Placental expression and activity of system A and system L amino acid transporters in pregnancies complicated by diabetes mellitus and fetal growth disorders: a systematic review.

UNLABELLED: Fetal growth disorders, encompassing both fetal growth restriction (FGR) and fetal macrosomia, are associated with increased neonatal morbidity and mortality rates as well as predispose to metabolic and cardiovascular diseases later in life. Regardless of these negative consequences, the molecular mechanisms underlying different fetal growth patterns remain incompletely understood. Recognizing that fetal growth in utero relies on the transplacental transfer of nutrients such as amino acids, we conducted the first systematic review to evaluate the expression and functional activity of System A (SNAT) and System L (LAT) transporter proteins in placentas from pregnancies complicated by diabetes mellitus (DM) and the most common types of fetal growth abnormalities. In alignment with PRISMA guidelines, seventeen studies were selected for data extraction and inclusion within this systematic review. The conducted analysis revealed a distinct functional dichotomy, wherein pregnancies with FGR or small-for-gestational age (SGA) fetuses are characterized by a significant downregulation of System A and L activity and reduced expression of placental isoforms (SNAT1, SNAT2, LAT1). Conversely, pregnancies complicated by DM or fetal overgrowth exhibit upregulated transport capacity, often driven by greater placental mass and increased expression of SNAT1 and LAT1 isoforms, which correlate directly with the neonatal birth weight and adiposity. Alongside the observed differences between the two major cohorts, we documented time-dependent variations within a single pathology; notably, the downregulation of SNAT4 transporter being specific to early-onset FGR, and distinguishing it from the late-onset variant. Our findings demonstrate that during the course of pregnancy, placental amino acid transport capacity adapts to the maternal metabolic environment. As a consequence, the observed alterations in the expression and activity of amino acid transporters at the maternal-fetal interface may determine fetal growth trajectory and body composition, thereby emphasizing the significance of transplacental nutrient flux as a critical target for investigating the developmental origins of metabolic health in the offspring.

SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD420251208578.