Prilocaine-associated methemoglobinemia after neonatal and infant circumcision: a scoping review of published cases with pharmacovigilance context

Abstract Background Prilocaine, given by injection or as topical lidocaine-prilocaine (EMLA) cream, is widely used for analgesia during neonatal and infant circumcision, and methemoglobinemia is a recognized adverse drug reaction in this susceptible population. We aimed to map the published cases for this drug–procedure–population triad, characterize clinical patterns, treatment, and outcomes, assess the completeness of case reporting, and add global pharmacovigilance context. Methods Following Joanna Briggs Institute scoping-review methodology and PRISMA-ScR reporting (PROSPERO CRD420261340727), PubMed, Scopus, and Web of Science were searched on 14 March 2026 without date or language limits, with hand-searching and regional Turkish journals. Individual cases of methemoglobinemia after prilocaine for circumcision at ages 0–12 months were eligible; two reviewers screened independently (kappa = 0.849). WHO VigiBase, FDA FAERS, and EudraVigilance were queried as contextual reference only. Results Twenty-four studies (1989–2026) provided 38 cases; 33 (86.8%) from Türkiye—a feature of the published literature, not a measured incidence. Oxygen-refractory cyanosis was reported in all cases with presentation data; the mean methemoglobin level was 33.6% ( n = 37, range 11.9–62.0%). Prilocaine was injected in 89.5% and applied topically in 10.5%. Methylene blue was given in 20 cases and ascorbic acid in 21, alone or combined; all published cases recovered fully, although spontaneous recovery, supportive care, treatment timing, and natural course cannot be separated in uncontrolled reports. Methemoglobin level and treatment were each reported in 97.4% of cases, prilocaine dose in 44.7%. Three pharmacovigilance databases held reports beyond the circumcision-specific literature, including fatal-outcome reports whose causality and procedural context cannot be confirmed. Conclusions Published reports describe a recurring presentation of cyanosis poorly responsive to oxygen, but cannot establish incidence or comparative treatment efficacy; the uniformly full recovery may reflect publication and survivorship bias. Methylene blue remains the established first-line antidote for clinically significant acquired methemoglobinemia, whereas ascorbic acid has been described in isolated reports, sometimes as adjunctive therapy; comparative efficacy cannot be inferred. Depending on clinical context, indication, and dose, minimizing prilocaine exposure and observing for post-procedure cyanosis may be considered. Pharmacovigilance reports add broader context but do not confirm causality or procedural relevance and are not a quantitative comparator. Clinical decisions should be individualized. Systematic review registration PROSPERO CRD420261340727.