Acute and chronic Food Protein-Induced Enterocolitis Syndrome (FPIES) has been well characterized in children; otherwise, neonatal FPIES (N-FPIES) remains poorly understood. In terms of pathophysiology, neonatal FPIES appears to have a more prevalent TH2 response and is characterized by specific clinical features that make the diagnosis challenging. Genetic and environmental risk factors may predispose to the development of FPIES. Recent evidence indicates that a characteristic microbiota signature may lead to barrier dysfunction, reduced regulatory T cells, and abnormal intestinal production of serotonin, responsible for the symptoms of FPIES. Regarding clinical presentation, newborns with FPIES may not fully meet the current guideline’s diagnostic criteria at disease onset, being more similar to clinical entity specific of neonatal age than to acute FPIES in infants and children. Hence, differentiation from other neonatal medical and surgical conditions—particularly necrotizing enterocolitis (NEC)—remains a critical challenge for clinicians. This present review highlights our current understanding of N-FPIES, in term of pathophysiology, clinical presentation diagnosis, and treatment strategies. Refining diagnostic criteria for N-FPIES represents a clinical priority to help physicians in diagnosing and managing this challenging condition. Last, but not least, larger clinical trials are needed to optimize treatment practices in term and preterm newborns with FPIES.

Acute and chronic FPIES have been well characterized in children. Few data still exist on neonatal FPIES (N-FPIES) which may involve a distinct pathophysiology and is characterized by specific clinical features which make challenging the diagnosis. Although risk factors remain poorly understood, scientific evidence suggests that gut microbiota alterations may play an important role in the development of FPIES. In regard to N-FPIES clinical presentation, there is evidence of two distinct phenotypes, according to the presence or absence of bloody stools. Although N-FPIES shares symptom similarities with infant acute FPIES, it may not fully meet the diagnostic criteria at onset. The present review highlights our current understanding of N-FPIES, focusing on risk factors, including microbiota alterations, clinical characteristics and differential diagnosis with other neonatal medical and surgical conditions. In addition, current treatment strategies for both term and preterm infants are also described and commented. Refining diagnostic criteria for N-FPIES represents a clinical priority to help physicians in approaching this challenging condition. Last, but not least, larger clinical trials are needed to optimize treatment practices in term and preterm newborns with FPIES.