Likis, Frances E. DrPH, NP, CNM*; Andrews, Jeffrey C. MD*‡; Collins, Michelle R. PhD, CNM, RN-CEFM§; Lewis, Rashonda M. JD, MHA*‡; Seroogy, Jeffrey J. BS*; Starr, Sarah A. MD‖; Walden, Rachel R. MLIS¶; McPheeters, Melissa L. PhD, MPH*‡
Nitrous oxide is an inhaled anesthetic and analgesic gas commonly used in general anesthesia and dental care. Use of nitrous oxide during labor began in the late 1800s, and equipment for self-administration was introduced by Minnitt in England in 1934.1 Nitrous oxide in a 50/50 mix with air, administered with a blender device (e.g., Nitronox) or premixed (e.g., Entonox), is the most common concentration of nitrous oxide used for labor pain management. Nitrous oxide is usually self-administered via a facemask or mouthpiece intermittently, beginning approximately 30 seconds before each contraction.2
Use of inhaled nitrous oxide for labor pain management is common in several countries. A 2002 systematic review cites evidence that nitrous oxide is used by 50% to 75% of women in the United Kingdom and 60% of women in Finland; use in Australia and New Zealand is also common.1 Only 5 centers in the United States were known to provide nitrous oxide as an option for labor pain management at the time this review was conducted (J. P. Rooks, MPH, CNM, personal communication).
With widespread use of nitrous oxide during labor in some other countries and increasing interest in this method in the United States, we systematically reviewed the effectiveness of nitrous oxide for the management of labor pain, the influence of nitrous oxide on women’s satisfaction with their birth experience and labor pain management, and adverse effects associated with nitrous oxide for labor pain management. Comparators included no analgesic/anesthetic intervention; other inhaled, epidural, or systemic opioid analgesia; paracervical or pudendal nerve block; transcutaneous electrical nerve stimulation; sterile water injections; hydrotherapy; and psychoprophylaxis.
Our searches, executed between July 2010 and July 2011 and not limited by date, included the MEDLINE (via PubMed), Embase, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases. Searches used both controlled vocabulary and keyword terms representing nitrous oxide and known brand names (such as “nitrous oxide,” “laughing gas,” and “Entonox”) and concepts of obstetric labor, pain, or analgesia (such as “labor pain,” “labor, obstetric,” “analgesia,” “obstetrical,” “labor,” and “birth”). We excluded ineligible publication types (e.g., letters, editorials), animal or in vitro research, and non-English articles. Detailed search strategies, including complete search terms, search structure, limits, and numbers of results, are available.3 We also hand searched the reference lists of included studies to identify additional potentially relevant items, and searched grey literature for relevant information, including sources of U.S. regulatory and occupational safety information, theses/dissertations, and meeting abstracts. A complete list of sources is available.3
Studies had to include pregnant women in labor intending a vaginal birth (any parity or risk status) and using nitrous oxide for labor pain management, birth attendees or health care providers who may be exposed to nitrous oxide during labor, and fetuses/neonates. We included studies of any type/design that reported outcomes on at least 20 women.
Study Selection and Data Extraction
Two reviewers separately evaluated abstracts for inclusion. If 1 reviewer concluded that an article could be eligible for the review based on the abstract, we retained it. Full publications were then dually reviewed for final inclusion, with discrepancies resolved by third party adjudication. Two reviewers independently extracted outcomes data, including pain management, satisfaction with pain management, satisfaction with birth experience, and adverse effects associated with the use of nitrous oxide for the management of labor pain, and entered this information into evidence tables.3 The team evaluating the literature included 3 physicians (2 obstetrician-gynecologists and an anesthesiologist), 2 certified nurse-midwives, 2 health services researchers, and 2 library scientists.
Rating Quality of Individual Studies
We used the Cochrane Risk of Bias tool4 to assess the quality of randomized controlled trials (RCTs). Fundamental domains include sequence generation, allocation concealment, blinding, completeness of outcome data, and selective reporting bias. The Newcastle-Ottawa Quality Assessment Scale5 was used to assess the quality of nonrandomized studies. This scale’s 3 broad perspectives include the selection of study groups, the comparability of study groups, and the ascertainment of either the exposure or outcome of interest for case-control or cohort studies, respectively. Four investigators independently assessed the quality of individual studies; the Senior Scientist (JCA) reviewed and resolved any discrepancies. A description of both tools and the thresholds for converting their results to the Agency for Healthcare Research and Quality’s standard of “good,” “fair,” and “poor” quality designations is available.3
Evidence Synthesis and Grading Strength of Evidence
Once data extraction and quality assessment were complete, we developed an extended analysis of the research evidence, including text and summary tables.3 We graded available evidence for each of the following domains: risk of bias, consistency of findings, directness, and precision. We combined the grades of each domain to develop the strength of evidence for each key outcome and assigned one of the following grades: high, moderate, low, or insufficient. Two reviewers independently graded the body of evidence; disagreements were resolved through discussion or a third reviewer adjudication.
We identified 1428 nonduplicate titles or abstracts, with 574 proceeding to full text review (Fig. 1). Fifty-eight publications were included in the review; one publication reported on 2 distinct study populations. Thus, there are 59 distinct study populations: 13 RCTs, 7 crossover RCTs, 4 nonrandomized clinical trials, 14 prospective cohorts, 1 retrospective cohort, 3 case series, 4 case-control studies, 11 cross-sectional studies, and 2 trend studies. Tables 1, 2, and 3 provide an overview of included studies; the summary in this section focuses on the studies for which quality was assessed as good or fair. Seven studies of occupational exposure to nitrous oxide6–12 and 4 studies of outcomes in offspring following maternal nitrous oxide use13–16 are not included in the tables but are described in the section on adverse effects.
Effectiveness of Nitrous Oxide for Labor Pain Management
Twenty-one publications representing 22 studies of distinct populations addressed the effectiveness of nitrous oxide for labor pain management (see Tables 1–3). These studies included 6 RCTs,17–22 6 crossover RCTs,18,23–27 4 cross-sectional studies,28–31 2 nonrandomized clinical trials,32,33 2 prospective cohort studies,34,35 1 case series,36 and 1 trend study.37 One study included an RCT and a crossover RCT with 2 distinct populations.18 Four studies were of fair quality,28,29,36,37 and 17 were of poor quality.17–27,30–35
One study compared nitrous oxide with methoxyflurane, which is no longer used for labor pain management in the United States.36 Three cross-sectional studies retrospectively assessed the effectiveness of labor pain management methods.28,29,37 In 1 study, 2482 women completed a questionnaire 2 months after labor and birth that included assessment of their pain management methods as very effective, some effect, or no effect.37 The proportion of very effective responses for primiparas and multiparas respectively was 84% and 72% for epidural analgesia, 38% and 49% for nitrous oxide, 39% and 47% for psychoprophylaxis, 41% for both groups for meperidine, 29% and 35% for bath or shower, and 10% and 23% for acupuncture. In a study with 278 women who were interviewed 1 day after giving birth, the proportion who rated their pain as worst imaginable (7 on a 7-point scale) was 86% for nitrous oxide, 46% for bath, 39% for epidural analgesia, 27% for local infiltration, 26% for breathing technique, and 24% for acupuncture.28 The third study used graphical data from which nitrous oxide results could not be clearly determined.29
Effect of Nitrous Oxide on Women’s Satisfaction with Their Birth Experience and Labor Pain Management
Nine studies addressed the effect of nitrous oxide on women’s satisfaction (Tables 1–3). These studies included 3 RCTs,17,19,20 3 prospective cohorts,34,35,38 and 3 cross-sectional studies.31,39,40 One study was of good quality,38 1 of fair quality,40 and 7 of poor quality.17,19,20,31,34,35,39
One fair quality study assessed women’s satisfaction with their birth experience.40 This cross-sectional study surveyed 1111 women about their birth experience at 2 months postpartum.40 Of 362 women who had nitrous oxide, 57% reported a positive or very positive birth experience compared with 49% of women who had meperidine (n = 94) and 34% of women who had epidural analgesia (n = 129). One good quality study assessed women’s satisfaction with their labor pain management.38 In this prospective cohort study, only 6% of women who had epidural analgesia were not satisfied with their pain relief compared with 46% of women who had Entonox and meperidine.38
Adverse Effects of Nitrous Oxide for Labor Pain Management
Forty-nine publications addressed maternal, fetal, neonatal, and occupational adverse effects related to nitrous oxide for labor. These studies include 12 RCTs,17,19–22,41–47 6 crossover RCTs,23–27,48 4 case-control studies,13–16 4 nonrandomized clinical trials,32,33,36,49 13 prospective co-horts,10,12,34,38,50–58 1 retrospective cohort,59 3 case series,60–62 5 cross-sectional studies,6,7,9,11,63 and 1 trend study.8 Two were of good quality,16,38 7 of fair quality,6,10–12,36,44,63 and 40 of poor quality.7–9,13–15,17,19–27,32–34,41–43,45–62
Maternal Adverse Effects
In 32 studies reporting maternal adverse effects related to nitrous oxide, the most clinically significant and frequently reported harms were nausea, vomiting, dizziness, and drowsiness (Table 4). Historically, nitrous oxide for labor was coadministered with other analgesic, anesthetic, anxiolytic, and sedative drugs in various combinations titrated to induce sedation and amnesia. These co-agents have a significant impact on the rate and degree of adverse effects associated with nitrous oxide for labor analgesia. To maintain consistency with contemporary practice, 13 studies published before 1980 in which nitrous oxide was given in combination with unspecified doses of opioids and sedatives are not included in Table 4.21,22,27,32,33,36,46,47,49,50,58,62,64
One fair quality study of nitrous oxide as a sole drug reported nausea and vomiting in 13% (95% confidence interval [CI], 9–19) of women.63 In 2 fair quality studies with nitrous oxide as a sole drug,44,63 the incidence of dizziness was 3% to 5% (95% CI, 0.1–15). In another fair quality study, the incidence of drowsiness incidence was 4%, reduced awareness of experience was 18%, and mask phobia was 5% with nitrous oxide used as a sole drug.63 No good or fair quality but several poor quality studies reported data on unconsciousness,21,32,41,48–50,57,60 amnesia or hazy memory of labor or birth,17,19–22,33,41,49,50 hypoxia and/or maternal oxygen saturation,23,24,43,52,54,55,61 diffusion hypoxia,24,43,50 restlessness,21,22,32,41,49,50 dreams,21,22,41,49,50 dry mouth or nose,27,42,45,50 tingling or pins and needles,42,45 numbness,27 paresthesias,50 bothersome smell,22,27 euphoria,27 hiccups,27 inactivation of methionine synthase,53 and effects on maternal circulation.48
Fetal and Neonatal Adverse Effects
Twenty-nine studies reported fetal and neonatal adverse effects. The most clinically significant and frequently reported outcomes were umbilical cord blood gases and Apgar scores. In a good quality study comparing nitrous oxide and meperidine with epidural analgesia, there were no statistically significant differences in Apgar scores or special care nursery admission rates between the 2 groups, and no newborn had an Apgar score lower than 7 at 5 minutes (95% CI, 0%–4%).38 One fair quality study that reported umbilical cord blood gases and Apgar score data had unspecified coadministration of opioids, pudendal nerve block, or spinal or lumbar epidural in all groups.36 No good or fair quality studies reported fetal resuscitation,57,60 asphyxia,58 depressed neonates,20 sleepy neonates,58 prolonged time to sustained respiration,62 treatment for apnea,60or neurobehavioral status.17,19,56,58
Long-term offspring outcomes were addressed in 4 retrospective case-control studies;13–16 no prospective studies were identified. One of these 4 studies was of good quality; the multivariate odds ratio for childhood leukemias after in utero exposure to nitrous oxide was 1.3 (95% CI, 1.0–1.6). These results may be coincidental because the increased odd ratios was not observed in all subgroups (e.g., the odds ratio was increased for boys but not girls).16
Occupational exposure in labor and birth settings was addressed in 7 studies.6–12 Three studies of poor quality examined occupational exposure-related adverse effects in midwives.7–9 The measurement of nitrous oxide exposure is addressed in 4 fair quality studies, which report nitrous oxide levels but not specific adverse effects.6,10–12 A study in the United Kingdom collected data on midwives wearing exposure badges for 242 shifts (each 7.5–11 hours) in labor wards without scavenging and with standard room ventilation only.12 Midwives had exposure greater than 100 ppm (the Swedish occupational exposure limit) during 23% of shifts and >25 ppm (the U.S. limit) during 53% of shifts. An evaluation of scavenging systems in Swedish labor wards found a 4-fold reduction in nitrous oxide levels with use of efficient scavenging systems. Nitrous oxide concentrations in diffusive air samplers varied from 2.5 to 260 mg/m3, and mean 8-hour time weighted averages were 17 mg/m3 for midwives and 42 mg/m3 for assistant midwives, respectively.10 The 8-hour time weighted averages exceeded the American Conference of Industrial Hygienists’ average threshold limit value (50 ppm or 90 mg/m3) in 16% of midwives and 45% of assistant midwives. The authors attribute these differences to the fact that assistant midwives have a longer average exposure time and are also working more closely with women earlier in labor when nitrous oxide is used more frequently.10
Another study in the United Kingdom correlated nitrous oxide exposure to urine nitrous oxide levels in a descriptive study of unscavenged and poorly ventilated delivery suites.6 Environmental levels exceeded 100 ppm over 8-hour time weighted averages in 35 of 46 midwife shifts monitored. Notably, 22 of 46 midwives had nonzero baseline values of nitrous oxide in their urine, which the authors propose may indicate tissue clearance occurs over a longer time period than previously thought.
Newton et al.11 evaluated 8-hour time weighted average nitrous oxide exposure (in ppm) for 15 midwives at a newly built hospital in the United Kingdom with a ventilation system incorporating 6 to 10 air changes per hour, comparing the results with historical data from an older building in which there was no ventilation (Entonox machines were unscavenged in both hospitals). Nitrous oxide levels in the new hospital were significantly lower, and none of the 15 midwives in the new hospital was exposed to levels of nitrous oxide greater than 100 ppm. Six of the 15 midwives were exposed to levels of nitrous oxide >25 ppm (the U.S. limit).
Fifty-nine distinct studies reported in 58 publications met our review criteria: 2 of good quality; 11 fair; and 46 poor. One-third of the studies are RCTs, 7% are clinical trials without clear evidence of randomization, and the majority is observational research. Overall, the strength of the evidence was insufficient for effectiveness in managing labor pain, low for satisfaction, and moderate for harms (Table 5). Deficiencies in the strength of evidence most often related to a preponderance of study designs with a high risk of bias, inconsistent findings across studies and inconsistencies among outcomes that would be expected to show corresponding benefit, use of intermediate outcomes, and studies with poor precision.
Twenty-one studies that addressed the effectiveness of nitrous oxide using some measurement of pain or pain relief varied in many aspects including the concentration of nitrous oxide and frequency (continuous versus intermittent) administered, additional pain management methods used, and methods and persons (i.e., women, obstetricians, midwives, and anesthesia providers) assessing pain and pain relief. The substantial variation in timing of assessment may have affected the reported outcomes because women’s opinions about pain relief change with time lapsed after birth.21,22,32 Most of the effectiveness studies (12 of 21) had as comparators other inhaled anesthetic gases that are no longer used to manage labor pain. Only 1 study compared nitrous oxide with placebo and found no significant difference in pain scores.24 Epidural analgesia provided more effective pain relief than nitrous oxide. These studies are unable to demonstrate whether nitrous provided adequate pain relief for women who knowingly accept less effective pain relief in exchange for increased mobility and less intervention and monitoring. In addition, it may be counterproductive to evaluate pain scores, which require focusing on the level of pain, in women using nitrous oxide, which is intended to produce dissociation from pain. Generally speaking, therefore, pain relief is likely to be an inadequate measure of effectiveness for nitrous oxide in the absence of other outcomes such as women’s satisfaction.
In 9 studies that addressed women’s satisfaction with their birth experience or pain management, measurements of satisfaction were not uniform, making it impossible to synthesize findings. Satisfaction may be a more relevant measure of effectiveness than assessment of pain because nitrous oxide is not intended to provide complete pain relief.
Of 49 studies reporting adverse effects, one-third (n = 16) were conducted before 1980 when nitrous oxide was often used in combination with sedatives and other inhaled anesthetics in labor, a largely abandoned practice. Studies reporting harms associated with sedative analgesic regimens may not translate effectively to contemporary labor analgesia practice. For example, in older studies, amnesia in labor was considered to be a positive outcome.
Most maternal adverse effects reported in the literature were unpleasant side effects that affect tolerability (e.g., nausea, vomiting, dizziness, and drowsiness). Some maternal adverse effects of analgesia (e.g., nausea) are common in all laboring women regardless of whether analgesia is used. Study sizes were inadequate to assess unusual or rare harms that might be more serious in terms of morbidity.
Nitrous oxide is transmitted via the placenta and is rapidly eliminated by the neonate after birth once breathing begins. 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 analgesia. Follow-up of newborns was short, most frequently lasting only to birth or discharge of the neonate from the hospital.
Limited data on occupational adverse effects are available, thus drawing conclusions regarding potential occupational harms of exposure is difficult. Evidence about occupational levels of nitrous oxide is limited, and some studies were conducted before the use of room ventilation systems or scavenging systems. The implementation of these systems in clinical practice appears to reduce occupational exposure, which should in turn mitigate potential risks of exposure.
Nitrous oxide provides analgesia, decreases women’s perception of pain, and has an anxiolytic effect that may be helpful if women are restless or doubt their ability to cope as commonly occurs near the end of the first stage of labor.2 Although nitrous oxide is not as effective for pain relief as epidural analgesia, nitrous oxide has other benefits including that it is inexpensive and noninvasive. Nitrous oxide has a rapid onset and offset. Women who do not like nitrous oxide or find it inadequate for pain management can easily discontinue its use and switch to another method for pain management, unlike the prolonged effects of epidural analgesia and systemic opioids that diminish gradually over a much longer time period. Nitrous oxide preserves mobility and does not require additional monitoring and potential anesthesia-related interventions (e.g., bladder catheterization). Women self-administer nitrous oxide, which allows them to control the amount they need.2 Nitrous oxide may not be an ideal method for women who want maximum pain relief but may be preferable to other pharmacologic pain management methods for women who want increased mobility with less intervention and monitoring. Nitrous oxide can also be useful when a woman wants to delay use of epidural analgesia until later in labor, when epidural analgesia is not immediately available (e.g., in hospitals that do not have 24-hour anesthesia service), when a woman arrives at the hospital too late in labor to allow for epidural analgesia to be placed and take effect, or when epidural analgesia is ineffective or inadequate.
In summary, the literature addressing nitrous oxide for the management of labor pain includes few studies of good or fair quality. Suggested priorities for future research are identified in Table 6. Research assessing nitrous oxide is needed across all of the areas examined: effectiveness, satisfaction, and adverse effects.
Name: Frances E. Likis, DrPH, NP, CNM.
Contribution: This author led design and conduct of the review, assessed literature and extracted outcomes, wrote and reviewed the manuscript, and provided clinical and methodological expertise.
Attestation: Frances E. Likis approved the final manuscript and is the archival author.
Name: Jeffrey C. Andrews, MD.
Contribution: This author contributed to design and conduct of the review, assessed literature and extracted outcomes, wrote and reviewed the manuscript, and provided clinical and methodological expertise.
Attestation: Jeffrey C. Andrews approved the final manuscript.
Name: Michelle R. Collins, PhD, CNM, RN-CEFM.
Contribution: This author contributed to design and conduct of the review, assessed literature and extracted outcomes, wrote and reviewed the manuscript, and provided clinical expertise.
Attestation: Michelle R. Collins approved the final manuscript.
Name: Rashonda M. Lewis, JD, MHA.
Contribution: This author contributed to design and conduct of the review, assessed literature and extracted outcomes, and wrote and reviewed the manuscript.
Attestation: Rashonda M. Lewis approved the final manuscript.
Name: Jeffrey J. Seroogy, BS.
Contribution: This author contributed to design and conduct of the review, assessed literature and extracted outcomes, and wrote and reviewed the manuscript.
Attestation: Jeffrey J. Seroogy approved the final manuscript.
Name: Sarah A. Starr, MD.
Contribution: This author contributed to design and conduct of the review, assessed literature and extracted outcomes, wrote and reviewed the manuscript, and provided clinical expertise.
Attestation: Sarah A. Starr approved the final manuscript.
Name: Rachel R. Walden, MLIS.
Contribution: This author contributed to design and conduct of the review, assessed literature and extracted outcomes, wrote and reviewed the manuscript, and provided methodological expertise.
Attestation: Rachel R. Walden approved the final manuscript.
Name: Melissa L. McPheeters, PhD, MPH.
Contribution: This author contributed to design and conduct of the review, wrote and reviewed the manuscript, and provided methodological expertise.
Attestation: Melissa L. McPheeters approved the final manuscript.
This manuscript was handled by: Cynthia A. Wong, MD.
The authors thank Ms. Tracy Shields for assisting with study selection and data extraction, Ms. Nila Sathe for reviewing the manuscript, Dr. Shanthi Krishnaswami for providing statistical assistance, Ms. Kerry Jordan for managing data coordination, Ms. Kathy Lee for providing administrative support, and Ms. Sanura Latham for providing editorial assistance.
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