Blue Babies with a Red Flag: Methemoglobinemia as a Sentinel Sign of Cow's Milk Protein Intolerance in Infants - A retrospective Case Series

Abstract

Background: Cow's milk protein intolerance (CMPI), often referred to as cow's milk protein allergy (CMPA), is among the most prevalent food hypersensitivities in children, typically manifesting with gastrointestinal symptoms, including diarrhea and vomiting. Methemoglobinemia is an exceedingly rare complication of CMPI, a life-threatening illness marked by the pathological oxidation of hemoglobin, resulting in impaired tissue oxygen transport and clinically observable cyanosis. Since the precise pathophysiologic mechanism linking intestinal inflammation to methemoglobin accumulation remains unclear, this uncommon association poses diagnostic and therapeutic challenges. This study was done to describe the clinical presentation, diagnostic evaluation, and outcomes of infants with methemoglobinemia due to CMPI, to facilitate early identification and prompt dietary intervention. Materials and Methods: A retrospective case series of 6 infants with methemoglobinemia associated with CMPI is presented here. All patients were either term or late preterm infants with a history of formula or combination feeding. Clinical and laboratory data, encompassing symptomatology, acid-base status, and sequential methemoglobin levels, were systematically evaluated. Results: All six newborns exhibited diarrhea, metabolic acidosis, and elevated methemoglobin levels, with a median methemoglobin concentration of 26% (range 11–30.7%). The therapeutic intervention involved transitioning to extensively hydrolyzed or amino acid-based elemental formulations, together with pharmaceutical treatment of methylene blue and/or ascorbic acid (vitamin C). All patients had full clinical and biochemical remission within 2-3 days of initiating medication. Conclusion: CMPI must be included in the differential diagnosis of unexplained infantile methemoglobinemia. Timely recognition and removal of cow's milk protein from the diet, along with appropriate pharmacological treatment, can lead to rapid and lasting recovery.