Fetal Hepatosplenomegaly: Stepwise Diagnostic Framework, Diagnostic Approach to Fetal Hepatosplenomegaly

Background/Objectives: Fetal hepatosplenomegaly is an uncommon but clinically significant prenatal finding associated with a wide range of heterogeneous conditions, including congenital infections, fetal anemia, genetic syndromes, metabolic disorders, and other, less common abnormalities. Because of its nonspecific presentation and diverse etiologies, it represents a diagnostic challenge that requires a structured, multidisciplinary approach. This review aims to present a practical, clinically oriented, stepwise approach to the prenatal evaluation of fetal hepatosplenomegaly, integrating current evidence to facilitate differential diagnosis and guide prenatal management. Methods: A comprehensive literature review was performed, focusing on ultrasound diagnosis, differential diagnosis, genetic evaluation, and prenatal management strategies in fetuses with hepatosplenomegaly. Results: The prenatal detection of hepatosplenomegaly should prompt a detailed ultrasound assessment, including the confirmation of organ enlargement, evaluation of associated structural abnormalities, Doppler studies, and screening for signs of fetal anemia, infection, hydrops fetalis, or cardiac dysfunction. The diagnostic workup should begin with targeted maternal and fetal investigations directed toward the most common causes. In unresolved cases, genetic testing-including chromosomal microarray analysis and next-generation sequencing-may help establish the diagnosis. The preservation of biological material obtained during invasive procedures should be considered to allow future molecular analyses if new clinical findings emerge. The management depends on the underlying etiology and may include fetal therapy, maternal treatment, or specific interventions in selected genetic and metabolic conditions. Conclusions: Fetal hepatosplenomegaly requires a systematic diagnostic strategy that integrates ultrasound, laboratory, and genetic assessment. A structured approach may improve diagnostic accuracy, optimize prenatal counseling, and facilitate the timely management of potentially treatable conditions.