Association Between Intrapartum Nitrous Oxide for Labor Analgesia and Short-Term Neonatal Outcomes

We read with great interest the article by Starosta et al in the May 2024 issue.1 We commend the authors for this large sample-size study examining the association between intrapartum nitrous oxide analgesia use and adverse short-term neonatal outcomes. The authors highlight that nitrous oxide analgesia was associated with a lower likelihood of neonatal intensive care unit admission but with an increased risk for hyperbilirubinemia; other outcomes did not differ. These findings are clinically relevant, and, therefore, we feel it is also necessary to bring attention to some considerations emerging from this original analysis. Firstly, nitrous oxide is known to readily cross the placenta, and, consequently, there is biological plausibility that there could be short-term effects on the newborn. Despite its increasingly common use, it remains unclear whether there are associated short-term adverse neonatal effects. Nitrous oxide is known to alter vitamin B12 metabolism and lead to inhibition of methionine synthesis, an essential amino acid involved in multiple metabolic pathways, including neonatal hyperbilirubinemia.2 Recently, it also has been shown that, in neonatal cases in which the neonatal hyperbilirubinemia etiology was idiopathic, vitamin B12 deficiency had a role at a rate as high as 60%. This study has demonstrated that vitamin B12 deficiency in newborns significantly leads to hyperbilirubinemia.3 Secondly, although during the past 40 years the American Academy of Pediatrics has addressed issues of prevention, risk assessment, monitoring, and treatment of hyperbilirubinemia in the newborn delivered at or after 35 weeks of gestation, the potential clinical effects of hyperbilirubinemia are still an important area of future investigation. Mothers have described having a newborn with hyperbilirubinemia or in phototherapy for treatment of neonatal hyperbilirubinemia as emotionally and physically exhausting, causing feelings of powerlessness in new mothers and impaired mother–newborn bonding.4 Although prior research suggests that fetal and neonatal bilirubin metabolism is influenced by many factors other than nitrous oxide, we strongly agree with Starosta et al's1 recommendation for future research on the pathways by which nitrous oxide may increase neonatal hyperbilirubinemia risk as a strategy to correctly inform clinical counseling for pregnant women who are considering use of intrapartum nitrous oxide analgesia.