Objective: Persistence of a fetal thickened Nuchal translucency (NT), one of the most sensitive and specific individual markers of fetal disorders, is strongly correlated with the possibility of a genetic syndrome, congenital infections or other malformations. Thickened NT can also be found in normal pregnancies. Several of its pathophysiological aspects still remain unexplained. Metabolomics could offer a fresh opportunity to explore maternal-foetal metabolism in an effort to explain its physiological and pathological mechanisms. Design: A population-based prospective cohort study (2020-2021). Setting: Cagliari, Italy. Population and Methods: Thirty-nine samples of amniotic fluids were collected from women who underwent amniocentesis due to an increased risk of aneuploidy, divisible into 12 foetuses with an enlarged nuchal translucency (>NT) and 27 controls (C). Samples were analyzed using a Gas Chromatography Mass Spectrometry platform. Subsequently, multivariate and univariate statistical analyses and Receiver Operator Curves (ROC) were performed to find a specific metabolic pattern of >NT class. Results: The supervised model analysis showed robust statistical parameters (R2X=0.2, R2Y=0.76, Q2=0.4, p<0.002). The correlation between the complete metabolic profile and clinical parameters were evaluated (NT showed an R2=0.75, p=0.002, foetal crown-rump length showed R2=0.65, p=0.002, pregnancy Associated Plasma Protein-A showed R2=0.60). Nine metabolites significantly differing between >NT foetuses and C were detected: 2-hydroxybutyric acid, 3-hydroxybutyric, 1,5 Anydro-Sorbitol, cholesterol, erythronic acid, fructose, malic acid, threitol and threonine which were linked to altered pathways involved in altered energetic pathways. Conclusion: Through the metabolomics approach it was possible to identified a specific metabolic fingerprint of the fetuses with >NT.