Group. Lancet. 
2000;356(9239):1375-1383. 
2. 
ACOG Committee Opinion No. 340. Mode of term singleton breech delivery. Obstet 
Gynecol. 2006;108(1):235-237. 
3. 
Fok WY, Chan LW, Leung TY, Lau TK. Maternal experience of pain during external 
cephalic version at term. Acta Obstet Gynecol Scand. 2005;84(8):748-751. 


4. 
Lavoie A, Guay J. Anesthetic dose neuraxial blockade increases the success rate of 
external fetal version: a meta-analysis. Can J Anaesth. 2010;57(5):408-414. 
5. 
Weiniger CF, Ginosar Y, Elchalal U, Sharon E, Nokrian M, Ezra Y. External cephalic version 
for breech presentation with or without spinal analgesia in nulliparous women at term: 
a randomized controlled trial. Obstet Gynecol. 2007;110(6):1343-1350. 
6. 
Likis FE, Andrews JC, Collins MR, et al. Nitrous oxide for the management of labor pain: a 
systematic review. Anesth Analg. 2014;118(1):153-167. 
7. 
Rosen MA. Nitrous oxide for relief of labor pain: a systematic review. American journal 
of obstetrics and gynecology. 2002;186(5 Suppl Nature):S110-126. 
8. 
Creeley CE, Olney JW. The young: neuroapoptosis induced by anesthetics and what to 
do about it. Anesth Analg. 2010;110(2):442-448. 
9. 
Jevtovic-Todorovic V, Hartman RE, Izumi Y, et al. Early exposure to common anesthetic 
agents causes widespread neurodegeneration in the developing rat brain and persistent 
learning deficits. The Journal of neuroscience : the official journal of the Society for 
Neuroscience. 2003;23(3):876-882. 
10. 
Schnabel A, Hahn N, Broscheit J, et al. Remifentanil for labour analgesia: a meta-analysis 
of randomised controlled trials. Eur J Anaesthesiol. 2012;29(4):177-185. 
11. 
Munoz H, Guerra S, Perez-Vaquero P, Valero Martinez C, Aizpuru F, Lopez-Picado A. 
Remifentanil versus placebo for analgesia during external cephalic version: a 
randomised clinical trial. Int J Obstet Anesth. 2014;23(1):52-57.