Common Numbing Drug Tied to Rare Blood Disorder in Infant Circumcision Cases

A widely used local anesthetic given to babies during circumcision can, in rare circumstances, trigger a dangerous blood condition that turns the skin a startling shade of blue, and a new review of nearly four decades of published cases is shining a spotlight on how clinicians recognize and treat it. The condition, methemoglobinemia, occurs when hemoglobin—the oxygen-carrying molecule in red blood cells—is chemically altered into a form that can no longer release oxygen to tissues. The result is cyanosis, a bluish discoloration of the skin and lips, that stubbornly refuses to improve even when the child is given supplemental oxygen. For panicked parents and frontline clinicians alike, it is one of the most dramatic adverse drug reactions in pediatric medicine.

The new analysis, published in BMC Pediatrics by Yılmaz Seçilmiş, Gülşah Kartal and Muhammet Sami Kayan of Erciyes University in Kayseri, Türkiye, takes the form of a scoping review. Following the Joanna Briggs Institute methodology and reporting to the PRISMA-ScR standard, the team searched PubMed, Scopus and Web of Science on 14 March 2026 without date or language restrictions, supplementing the search with hand-searching that included regional Turkish journals. Their PROSPERO-registered protocol (CRD420261340727) focused on a very specific triad: individual cases of methemoglobinemia following prilocaine administered for circumcision in infants aged zero to twelve months. Two reviewers screened studies independently, achieving an inter-rater agreement of kappa equal to 0.849, a level conventionally regarded as very strong.

The search identified twenty-four studies published between 1989 and 2026 that together documented thirty-eight cases. Strikingly, thirty-three of those cases—86.8 percent—came from Türkiye, a concentration the authors caution reflects the geography of the published literature rather than any measured difference in incidence. No reliable incidence rate can be extracted from case reports, which are subject to publication bias: dramatic recoveries get written up, routine events do not. Still, the consistency of the clinical picture across reports is what makes the review valuable. In every single case that reported presentation details, the defining feature was the same: cyanosis that did not respond to oxygen therapy, the classic fingerprint of methemoglobinemia.

The biochemistry explains why oxygen fails. Under normal conditions, hemoglobin carries iron in its ferrous (Fe2+) state, binding oxygen in the lungs and releasing it in tissues. Oxidizing agents can convert some of that iron to the ferric (Fe3+) state, producing methemoglobin, which binds oxygen tightly but cannot unload it. Worse, methemoglobin shifts the oxygen-dissociation curve of the remaining normal hemoglobin to the left, compounding the tissue hypoxia. Infants are especially vulnerable because their red cells contain fetal hemoglobin, which oxidizes more readily, and because the NADH-dependent reductase pathway that normally reduces methemoglobin back to hemoglobin is not fully mature in the first months of life. Glucose-6-phosphate dehydrogenase (G6PD) deficiency, which is more common in some populations, adds a further layer of susceptibility.

Prilocaine enters this picture because it is an amide local anesthetic whose metabolites, notably o-toluidine, are known oxidizing agents capable of overwhelming red-cell defenses. In the reviewed cases, prilocaine was given by injection—typically as a dorsal penile nerve block or subcutaneously—in 89.5 percent of reports, while 10.5 percent involved topical application of EMLA, the eutectic mixture of lidocaine and prilocaine that is widely marketed for procedural pain relief in infants. Both routes have been implicated, though dosing detail was surprisingly scarce: the prilocaine dose was reported in only 44.7 percent of cases, a gap the authors highlight as a failure of case-report completeness with direct consequences for understanding dose-response relationships.

The severity of the episodes was considerable. Among thirty-seven cases with laboratory data, the mean methemoglobin fraction was 33.6 percent, with individual values ranging from 11.9 to 62.0 percent. Normal levels sit below about one to two percent, and clinical signs such as cyanosis generally appear above ten to fifteen percent, with levels above roughly thirty percent considered clinically significant and above fifty percent potentially life-threatening. That the reported episodes reached such heights underscores how quickly a routine analgesic injection in a healthy infant can escalate into a pediatric emergency requiring immediate recognition and intervention.

Treatment in the published cases followed two main paths. Methylene blue, the established first-line antidote for clinically significant acquired methemoglobinemia, was administered in twenty cases. The drug works as an exogenous electron carrier, accepting electrons from NADPH via the hexose monophosphate shunt and reducing methemoglobin back to functional hemoglobin—essentially providing the infant red cell with an enzymatic shortcut it cannot yet perform efficiently on its own. Ascorbic acid, a slower-acting reducing agent described mainly in isolated reports and sometimes used as adjunctive therapy, was given in twenty-one cases, either alone or in combination with methylene blue. Every published case ended in full recovery, but the authors are careful to note that uncontrolled case reports cannot disentangle the effects of treatment from spontaneous recovery, supportive care, or the natural course of the condition, and no claim of comparative efficacy between antidotes can be made from such data.

To widen the lens beyond the formal case literature, the team also queried three major pharmacovigilance databases: the World Health Organization’s VigiBase, the US Food and Drug Administration’s FAERS, and the European EudraVigilance system. These spontaneous-report databases contained reports extending beyond the circumcision-specific literature, including some with fatal outcomes. The authors treat these as contextual reference only, stressing that spontaneous reports cannot confirm causality, cannot verify the procedural context, and must not be used as a quantitative comparator. The distinction matters: pharmacovigilance signals can justify scrutiny, but they are not evidence of risk magnitude, and conflating them with verified clinical case series distorts the risk picture for both clinicians and parents.

The completeness assessment is one of the review’s most practically useful contributions. Methemoglobin level and treatment were each documented in 97.4 percent of cases, reflecting awareness that both are central to the diagnosis and management narrative. But the prilocaine dose was reported in fewer than half the cases, and other details—timing of onset, use of screening for G6PD deficiency, cumulative exposure, and follow-up—varied widely. The authors argue that better-structured case reporting would allow future syntheses to move beyond description toward genuine risk characterization. Their quality appraisal used the Murad et al. tool for case reports, and the full charted dataset, search strategy and PRISMA-ScR checklist are available as supplementary files with the open-access article.

For clinical practice, the authors’ conclusions are measured rather than alarmist. The published reports describe a recurring, recognizable presentation—cyanosis poorly responsive to oxygen in a recently anesthetized infant—but cannot establish how often it occurs or which treatment is superior. Methylene blue remains the established first-line antidote for clinically significant acquired methemoglobinemia. Depending on the clinical context, indication and dose, minimizing prilocaine exposure and observing infants for post-procedure cyanosis may be considered, with clinical decisions individualized. The uniformly positive outcomes recorded in the literature, the team warns, may well reflect publication and survivorship bias rather than an inherently benign course. In other words, the absence of documented deaths in the case series should not be read as reassurance; it may simply mean that the worst outcomes go unreported. The review received no specific funding, and the authors declare no competing interests. Its message for clinicians is simple and urgent: when a circumcised infant turns blue and oxygen does not help, think methemoglobinemia, check a methemoglobin level, and act fast.

Subject of Research: Prilocaine-associated methemoglobinemia in neonates and infants undergoing circumcision

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

Article References: Seçilmiş, Y., Kartal, G., & Kayan, M. S. (2026). Prilocaine-associated methemoglobinemia after neonatal and infant circumcision: a scoping review of published cases with pharmacovigilance context. BMC Pediatrics. https://doi.org/10.1186/s12887-026-07741-2

Image Credits: AI Generated

DOI: 10.1186/s12887-026-07741-2

Keywords: prilocaine, methemoglobinemia, circumcision, neonates, infants, methylene blue, ascorbic acid, EMLA cream, pharmacovigilance, scoping review, cyanosis, pediatric emergency