Journal of Clinical Anesthesia 40 (2017) 40–45

Contents lists available at ScienceDirect

Journal of Clinical Anesthesia

Original Contribution

Nitrous oxide for labor analgesia: Utilization and predictors of conversion

to neuraxial analgesia
Caitlin D. Sutton, MD 1, Alexander J. Butwick, MBBS, FRCA,
Edward T. Riley, MD, Brendan Carvalho, MBBCh, FRCA ⁎
Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA

a r t i c l e i n f o a b s t r a c t

Article history: Study Objective: We examined the characteristics of women who choose nitrous oxide for labor analgesia and
Received 22 February 2017 identified factors that predict conversion from nitrous oxide to labor neuraxial analgesia.
Received in revised form 31 March 2017 Design: Retrospective descriptive study.
Accepted 4 April 2017 Setting: Labor and Delivery Ward.
Available online xxxx
Patients: 146 pregnant women who used nitrous oxide for analgesia during labor and delivery between Septem-
ber 2014 and September 2015.
Keywords:
Nitrous oxide
Interventions: Chart review only.
Labor analgesia Measurements: Demographic, obstetric, and intrapartum characteristics of women using nitrous oxide were ex-
amined. Multivariable logistic regression was performed to identify factors associated with conversion from ni-
trous oxide to neuraxial analgesia. Data are presented as n (%), median [IQR], adjusted relative risk (aRR), and 95%
confidence intervals (CI) as appropriate.
Results: During the study period, 146 women used nitrous oxide for labor analgesia (accounting for 3% of the total
deliveries). The majority (71.9%) of women who used nitrous oxide were nulliparous, and over half (51.9%) had
expressed an initial preference for “nonmedical birth.” The conversion rate to neuraxial blockade was 63.2%,
compared to a concurrent institutional rate of 85.1% in women who did not use nitrous oxide. Factors associated
with conversion from nitrous oxide to neuraxial blockade were labor induction (aRR = 2.0, CI 1.2–3.3) and labor
augmentation (aRR = 1.7, CI 1.0–2.9).
Conclusion: Only a small number of women opted to use nitrous oxide during labor, analgesia was minimal, and
most converted to neuraxial analgesia. Women with induced and augmented labors should be counseled about
the increased likelihood that they will convert to neuraxial analgesia.
© 2017 Elsevier Inc. All rights reserved.

1. Introduction
Nitrous oxide is an anesthetic gas with NMDA antagonistic proper-
ties that offers rapid-onset inhaled mild analgesia. The first description
of its use during labor and delivery was in 1881 [1], and women
throughout the world continue to use it as a labor analgesic today. The
minimally invasive delivery method of nitrous oxide offers a modality
for managing labor pain that appeals to women who desire labor anal-
gesia without a neuraxial block. This group of women could comprise
a significant proportion of obstetric patients, with 26% of women ex-
pressing a preference for delivery without neuraxial analgesia in a
2010 national survey performed in France [2]. However, until recently,
⁎ Corresponding author.
E-mail address: bcarvalho@stanford.edu (B. Carvalho).
1
Present address: Department of Pediatric Anesthesiology, Perioperative, and Pain
Medicine, Texas Children's Hospital, Baylor College of Medicine, 6621 Fannin Street,
Houston, Texas 77030, USA.
nitrous oxide was not widely available in the United States [3]. In a na-
tionwide survey performed in the United States in 2000, only a small
minority of women (2%) reported using nitrous oxide [4]. Since that
time, patient expectations fueled by media coverage have promoted
greater nitrous oxide use in the United States. The availability of nitrous
oxide for labor analgesia has increased from only five United States in-
stitutions in 2012 [3] to several hundred hospitals and birth centers in
2016 [5].
Cultural and societal expectations play a large role in labor prefer-
ences [6,7]. Despite the recent resurgence of nitrous oxide use for
labor analgesia in the United States, few studies have examined popula-
tions of women that use nitrous oxide for labor analgesia that are appli-
cable to pregnant women in the United States today. The utilization of
nitrous oxide for labor analgesia, the rate of conversion from nitrous
oxide to neuraxial analgesia for labor, and predictors of which patients
are most likely to convert to neuraxial analgesia are unknown. This in-
formation can assist anesthesia providers in the United States who are
interested in offering a new nitrous oxide service for labor analgesia to

http://dx.doi.org/10.1016/j.jclinane.2017.04.005
0952-8180/© 2017 Elsevier Inc. All rights reserved.
 C.D. Sutton et al. / Journal of Clinical Anesthesia 40 (2017) 40–45
help determine expected demand and utilization. It will also help anes-
thesiologists to tailor their labor analgesia counseling and consent to in-
dividual patients who are more likely to convert to neuraxial analgesia.
The primary aim of this study was to determine the utilization and
characteristics of women who choose to use nitrous oxide for labor an-
algesia. The secondary objective was to evaluate factors that predict the
conversion to neuraxial analgesia.
2. Materials and methods
After obtaining Stanford University IRB approval, we reviewed elec-
tronic medical records of women who used nitrous oxide for labor anal-
gesia over 13 months (September 2014 to September 2015). The study
was conducted at Lucile Packard Children's Hospital, a tertiary obstetric
center with approximately 4500 deliveries per year and a labor epidural
rate of over 80%.
There is dedicated, “around-the-clock” anesthesia coverage for the
obstetric patients, with anesthesia care provided by an anesthesia at-
tending, residents, and fellows. At our institution, we offer intravenous
opioids, nitrous oxide, and neuraxial analgesia as labor analgesic op-
tions. Currently, only the obstetric anesthesia team prescribes and initi-
ates nitrous oxide, and a standardized protocol is followed (Fig. 1).
Indications for nitrous oxide include labor pain as well as other painful
obstetric procedures, including assisted delivery, laceration/episiotomy
repair, manual removal of placenta, uterine exploration/examination,
external cephalic version, and difficult vaginal exams. Contraindications
to the use of nitrous oxide include inability of the patient to hold face
mask; impaired level of consciousness; decreased oxygenation; catego-
ry III fetal heart tracing; or recent history of trauma, pneumothorax, in-
creased intracranial or intraocular pressure, bowel obstruction, middle
ear or intraocular surgery, emphysema, or pulmonary hypertension.
Fig. 1. Institutional protocol for the use of N2O during labor. N2O: nitrous oxide.
41
Pregnant women self-administer nitrous oxide using a gas mixer in a
fixed ratio of 50% nitrous oxide:50% oxygen (Sedara Healthcare, The
Linde Group, Munich, Germany).
All electronic medical records between September 2014 and Sep-
tember 2015 which involved the use of nitrous oxide at any time during
a woman's labor and delivery were reviewed. For our primary study aim
of examining the characteristics of patients who used nitrous oxide, we
abstracted the following data: demographic information, the patient's
initial analgesic preference from the birth plan documented at admis-
sion to the labor and delivery suite, relevant obstetric data (including
labor stage and cervical dilation at time of initiation of nitrous oxide,
labor induction, and labor augmentation), numerical verbal pain scores
(VPS, 0 = no pain and 10 = worst pain imaginable) prior to and just
after nitrous oxide initiation, as well as all pain scores recorded by the
nurse until either delivery or epidural placement. We also abstracted
duration of nitrous oxide use, rate of conversion to neuraxial labor anal-
gesia, and mode of delivery. Side effects (e.g. maternal dizziness) related
to nitrous oxide administration noted in the anesthetic or nursing re-
cords were also recorded.
As a secondary objective, factors that were associated with conver-
sion from nitrous oxide to neuraxial analgesia for labor were evaluated.
We created a multivariable regression model to determine if any factors
were predictors of conversion to neuraxial analgesia. While our primary
aims were descriptive, we used methods as described in the STROBE
statement for the comparative analysis.
We compared the neuraxial analgesia rates between patients who did
and did not use nitrous oxide. To determine the rate of neuraxial labor an-
algesia in patients who did not use nitrous oxide, the number of patients
who received neuraxial labor analgesia but not nitrous oxide was divided
by the sum of all vaginal deliveries and intrapartum cesarean deliveries
performed with epidural during the same study period.
42 C.D. Sutton et al. / Journal of Clinical Anesthesia 40 (2017) 40–45

2.1. Statistical analysis Table 1

Maternal demographic and obstetric characteristics.

For our primary analysis, we examined utilization and characteris- Variable n (%)
tics of women who used nitrous oxide. Demographic, obstetric, analge- Age (y) 30 ± 6
sic, and outcome data are presented as mean ± standard deviation, Ethnicity/race
median [interquartile range], number (percentage), adjusted relative Caucasian 55 (37.9)
risk (aRR), and 95% confidence intervals (CI) as appropriate. The Hispanic 44 (30.3)
Asian 27 (18.4)
neuraxial analgesia rate between patients who did and did not use ni-
Other 19 (12.9)
trous oxide was compared using a difference in proportions Z test. Preferred language
For our secondary analysis, we examined factors associated with English 119 (82.1)
conversion from nitrous oxide to labor epidural analgesia. For this anal- Non-English 26 (17.9)
ysis, we excluded women who initiated the use of nitrous oxide after Body mass index (kg/m2) 28 [25–31]
Insurance
the first stage of labor, underwent a trial of labor after cesarean, had Private 90 (61.6)
multiple gestations, or received neuraxial anesthesia after a decision Government/none 56 (38.4)
for an intrapartum cesarean delivery was made (Fig. 2). While it is not Nulliparity 105 (71.9)
required for patients with multiple gestations or undergoing trial of Gestational age (weeks) 40 [39–40]
Type of labor
labor after cesarean delivery to receive epidural analgesia at our institu-
Spontaneous 49 (33.6)
tion, counseling for these patients often emphasizes the benefits of epi- Oxytocin augmentation 56 (38.4)
durals which may confound results; therefore, these patients were Induction 41 (28.1)
excluded. Initial birth plan
Patient and obstetric characteristics of women who did and did not Nonmedical 67/129 (51.9)
Medicated (iv, epidural, nitrous) 40/129 (31.0)
convert to neuraxial analgesia were compared using Student's t-test
Undecided 17/129 (13.2)
for normally distributed data, Mann-Whitney U tests for continuous
Data are n(%), mean ± standard deviation, or median [interquartile range].
data, and chi-squared test for categorical data.
Multivariable logistic regression was then performed, which includ-
ed all variables with a P-value b 0.2 from the univariable analyses. Race according to their birth plan at the time of admission. Nitrous oxide
was forced into the model based on prior research showing that dispar- was used as an adjunct to inadequate epidural analgesia in 4 patients,
ities exist for labor epidural use [7,8]. Because pain score and cervical di- during postpartum laceration repair in 2 patients, and during a painful
lation prior to initiation of nitrous oxide had non-linear relationships vaginal exam in 1 patient. Analgesic and labor outcomes are shown in
with the predictive probability of conversion to neuraxial analgesia, a Table 2. Median duration of use was 80 (38–143) minutes. The median
quadratic function for each variable was used. All data were analyzed VPS change upon initiation of nitrous oxide was 0 [− 2 to 1]; Fig. 3
using Stata version 12 (StataCorp, College Station, TX, USA). shows the change in pain score for each patient after initiation of nitrous
oxide.
3. Results Adverse effects were reported in only 3 patients who used nitrous
oxide: 1 patient with dizziness, 1 with dry mouth, and 1 with syncope
We abstracted data from 146 records of women who used nitrous (though the syncope occurred after delivery N1 h after discontinuation
oxide. During the study period 4698 women delivered at our institution, of nitrous oxide).
therefore women who used nitrous oxide accounted for 3.1% of all deliv- Ultimately, 84 (63.2%) women who used nitrous oxide converted to
eries. Demographic and obstetric characteristics of these women are epidural analgesia, which is significantly lower than the 85.1% concur-
outlined in Table 1. Women who used nitrous oxide were primarily rent institutional labor neuraxial rate in women not using nitrous
English-speaking (82.1%), and nulliparous (71.9%). More than half oxide (p b 0.0001). Of the women converting from nitrous oxide to
(51.9%) had initially indicated a preference for “nonmedical birth” neuraxial labor analgesia, 59.5% received a combined spinal-epidural
versus 40.5% who received a standard epidural.

Table 2
Nitrous oxide utilization, analgesic efficacy provided, and obstetric outcomes.

Variable n (%)

Stage of labor at initiation of nitrous oxide

1 139 (94.6)
2 5 (3.4)
3 3 (2.0)
Dilation at initiation of N2O (cm) 5 (3–7)
Pain score prior to initiation of N2O 8 [6–9]
Pain score change upon initiation of N2O 0 [−2 to 1]
Use of opioids 66 (44.9)
Duration of use of N2O (min) 80 [38–143]
Converted to epidural analgesia
Yes 88 (60.3)
No 58 (39.7)
Delivery type
Vaginal 119 (81.5)
Operative vaginal 5 (3.4)
Cesarean 22 (15.1)
Apgar
Fig. 2. Flowchart of electronic medical records reviewed and excluded for the study
1 min 8 [8–9]
analysis of conversion to neuraxial analgesia (all records included for descriptive section
5 min 9 [9–9]
of study). TOLAC: trial of labor after cesarean. *One patient excluded initiated nitrous
during stage 2 and was also a TOLAC. Data are n(%), and median [interquartile range].
 C.D. Sutton et al. / Journal of Clinical Anesthesia 40 (2017) 40–45
Fig. 3. Pain score change upon initiation of nitrous oxide. Each line represents one patient. Pain scores were recorded using verbal numerical pain scores (0–10, 0 = no pain, and 10 =
worst pain imaginable) by anesthesia providers or nurses as part of normal clinical care.
Women who converted from nitrous oxide to labor epidural analge-
sia were more likely to be English-speaking, nulliparous women whose
initial birth plan indicated a preference for medicated rather than “non-
medical” birth (Table 3). They were more likely to undergo labor induc-
tion or augmentation, and have lower pain scores and lower cervical
dilation prior to nitrous oxide initiation. Factors independently associat-
ed with conversion to labor epidural analgesia were: labor induction
(aRR = 2.0, CI 1.2–3.3) and augmentation with oxytocin (aRR = 1.7,
CI 1.0–2.9) (Table 4).
4. Discussion
Only a small proportion (3%) of women at our institution chose to
use nitrous oxide. This stands in stark contrast to reports outside the
United States showing over 50% to nearly 80% utilization of nitrous
oxide in Australia and the United Kingdom, respectively [9,10]. The rea-
sons for this large disparity in use of nitrous oxide for labor analgesia are
not well established. The Agency for Healthcare Research and Quality
identified many potential factors influencing the use of nitrous oxide
for labor analgesia in the United States, including individual characteris-
tics (e.g. parity and past birth experience; cultural or familial influences;
knowledge of pain management methods) and health system factors
(e.g. provider type, knowledge, and preferences; availability of
methods; pain assessment methods; cost and regulation) [11].
Individual characteristics of women in our study may have affected
their choice to use nitrous oxide for labor analgesia. The vast majority
of women (72%) were nulliparous and thus had no personal prior expe-
rience with labor pain, so past labor analgesic options received did not
influence nitrous oxide utilization in these women. Previous studies
found that nulliparous parturients use nitrous oxide slightly more
43
often than multiparous women but are less likely to use it as a sole an-
algesic modality [9]. While the study design did not allow us to obtain
information on the cohort's baseline awareness and knowledge of ni-
trous oxide for labor analgesia, only 10% of women who used nitrous
oxide indicated it as part of their initial plan for labor analgesia. This
could be related to its recent introduction in our hospital or women's
unfamiliarity with it as an option for labor analgesia until informed by
nurses and doctors.
Our study found that the analgesia provided by nitrous oxide was
minimal with pain scores largely unchanged after initiation of nitrous
oxide. These results support prior analyses that found no significant dif-
ference in labor pain scores comparing nitrous oxide to placebo [12,13],
or a very weak relationship between nitrous oxide use and decreased
labor pain [14]. Compared with epidural analgesia, nitrous oxide is sig-
nificantly less effective for pain relief during labor [15]. Since the first
pain score obtained after nitrous oxide initiation was used for the anal-
ysis, the lack of analgesic effect of nitrous oxide at initiation cannot be
explained by increase in pain due to the normal progression of labor
[16].
Given that nitrous oxide does not provide significant analgesia [3],
and patients' satisfaction in labor is not fully explained by pain relief
alone [17], pain scores may be a poor measure of success of nitrous
oxide in labor and tools assessing maternal satisfaction may be prefera-
ble in this setting. Unfortunately, we were unable to obtain maternal
satisfaction scores, as this outcome was not routinely measured during
the study period. Previous studies assessing satisfaction have shown
mixed results, reporting both increased [15] and decreased [18] mater-
nal satisfaction with nitrous oxide compared with neuraxial analgesia.
Two systematic reviews and one Cochrane review that have evaluated
the use of nitrous oxide for labor analgesia report that there are few
44 C.D. Sutton et al. / Journal of Clinical Anesthesia 40 (2017) 40–45

Table 3 Table 4
Bivariate association with conversion to epidural analgesia. Analysis of factors contributing to conversion to epidural analgesia.

No epidural Epidural Variable aRR 95% CI

Variable n(%) n(%) P value
Race
Age (y) 30 (6) 31 (6) 0.39 Caucasian Reference
Race/ethnicity Asian 0.94 0.79–1.11
Caucasian 17(34.7) 33(41.3) 0.6 Hispanic 1.05 0.81–1.36
Hispanic 17(34.7) 21(26.3) Other 1.15 0.82–1.63
Asian 7(14.3) 16(20) Language
Other 8(16.3) 10(12.5) English Reference
Preferred language Non-English 0.69 0.45–1.06
English 37(77.1) 70(86.4) 0.17 Type of pregnancy
Non-English 11(22.9) 11(13.6) Multiparous Reference
Insurance information Nulliparous 1.07 0.84–1.38
Private 29(59.2) 56(69.1) 0.25 Labor type
Government/none 20(40.8) 25(30.9) Spontaneous Reference
BMI (kg/m2) 28 [26–30] 29 [25–31] 0.97 Induced 1.72 1.01–2.89
EGA (w) 40 [39–41] 40 [39–40] 0.54 Augmented 2.03 1.24–3.32
Nulliparity Birth plan
No 21(42.9) 16(19.8) 0.005 Non-medicated Reference
Yes 28(57.1) 65 (80.3) Medicated 1.15 0.91–1.45
Labor type Unknown 1.26 0.86–1.84
Spontaneous 30(61.2) 12(14.8) b0.0005 Undecided 1.06 0.76–1.48
Spont, augmented 9(18.4) 43(53.1) Pain scorea 0.99 0.97–1.00
Induced 10(20.4) 26(32.1) Cervical dilationa (cm) 0.97 0.95–1.00
Opioid pre-nitrous a
Because pain score and cervical dilation prior to initiation of nitrous oxide had non-
Yes 16(33.3) 22(27.5) 0.48
linear relationships with the predictive probability of conversion to neuraxial analgesia, a
No 32(66.7) 58(72.5)
quadratric function for each variable was used.
Opioid at any time
Yes 21(42.9) 38(46.9) 0.65
No 28(57.1) 43(53.1)
Birth plan
utilization with a relatively high rate of conversion to neuraxial analge-
Nonmedical 27(55.1) 32(39.5) 0.03 sia, suggest that offering nitrous oxide probably has a minimal impact
Medicateda 8(16.3) 31(38.3) on the overall rate of neuraxial analgesia use in the United States [5].
Undecided 5(10.2) 11(13.6) Based on our regression analyses, we found that labor induction and
Unknown 9(18.4) 7(8.6)
augmentation with oxytocin were independently associated with con-
Pain scoreb prior to nitrous oxide 9 [7–10] 7 [5–8] 0.0005
initiation version to neuraxial labor analgesia. These findings align with those of
Pain scoreb change with nitrous oxide −1.5[−3 to 0] 0[−2 to 1] 0.04 previous studies, which have found that women undergoing labor in-
initiation duction have a higher likelihood of using neuraxial labor analgesia com-
Cervical dilationc (cm) 7 [5–8] 4 [2–5] b0.00005
pared to those with spontaneous labor [27–30]. Oxytocin use has been
Data are n(%), and median [interquartile range]. associated with 48% more pain at the start of labor [16], and its use is
BMI = body mass index, EGA = estimated gestational age. likely to be a factor in the decision for labor analgesia. This information
a
Medicated birth includes plan for epidural, intravenous medication, or nitrous oxide.
b
Pain scores were recorded using verbal numerical pain scores (0–10, 0 = no pain, and
can help healthcare providers who prescribe nitrous oxide for labor an-
10 = worst pain imaginable) by anesthesia providers or nurses as part of normal clinical care. algesia to better tailor their informed consent discussions with patients
c
Cervical dilation (measured in cm) from exam nearest to initiation of nitrous recorded. regarding the likelihood of conversion to neuraxial analgesia. Previous
authors have found that ethnicity, educational level, religion, pain
level, and parity are factors in preference for and use of neuraxial anal-
good or fair quality studies and that overall nitrous oxide has minimal gesia in labor [30–35]. In our study, patient education level and religion
impact on labor pain and maternal satisfaction as currently evaluated were not available and therefore were not assessed, and ethnicity, par-
[3,14,19]. Until further studies provide an improved method of evaluat- ity, and pain did not reliably predict conversion to epidural. In a study
ing nitrous oxide for labor analgesia, anesthesiologists should frame dis- that assessed factors associated with neuraxial analgesia use in
cussions with women desiring nitrous oxide in a way that sets women who initially preferred to labor without an epidural, parity,
appropriate expectations about its effects on both pain and coping in labor management, and availability of an anesthesiologist played a
labor. major role in the decision to ultimately use neuraxial analgesia [2]. Dif-
There were no differences in the Apgar scores for babies of women ferences between study populations and methodology may in part ex-
who used nitrous compared to those receiving epidural analgesia. Previ- plain the variations in reported predictors for conversion to neuraxial
ous studies have found no difference in clinical measures of newborn analgesia.
well-being following nitrous oxide exposure [18], however subtle ef- There are a few potential limitations of this study. Because data were
fects with regards to nitrous oxide exposure of the developing brain sourced from a single obstetric center, these findings may not be gener-
are a potential concern [21–24]. alizable to other non-academic obstetric centers. However, our patient
Although the majority of women using nitrous oxide converted to population has a high level of diversity of race, education, and socioeco-
neuraxial analgesia, the epidural rate was significantly lower than in nomic status [8,37]. As this is a descriptive study, we cannot determine
women who did not use nitrous oxide (63% vs 85%). Another study factors that are associated with nitrous oxide use, and can only com-
showed a lower rate (42%) of conversion to epidural analgesia in nitrous ment on the characteristics of women who use nitrous oxide. In addi-
oxide users, but predictors of who converted were not assessed [25]. It is tion, we did not have patient information to examine reasons why
clinically plausible that nitrous oxide use could lead to a lower epidural patients included nitrous oxide on their birth plan nor why they re-
rate, especially since most women choosing to use nitrous oxide did not quested nitrous oxide for labor analgesia. Furthermore, there are likely
initially desire neuraxial analgesia. However, an impact study compar- to be a number of patient-level and hospital-level factors that are asso-
ing the rate of epidural use before and after implementation of nitrous ciated with conversion to neuraxial labor analgesia that we could not
oxide did not show a change in the rate of labor epidural utilization account for, such as the framing of nitrous oxide during the informed
[26]. This study, along with our findings of a low rate of nitrous oxide consent process by an individual provider.
 C.D. Sutton et al. / Journal of Clinical Anesthesia 40 (2017) 40–45
In summary, we found that nitrous oxide utilization was limited, and
the majority of women who used nitrous oxide convert to neuraxial an-
algesia. We observed minimal reductions in recorded pain scores after
nitrous oxide initiation, and the majority of women who used nitrous
oxide converted to epidural analgesia after a relatively short time.
Women receiving oxytocin for induction or augmentation are most like-
ly to convert to epidural analgesia. Obstetric anesthesia providers
whose institutions offer nitrous oxide should discuss goals with patients
desiring it for labor analgesia and set appropriate expectations regard-
ing its efficacy. They should also discuss the high likelihood of
converting to neuraxial analgesia, particularly in women with induced
and augmented labors. Future studies are needed to evaluate nitrous
oxide's impact on maternal satisfaction and whether the availability of
nitrous oxide influences a woman's decision about where to deliver.
Disclosures
None.
Acknowledgements
This paper has been presented at the 2016 Society of Obstetric Anes-
thesiology and Perinatology Annual Meeting in Boston, Massachussetts
and at the 2016 American Society of Anesthesiology Annual Meeting in
Chicago, Illinois.
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