In the second season of the hit television series “Call the Midwife,” the midwives who attend home births in East London in 1958 are introduced to what they call “gas and air” or 50%/50% nitrous oxide/oxygen (N2O/O2) mix. Soon all the expectant “mums” in East London start using it, and the midwives trade in their bicycles for cars, so gas and air can be transported to homes. It appeared that N2O was the silver bullet laboring women desired. In fact, this 50/50 mixture of N2O/O2 is a common labor analgesic in Europe today. Although it has been used for labor pain management in a small number of labor and delivery units, until recently, N2O/O2 has been largely unknown in the United States. However, as clinicians and consumers alike look for alternatives to systemic opioid or neuraxial labor analgesia, and as public awareness of N2O’s potential use in labor and delivery expands, the time has come to look at use of gas and air in the childbirth setting more closely.
N2O is a colorless, sweet-smelling, nonflammable gas with low potency, low solubility, and minimal metabolism that is used for inhaled analgesia/anesthesia. Overdose is unlikely as long as the concentration is controlled so that delivery of a hypoxic gas mixture is not possible. The low solubility facilitates rapid onset (30 to 50 seconds) and rapid offset of effect. These properties allow the gas to be self-administered with relative safety.
In 2011, the U.S. Agency for Health Care Research and Quality (AHRQ) Effective Health Care Program funded a comparative effectiveness review on use of N2O for managing labor pain. This issue of Anesthesia & Analgesia includes an article derived from the AHRQ systematic review by Likis et al.,1 authors of the original AHRQ report.1 The review included studies of any type and design that addressed the effectiveness of N2O for labor analgesia as well as women’s satisfaction with the birth experience, adverse effects to the mother and child, and safety, including occupational hazards. The systematic review was well conducted with sound methodology. Unfortunately, of the 58 identified relevant publications, only 2 were of good quality. Given the paucity of good data, it is not surprising that the results are frustratingly inconclusive. The strength of the evidence for effectiveness of N2O in managing labor pain was insufficient; there was a high risk of bias for all the analyzed outcomes, and findings were inconsistent across studies. In addition to poor-quality study designs, the studies varied in many aspects, including concentration and frequency of N2O use, use of additional methods of analgesia, and type and timing of assessments. Older studies used comparator analgesic methods that are no longer available. Likis et al.1 concluded that further research assessing N2O use during childbirth is needed for all outcomes of interest, including adverse effects, effectiveness, and maternal satisfaction.
What do we know about the safety and effectiveness of this agent? In addition to the Likis et al.1 study published in this issue, 3 other reviews of N2O have been published using somewhat different methodologies.2–4 The systematic review conducted by Rosen2 found 19 mixed methods studies that were used to evaluate adverse effects and 11 randomized controlled trials that were used to evaluate effectiveness. Similar to the findings of Likis et al.,1 Rosen2 found that N2O provides pain relief that is well tolerated and appears to be safe to the mother and fetus, but the varied comparisons and mix of doses among the studies precluded reaching any quantitative conclusions about the degree of pain relief that N2O provides. Despite not being able to quantitate pain relief, Rosen2 concluded that most women using N2O reported positive results, and most would choose to use it again in a subsequent labor.
The review published by Rooks3 examined the literature on safety of N2O. She found that adverse effects of N2O/O2 were associated with large doses (concentration higher than 50%) and long duration exposures. In addition, when scavenging was appropriate, the occupational exposures were less than the standard set by the National Institute for Occupational Safety.
Finally, Collado et al.4 conducted a literature review for the purpose of assessing the safety of N2O/O2. The authors identified 140 articles on 50%/50% N2O/O2 that addressed adverse events following perioperative use or chronic exposure of health care workers. Few of the studies prospectively determined the criteria used to define adverse events, and there was a great deal of heterogeneity among studies. Nonetheless, a consistent story emerged with regard to vertigo and hallucinations, which occurred in 1% of patients, and nausea and vomiting, which occurred in 0.8% of patients. The authors calculated that serious adverse effects related directly to N2O/O2 occur in 3/10,000 individuals. The Collado et al.4 study did not conduct a separate analysis of obstetric use.
It is somewhat ironic that as interest in the use of N2O/O2 in the childbirth setting increases, N2O use in operating rooms across the country is decreasing (http://www.hraresearch.com/expertise/hospital-data-audits). For the past half century, the routine use of N2O in anesthesia has been under “almost continuous challenge” because of concerns about neurologic and hematologic toxicity, adverse immunologic effects, genotoxicity, risk of myocardial ischemia, expansion of air-filled body cavities, and increased risk for postoperative nausea and vomiting.5,6 In fact, new hospitals are being built without plumbing for central delivery of N2O into operating rooms (personal communication: Tom Krejcie, Tony Gin, August 2013). In 2012 and 2013 (through August 14) alone, 6 editorials that addressed the controversies surrounding the use of N2O as a component of general anesthesia have been published.a
Most labor studies have not identified adverse outcomes in the offspring of mothers who use N2O during labor. However, as summarized by Likis et al.1, study quality is poor. In addition, important outcomes have not been studied. For example, N2O affects methionine synthase function. This enzyme plays an important role in the synthesis of DNA, RNA, myelin, and catecholamines, among other substances.5 Relatively short periods of N2O anesthesia (several hours) completely inhibit methionine synthase activity. Adverse clinical effects have been noted in individuals with cobalamin deficiency. Potential adverse effects may depend on diet (e.g., vitamin B12 and folate), and there is some evidence that common polymorphisms in the gene encoding an important enzyme in the folate cycle (5, 10-methylenetetrahydrofolate reductase [MTHFR]), may play a role.5 What does this mean to the fetus/neonate with a rapidly developing nervous and hematologic system? To our knowledge, no studies have addressed this concern.
The mechanism of N2O’s anesthetic action is thought to relate to noncompetitive inhibition of the N-methyl-D-aspartate subtype of glutamate receptors. Evidence from animal studies shows that exposure of the developing nervous system to N-methyl-D-aspartate antagonists and γ-aminobutyric acid agonists may adversely affect neurologic, cognitive, and social development because of altered neuroapoptosis during periods of rapid synaptogenesis.7,8 This period in humans extends from midgestation to several years after birth.7 Studies in rodents and nonhuman primates have identified significant neuroapoptosis and postnatal functional changes after in utero exposure to clinically relevant mixtures of anesthetic drugs that include N2O. Subanesthetic exposure to individual drugs such as ketamine, propofol, and isoflurane also results in these changes, although subanesthetic exposure to N2O alone triggered little or no neuroapoptosis in rats.
The human relevance of these drug-induced changes is not clear.7,8 Recent data suggest exposure to general anesthesia in early infancy may be associated with learning disabilities.7 However, it is unclear whether the anesthetic per se is the cause of the learning disability, given that anesthesia is always associated with surgery and perhaps systemic illness. Although prospective studies are ongoing,8 many will take years to complete and may still not definitively answer the question of whether the anesthetic is responsible for the adverse outcome. These studies will not determine whether in utero exposure to N2O analgesia during labor has adverse short- or long-term effects on children.
Another final safety concern regarding use of N2O in the childbirth setting is reproductive toxicity secondary to chronic occupational exposure. Waste gas scavenging may be more difficult in a labor ward than in an operating room because it depends on the parturient consciously exhaling through the mask. Although available data do not support toxicity due to occupational exposure to N2O, no prospective, well-controlled epidemiologic studies exist.5 One primary limitation to the use of N2O/O2 in the obstetric setting has been lack of equipment, including proper scavenging equipment. However, this year, the manufacturer Nitronox has resumed manufacturing and has begun selling the Nitronox delivery system to hospitals and birthing centers.
The Likis et al.1 study also shows that we need to reassess measures of effectiveness. It seems self-evident that effectiveness of an analgesic agent is measured by the degree of pain relief. Likis et al.1 noted that N2O/O2 is not as effective as epidural analgesia. This is an expected finding, and frankly, it is a comparison that one could argue does not require further study. Labor is a complex physiologic event in which multiple endogenous and exogenous mediators of pain play a role. We are nowhere near understanding this phenomenon in full. The complexity of the labor is underscored by the results of multiple studies of women’s experiences. The systematic review of labor satisfaction studies by Hodnett9 found that personal expectations, caregiver support, quality of caregiver–patient relationship, and involvement in decision making are stronger influences on the childbirth experience than is the type or degree of pain control achieved.9 Additional studies have validated these findings, including the most recent Listening to Mothers survey.10 The degree of pain relief achieved during labor is not the most salient component of women’s experience of labor and birth.
It is clear from this body of literature that to comprehensively assess the effects of a pain relief technique such as N2O/O2, we need tools that assess women’s experiences in more depth. As Angle et al.’s11 work on labor pain relief after neuraxial analgesia indicates, an evaluation of the quality of labor analgesia must include measures of physical, cognitive, and emotional dimensions. This type of assessment is akin to a quality of recovery score in which the quality of postoperative recovery is assessed using a 40-question survey tool with several domains, including emotional state, physical comfort, psychologic support, physical independence, and pain.12
One option is to assess a woman’s perception of her coping rather than her report of pain reduction on a scale of 0 to 10. Midwives at the University of Utah, Salt Lake City, Utah, have developed a coping scale that has been validated and accepted by The Joint Commission as a replacement for the verbal rating scale for pain in laboring women.13,14 More importantly, it bypasses the problem of measuring only one component of a multifactorial experience. N2O labor analgesia would be an ideal subject for studies that use more comprehensive measures of patient outcomes. Because N2O/O2 labor analgesia includes a degree of parturient control and autonomy, part of its effectiveness is likely to be secondary to the value of personal control.
Where should we go from here? The systematic review by Likis et al.1 as well as other reviews suggest that N2O may be a safe agent to provide analgesia and improve coping and maternal satisfaction during labor. However, to date, there is virtually no good evidence that this is the case. The history of obstetric analgesia has a cycle wherein a new agent is introduced, widely adopted into clinical practice, found to have some adverse effects, and then withdrawn as the search for a new agent begins. Remember Twilight Sleep? This history should not be ignored.
Thus, if we want to use N2O in the childbirth environment, additional rigorous study is necessary. Studies that assess low-hanging fruit should be done first. These might include rigorous case-controlled or randomized controlled trial(s) in various patient populations and practice environments, using a consistent N2O dose and delivery system and using a validated tool(s) for maternal outcomes of the labor experience in additional to traditional pain scores. Suggested neonatal outcomes of interest include effects on lactation. Intermediate outcomes might include using umbilical cord blood for measurement of homocysteine15 and leukocyte DNA damage6 from mother/baby dyads exposed and not exposed to N2O.
It may be almost impossible to perform human studies addressing whether in utero exposure to N2O during labor has adverse effects on the infant central nervous system, although performing these studies in a nonhuman primate model may be helpful. Thus, women who ask to use N2O/O2 during labor should be informed that we lack data about this outcome.
Children are our best natural resource. To the best of our ability, we should carefully evaluate any procedures and drugs that might expose them to harm. N2O for labor analgesia is one such drug.
Dr. Cynthia Wong is the Section Editor for Obstetric Anesthesiology for the Journal. This manuscript was handled by Dr. Steven L. Shafer, Editor-in-Chief, and Dr. Wong was not involved in any way with the editorial process or decision.
Name: Tekoa King, CNM, MPH, FACNM.
Contribution: This author helped write the manuscript.
Attestation: Tekoa King approved the final manuscript.
Conflicts of Interest: Tekoa King is Deputy Editor for the Journal of Midwifery and Women’s Health. Frances E. Likis (first author of the manuscript that the editorial accompanies) is the Editor-in-Chief of the Journal of Midwifery and Women’s Health.
Name: Cynthia A. Wong, MD.
Contribution: This author helped write the manuscript.
Attestation: Cynthia A. Wong approved the final manuscript.
Conflicts of Interest: The author has no conflicts of interest to declare.
a Pubmed search using “nitrous oxide” and limiting the search to “editorials.”
1. Likis FE, Andrews JC, Collins MR, Lewis RM, Seroogy JJ, Starr SA, Walden RR, McPheeters ML. Nitrous oxide for the management of labor pain: a systematic review. Anesth Analg. 2014;118:153–67
2. Rosen MA. Nitrous oxide for relief of labor pain: a systematic review. Am J Obstet Gynecol. 2002;186:S110–26
3. Rooks JP. Safety and risks of nitrous oxide labor analgesia: a review. J Midwifery Womens Health. 2011;56:557–65
4. Collado V, Nicolas E, Faulks D, Hennequin M. A review of the safety of 50% nitrous oxide/oxygen in conscious sedation. Expert Opin Drug Saf. 2007;6:559–71
5. Sanders RD, Weimann J, Maze M. Biologic effects of nitrous oxide: a mechanistic and toxicologic review. Anesthesiology. 2008;109:707–22
6. Hogan K. Nitrous oxide genotoxicity. Anesthesiology. 2013;118:1258–60
7. Creeley CE, Olney JW. The young: neuroapoptosis induced by anesthetics and what to do about it. Anesth Analg. 2010;110:442–8
8. Rappaport B, Mellon RD, Simone A, Woodcock J. Defining safe use of anesthesia in children. N Engl J Med. 2011;364:1387–90
9. Hodnett ED. Pain and women’s satisfaction with the experience of childbirth: a systematic review. Am J Obstet Gynecol. 2002;186:S160–72
10. Declercq ER, Sakala C, Corry MP, Applebaum S, Herrlich A Listening to Mothers III. Pregnancy and Birth. May 2013 New York, NY Childbirth Connection
11. Angle P, Landy CK, Charles C, Yee J, Watson J, Kung R, Kronberg J, Halpern S, Lam D, Lie LM, Streiner D. Phase 1 development of an index to measure the quality of neuraxial labour analgesia: exploring the perspectives of childbearing women. Can J Anaesth. 2010;57:468–78
12. Myles PS, Weitkamp B, Jones K, Melick J, Hensen S. Validity and reliability of a postoperative quality of recovery score: the QoR-40. Br J Anaesth. 2000;84:11–5
13. Gulliver BG, Fisher J, Roberts L. A new way to assess pain in laboring women: replacing the rating scale with a “coping” algorithm. Nurs Womens Health. 2008;12:404–8
14. Roberts L, Gulliver B, Fisher J, Cloyes KG. The coping with labor algorithm: an alternate pain assessment tool for the laboring woman. J Midwifery Womens Health. 2010;55:107–16
15. Nagele P. Notorious oxide. Anesthesiology. 2012;117:3–5