Objective: Twin-twin transfusion syndrome (TTTS) causes perinatal mortality and morbidity in monochorionic (MC) twins. Early recognition and interventional therapy for TTTS is associated with a more favorable overall prognosis. However, the prediction by ultrasound in the first trimester has relatively poor sensitivity and specificity. This study aims to profile maternal metabolic changes before the clinical onset of TTTS and identify potential metabolic biomarkers to aid ultrasound screening. Method: Maternal plasma was prospectively collected between 11-15 weeks of gestation in apparently uncomplicated MCDA pregnancies. This cohort was divided into: i) patients subsequently diagnosed using ultrasound with TTTS and ii) uncomplicated matched controls. Gas chromatography-mass spectrometry was used for metabolomic profiling. Results: The levels of fatty acids, organic acids, oxaloacetic acid, and beta-alanine were significantly lower in the maternal plasma of TTTS at 11-15 weeks of gestation, while methionine and glycine were higher (p<0.05, FDR<0.12). Generally, in TTTS pregnancies, metabolism of amino acid, carbohydrate, cofactors, vitamins, and purine were ‘down-regulated’; whilst bile secretion and pyrimidine metabolism were ‘upregulated’. Conclusions: Metabolomics scanning of early gestation maternal plasma may identify those pregnancies that subsequently develop TTTS, especially, downregulated fatty acid level may be biologically plausible to be implicated in the pathogenesis of TTTS. Keywords: Twin-twin transfusion syndrome, GC-MS, metabolite, biomarker Acknowledgments We thank team members for their support and contribution to this study. Especially, thanks for all participants who volunteered to provide blood samples.