Background: The single umbilical artery (SUA), an entity with almost unknown etiology, is still subject to discussion regarding its clinical significance, especially when it is an isolated discovery (iSUA). Methods: This retrospective study focused on the evaluation of fetuses with ultrasound proven SUA during second trimester screening. These fetuses were carefully investigated for other malformations. The respective pregnancies were attentively followed up and the newborns were evaluated confirming SUA. Results: The incidence of SUA was 0.57%, with 34.6% of these fetuses having associated abnormalities being 19.2% cardiovascular, 15.3% gastrointestinal, 11.5% cerebral, 7.6% osteomuscular and 3.8% urogenital. Aneuploidy was present in 8% of these infants. These rates were significantly greater compared with those noticed in “normal” three vessels umbilical cord (TVC) fetuses (control group) (p 0.001). Similar relations were found for the rates of IUGR and/or SGA, polyhydramnios and oligohydramnios (p 0.001). Interestingly, in iSUA group (65.4% of all SUA cases), only the rate of oligohydramnios was significantly increased compared with the control group (p = 0.038). Furthermore, in a dichorionic diamniotic twin pregnancy, with only one fetus revealing iSUA, the “affected” fetus paradoxically weighted more than the “healthy” one. Conclusion: We concluded that SUA is an important finding during morphological ultrasound examination. When associated with other anomalies, a fetal karyotype is mandatory due to the increased risk of aneuploidy. Furthermore, the pregnancy should be meticulously monitored in order to promptly diagnose other developmental anomalies associated with abnormalities of the amniotic fluid volume and to detect any anatomical anomalies missed at the initial prenatal evaluation. Finally, we concluded that diabetes mellitus represents a strong favoring condition for SUA with first pregnancy also being a contributor.