This article pertains to non-COVID-19 patient care. There is currently insufficient information about the cleaning, filtering, and potential for aerosolization associated with use of nitrous oxide for labor analgesia in the setting of the ongoing COVID-19 pandemic. As such the Society for Obstetric Anesthesia and Perinatology reported that, “individual labor and delivery units should discuss the relative risks and benefits and consider suspending use.” https://soap.org/education/provider-education/expert-summaries/interim-considerations-for-obstetric-anesthesia-care-related-to-covid19/.

Nitrous oxide was discovered in 1772, first used as an analgesic in the 1800s, and has been incorporated into anesthetic practice for over 150 years. It is a colorless, non-pungent, poorly soluble gas with minimal metabolism and rapid onset and offset. Nitrous oxide’s anesthetic action is mediated by noncompetitive inhibition of the NMDA receptor, and its analgesic action is thought to be mediated through supraspinal activation of opioidergic and noradrenergic neurons.¹ While not sufficient to serve as a sole agent for general anesthesia, it possesses analgesic and anxiolytic properties at sub-anesthetic doses, and is useful as a component of general anesthesia and for procedural and dental sedation.² Nitrous oxide is used for management of labor pain in many parts of the world, although significant geographic variation exists. In the United Kingdom, for example, nitrous oxide is used by 50–75% of women, and use is also common in Finland, Australia, and New Zealand.³ In contrast, until recently, nitrous oxide labor analgesia was extremely rare in the United States; as of 2014, nitrous oxide was known to be in use for management of labor pain at only five United States centers.⁴ Since that time and concomitant with the introduction of FDA-approved devices for self-administration of a blended mixture of 50% N₂O and 50% O₂, interest in the use of nitrous oxide for labor analgesia in the United States has rapidly increased, and at least 500 centers in the United States are thought to currently offer nitrous oxide for labor pain management.⁵ While anesthesia professionals in the United States are familiar with the use of nitrous oxide in the operating room, the rapid introduction of nitrous oxide in obstetrics has raised questions about the utility and safety of nitrous oxide in this setting.^6,7 These concerns are primarily centered around the effectiveness of nitrous oxide for labor analgesia, as well as ensuring maternal, fetal, and occupational safety.

Epidural analgesia is the most effective form of pain relief in labor. Compared to the wealth of data on the effectiveness of neuraxial analgesia or parenteral opioids, there is relatively little regarding the degree of pain relief provided by nitrous oxide. Much of the available data suggests a modest analgesic effect at best. One study found no decrease in pain scores with nitrous oxide compared to placebo in early labor,⁸ and use of nitrous oxide did not lead to a significant decrease in pain scores in a recent study in the United States.⁹ Several studies on the effectiveness of nitrous oxide for labor pain relief have included comparators that are not used in contemporary obstetric analgesia, such as methoxyflurane¹⁰ or sevoflurane,¹¹ making interpretation of the degree of pain relief relative to modern analgesic strategies challenging. A recently conducted systematic review concluded that evidence regarding the effectiveness of nitrous oxide for labor analgesia is insufficient or of low strength.⁴ Establishing the degree of labor pain relief provided by nitrous oxide is an area ripe for future research.

Many women are satisfied with nitrous oxide, even if they report that it does not provide good pain relief.¹² Nitrous oxide has known nonanalgesic effects, such as anxiolysis, which may be valued by some women, and qualitative analysis of women’s experience with nitrous oxide during labor suggests that these nonanalgesic and partial analgesic effects contribute to maternal satisfaction.⁵ These findings highlight that pain relief is not the only driver of satisfaction with anesthetic care during labor and delivery and point to the complexities of the labor and birth experience.¹³ Nitrous oxide may be of particular benefit to women who place more value on the ability to freely ambulate during labor, the sense of control resulting from use of a self-administered, noninvasive agent, or nonanalgesic effects than on maximal pain relief. Nitrous oxide may also be valuable for women who prefer to avoid neuraxial analgesia and parenteral opioids as part of a birth plan, or who have contraindications to neuraxial analgesia.

A key consideration in the use of nitrous oxide for labor analgesia focuses on ensuring maternal safety. Nitrous oxide can expand air-filled spaces, and conditions such as a recent pneuomothorax or inner ear or retinal surgery represent contraindications to nitrous oxide use (Table 1). While these conditions are rare on labor and delivery, they must be considered. Patients should be counseled regarding known side effects of nitrous oxide, which include nausea, dizziness, sedation, and a sense of claustrophobia from the mask.¹⁴ Nitrous oxide irreversibly inhibits the vitamin B-12 dependent enzyme methionine synthase, which has key roles in the folate and S-adenosyl methionine (SAM) cycles. Concerns exist regarding the potential hematologic, neurologic, and cardiovascular risks associated with nitrous oxide use in general anesthesia,¹ although the bulk of the available evidence supports the overall safety of nitrous oxide in most settings and populations.² Nitrous oxide exposure has rarely been associated with subacute combined degeneration of the spinal cord in vitamin B12 or folate deficient patients,¹⁵ and known vitamin B-12 or folate deficiency is a contraindication to nitrous oxide use. Unfortunately, levels are not routinely checked during pregnancy, despite the fact that up to 29% of women in the third trimester may have vitamin B-12 insufficiency.¹⁶ Testing for B-12 and folate levels or avoiding nitrous oxide should be considered for patients at elevated risk for vitamin B-12 or folate deficiency, such as those following a vegan diet or with extensive bowel resections.

Table 1: Contraindications to Nitrous Oxide Use for Labor Analgesia

Absolute	Relative
Pneumothorax Recent retinal surgery Middle ear or sinus infection Pulmonary Hypertension Vitamin B-12 or folate deficiency	Risk for B-12 or folate deficiency (i.e., vegan diet, history of bowel resection) Recent opioid administration Acute intoxication Requirement for supplemental O2

Nitrous oxide at high concentrations has the potential to cause diffusion hypoxia, although this would not be expected to occur with the commonly used mixture of 50% O₂/50% N₂O.⁴ Nitrous oxide is also contraindicated for patients who require supplemental O₂ therapy, either for maternal oxygen desaturation or for intrauterine fetal resuscitation. Finally, nitrous oxide is a recreational drug of abuse with serious consequences from long-term use,¹⁷ and the possibility of an increased future risk for recreational abuse in women first exposed to nitrous oxide for labor analgesia has not been studied. In summary, while labor nitrous oxide is generally considered safe for the mother and is not known to have significant effects on labor progress,^3,18 mothers must be screened for known contraindications to nitrous oxide use to minimize maternal risk.

Fetal concerns surrounding maternal nitrous oxide utilization include the possibility of immediate neonatal effects as well as the potential for long-term hematopoietic or neurodevelopmental sequalae. While nitrous oxide freely crosses the placenta, the rapid offset of nitrous oxide predicts a limited immediate neonatal effect, and studies examining short-term outcomes such as umbilical cord gases and Apgar scores have not found any evidence of short-term adverse neonatal outcomes associated with maternal nitrous oxide use.^3,4 Thus, while intrapartum nitrous oxide does not appear to have immediate adverse neonatal consequences, the long-term effects are unknown. In adults, nitrous oxide exposure for greater than 6 hours as part of a general anesthetic inhibits hematopoiesis,¹⁹ but no similar studies have been done in the immediate neonatal period. Neurologic toxicity in the form of subacute combined spinal cord degeneration has been reported only in the setting of prolonged recreational abuse, in the setting of rare congenital disorders, or in patients that are vitamin B-12 or folate deficient.^1,2 In addition, nitrous oxide acts at the NMDA receptor, and NMDA receptor antagonists have been associated with neuroapoptosis in the developing brain in animal models in a time- and agent-dependent fashion.²⁰ Nitrous oxide as a sole agent has not been linked to neuroapoptosis,¹ and the relevance of these animal models to pediatric anesthesia or anesthetic agents administered in pregnancy has not been established and is widely debated. No studies on neurologic toxicity or sequalae have been conducted in neonates of mothers utilizing nitrous oxide in labor, although the lack of case reports of neurotoxicity despite the long history of nitrous oxide use in labor worldwide may be somewhat reassuring. The influence of nitrous oxide on either short- or long-term neonatal outcomes in premature infants, who may be particularly vulnerable to any potential adverse effects of nitrous oxide, has not been examined. The rapid offset of nitrous oxide mitigates potential concerns about its transfer into breast milk, although the influence, if any, of intrapartum nitrous oxide use on the initiation of breastfeeding is unknown. In summary, nitrous oxide use in labor does not appear to have immediate neonatal adverse effects, but the potential for long-term impact on the neonate has not been well studied.

In addition to concerns regarding maternal and neonatal safety, the use of nitrous oxide during labor and delivery raises occupational safety concerns. These concerns have been driven primarily by retrospective survey data suggesting the possibility of an increased risk of spontaneous abortion and/or low birth weight among women with occupational exposure to nitrous oxide.¹ While there is no clear evidence for toxicity associated with occupational exposure, long-term prospective epidemiological data are lacking. The National Institute of Occupational Safety and Health recommends a maximal time-weighted average level of exposure to nitrous oxide of no more than 25 ppm over an 8-hour period. Compared to well-ventilated operating rooms where nitrous oxide is most commonly delivered through a closed circuit, nitrous oxide utilization in a labor suite presents unique challenges. Without scavenging of exhaled gases, occupational exposure to nitrous oxide during labor and delivery can exceed recommendations.²¹ Scavenging requires not only appropriate equipment, but also that the patient exhale into a tight-fitting mask. Even some centers utilizing appropriate scavenging are not able to achieve compliance with recommended occupational exposure limits.²² It is clear that a monitoring plan is a key component of safe nitrous oxide implementation on labor and delivery.

In summary, the use of nitrous oxide for labor analgesia is rapidly expanding in the United States. The history of nitrous oxide use in this setting in other countries, as well as limited experience in the United States, suggests that it is likely safe for the mother, neonate, and for those who work on labor and delivery. Rigorous evidence demonstrating this, however, is lacking and should be a research priority. The availability of nitrous oxide is not a substitute for neuraxial analgesia, and 40%–60% of women who initially choose nitrous oxide later convert to neuraxial analgesia.^9,12 Furthermore, the introduction of nitrous oxide did not change the neuraxial labor analgesia utilization rate in one center.²³ The impact of nitrous oxide labor analgesia on the general anesthesia rate for intrapartum cesarean delivery has not been investigated. Women choosing nitrous oxide in labor should be screened for possible contraindications and counseled appropriately regarding the expected modest analgesic effects, side effects, and particularly the uncertainty regarding the long-term effects of fetal exposure. Additional research into these important questions should be a priority. Finally, appropriate patient education, scavenging, and monitoring is essential to prevent potential toxicity from occupational exposure.

 

Dr. Arnolds is an assistant professor in the Department of Anesthesia and Critical Care at The University of Chicago, Chicago, IL.

Dr. Scavone is a professor in the Departments of Anesthesia and Critical Care and Obstetrics and Gynecology at The University of Chicago, Chicago, IL.

---

The authors have no conflicts of interest.

---

References

1. Sanders RD, Weimann J, Maze M. Biologic effects of nitrous oxide: a mechanistic and toxicologic review. Anesthesiology. 2008;109:707–722.
2. Buhre W, Disma N, Hendrickx J, et al. European Society of Anaesthesiology Task Force on Nitrous Oxide: a narrative review of its role in clinical practice. Br J Anaesth. 2019;122:587–604.
3. Rosen MA. Nitrous oxide for relief of labor pain: a systematic review. Am J Obstet Gynecol. 2002;186:S110–S126.
4. Likis FE, Andrews JC, Collins MR, et al. Nitrous oxide for the management of labor pain: a systematic review. Anesth Analg. 2014;118:153–167.
5. Richardson MG, Raymond BL, Baysinger CL, et al. A qualitative analysis of parturients’ experiences using nitrous oxide for labor analgesia: it is not just about pain relief. Birth. 2019;46:97–104.
6. King TL, Wong CA. Nitrous oxide for labor pain: is it a laughing matter? Anesth Analg. 2014;118:12–14.
7. Vallejo MC, Zakowski MI. Pro-con debate: nitrous oxide for labor analgesia. Biomed Res Int. 2019;2019:4618798–12.
8. Carstoniu J, Levytam S, Norman P, et al. Nitrous oxide in early labor. Safety and analgesic efficacy assessed by a double-blind, placebo-controlled study. Anesthesiology. 1994;80:30–35.
9. Sutton CD, Butwick AJ, Riley ET, et al. Nitrous oxide for labor analgesia: utilization and predictors of conversion to neuraxial analgesia. J Clin Anesth. 2017;40:40–45.
10. Jones PL, Rosen M, Mushin WW, et al. Methoxyflurane and nitrous oxide as obstetric analgesics. II. A comparison by self-administered intermittent inhalation. Br Med J. 1969;3:259–262.
11. Yeo ST, Holdcroft A, Yentis SM, et al. Analgesia with sevoflurane during labour: II. Sevoflurane compared with Entonox for labour analgesia. Br J Anaesth. 2006;98:110–115.
12. Richardson MG, Lopez BM, Baysinger CL, et al. Nitrous oxide during labor: maternal satisfaction does not depend exclusively on analgesic effectiveness. Anesth Analg. 2017;124:548–553.
13. Hodnett ED. Pain and women’s satisfaction with the experience of childbirth: a systematic review. Am J Obstet Gynecol. 2002;186:S160–S172.
14. Richardson MG, Lopez BM, Baysinger CL. Should nitrous oxide be used for laboring patients? Anesthesiol Clin. 2017;35:125–143.
15. Patel KK, Munne JC, Gunness VRN, et al. Subacute combined degeneration of the spinal cord following nitrous oxide anesthesia: a systematic review of cases. Clin Neurol Neurosurg. 2018;173:163–168.
16. Sukumar N, Rafnsson SB, Kandala N-B, et al. Prevalence of vitamin B-12 insufficiency during pregnancy and its effect on offspring birth weight: a systematic review and meta-analysis. Am J Clin Nutr. 2016;103:1232–1251.
17. Garakani A, Jaffe RJ, Savla D, et al. Neurologic, psychiatric, and other medical manifestations of nitrous oxide abuse: a systematic review of the case literature. Am J Addict. 2016;25:358–369.
18. Rooks JP. Safety and risks of nitrous oxide labor analgesia: a review. J Midwifery Womens Health. 2011;56:557–565.
19. O’Sullivan H, Jennings F, Ward K, et al. Human bone marrow biochemical function and megaloblastic hematopoiesis after nitrous oxide anesthesia. Anesthesiology. 1981;55:645–649.
20. Vutskits L, Xie Z. Lasting impact of general anaesthesia on the brain: mechanisms and relevance. Nat Rev Neurosci. 2016;17:705–717.
21. Henderson KA, Matthews IP, Adisesh A, et al. Occupational exposure of midwives to nitrous oxide on delivery suites. Occup Envion Med. 2003;60:958–961.
22. Morley B, Paulsen AW, et al. Nitrous oxide for labor analgesia: is it safe for everyone? APSF Newsletter. 2017;32:19–20. https://www.apsf.org/article/nitrous-oxide-for-labor-analgesia-is-it-safe-for-everyone/ Accessed May 5, 2020.
23. Bobb LE, Farber MK, McGovern C, et al. Does nitrous oxide labor analgesia influence the pattern of neuraxial analgesia usage? An impact study at an academic medical center. J Clin Anesth. 2016;35:54–57.