Early Metabolic Profile in Neonates with Maternal Intrahepatic Cholestasis of Pregnancy

<b>Background/Objectives</b>: Intrahepatic cholestasis of pregnancy (ICP) is associated with adverse perinatal outcomes. However, its metabolic consequences on newborns remain inadequately characterized. This study investigated amino acid, carnitine, and acylcarnitine profiles in neonates born to mothers with ICP. <b>Methods</b>: This retrospective study encompassed 299 neonates born to mothers with ICP. For comparative analysis, term infants without additional complications (ICP-term, <i>n</i> = 150) were compared with term controls (<i>n</i> = 150). Capillary blood samples collected at 24-48 h of life as part of newborn screening were analyzed using LC-MS/MS for acylcarnitine and amino acid profiles. <b>Results</b>: The ICP cohort exhibited a high preterm delivery rate (46.2%), with maternal bile acids negatively correlating with gestational age (r = -0.266, <i>p</i> < 0.001). No inborn errors of metabolism were observed. Elevated levels of amino acids (alanine, leucine/isoleucine, valine, tyrosine, arginine, glycine, and ornithine) and specific acylcarnitines (C5, C5-OH, C10:1, and C18:2), along with decreased levels of amino acids (argininosuccinic acid and glutamic acid) and specific acylcarnitines (C3, C5-DC, C6-DC, C14, C14:1, C16, C16:1, and C18:1-OH), were observed in ICP-term neonates (<i>p</i> < 0.05). Receiver operating characteristic curve analysis identified ornithine (area under the curve [AUC] = 0.74) and leucine/isoleucine (AUC = 0.73) as strong discriminators. A multivariable model integrating multiple metabolites achieved high accuracy (AUC = 0.86 ± 0.03). <b>Conclusions</b>: This first comprehensive characterization of neonatal metabolic alterations in ICP reveals amino acid metabolism, fatty acid oxidation, and mitochondrial function disruptions, suggesting fetal adaptation to a cholestatic intrauterine environment. Metabolomic profiling may improve understanding of maternal-fetal interactions and inform strategies for risk stratification and long-term monitoring.