<i>Objective:</i> The pathogenesis and clinical significance of true umbilical cord knots remain controversial. Here, we tested the hypothesis of the presence of congenital oral mucosal changes in newborns with true umbilical cord knots. <i>Study design:</i> Seven consecutive infants with true umbilical cord knots and 50 gestational age- and sex-matched controls were enrolled. The proportion of oral frenulum abnormalities and the two-dimensional vascular network geometry [fractal dimension,<i> D,</i> at two scales: <i>D(1–46),</i> and <i>D(1–15),</i> with the relative Lempel-Ziv complexity, (L-Z)], were analyzed. <i>Results:</i> Infants with true umbilical cord knots showed significantly higher proportions of mandibular frenulum agenesis compared to controls (p = 0.000006). The oral vascular networks of these infants exhibited a significantly higher <i>D(1–46)</i> and <i>D(1–15)</i> (p < 0.0001, respectively), and higher L-Z values (p < 0.0001) than control networks. <i>Conclusion:</i> These findings indicate the presence of significant congenital oral mucosal changes in newborn infants with true umbilical cord knots, thus suggesting a previously unrecognized association between true umbilical cord knots and a subclinical extracellular matrix disorder.