The umbilical cord normally contains 2 arteries and a single vein. When an umbilical artery is absent, the condition is called single umbilical artery (SUA). The reported prevalence of SUA varies from 0.5% at the second-trimester prenatal ultrasound and in umbilical cord specimens from live-born infants to 2.1% in fetal deaths, autopsies, or aborted fetuses. Approximately 33% of fetuses with SUA have additional structural anomalies, and 10% are affected with aneuploidy. In ~65% of cases, SUA seems to be an isolated finding. In pregnancies with an apparently isolated SUA (iSUA), aneuploidy or fetal size (small for gestational age [SGA]) may become apparent later in pregnancy or at birth. This systematic review was undertaken to assess outcome of iSUA diagnosed at the midtrimester ultrasound scan and to determine whether data are sufficient to determine appropriate management of pregnancies with diagnosed iSUA. MEDLINE, EMBASE, and the Cochrane Library databases were searched for articles reporting on SUA. Randomized controlled trials, cohort studies, and case-control studies were eligible if they described 30 or more cases of apparent iSUA identified by ultrasound before a mean gestational age of 24 weeks. All studies that allowed construction of a 2 × 2 table were included, with the incidence of the outcome of interest in SUA fetuses and 3-vessel cord fetuses. Quantitative data on the outcome variables included incidence of SGA and perinatal mortality, median or mean birth weight, and frequency of aneuploidy. Odds ratios (ORs) with 95% confidence intervals (CIs) were determined for the occurrence of SGA, perinatal mortality, and frequency of aneuploidy in iSUA fetuses compared with those in 3-vessel cord fetuses. Of 449 articles, the final analysis included 3 cohort and 4 case-control studies, reporting on 68 and 297 cases of apparent iSUA, with a total of 982 patients with an iSUA. The mean gestational age at diagnosis of SUA was 19.0 to 24.3 weeks. A non-statistically significant association was found between iSUA and SGA at birth (OR for SGA in fetuses with iSUA, 1.6; 95% CI, 0.97-2.6; P = 0.06), with ORs in the cohort studies ranging from 1.1 to 3.3. In 3 of the case-control studies, iSUA fetuses did not have significantly lower mean birth weights compared with control fetuses (mean weight, 3154 vs 3176 g; mean difference, 51 g; 95% CI, -154.7 to 52.6 g; P = 0.33). The OR for preterm birth in fetuses with an iSUA compared with control fetuses was 2.1 (95% CI, 1.4-3.2) for delivery before 37 weeks and 3.3 (95% CI, 1.4-7.7) for delivery before 34 weeks. Although there was a positive association between iSUA and increased perinatal mortality, it did not meet statistical significance (OR, 2.0; 95% CI, 0.9-4.2; P = 0.07). Among 695 iSUA cases reported in 16 studies, 4 cases of aneuploidy (0.58%) occurred; the mean maternal age was 30.1 years. These results indicate that iSUA is associated with a nonsignificant trend for increased risk for SGA and perinatal mortality. The relatively low birth weight in iSUA neonates may occur as a result of a relatively high prevalence of preterm birth. On the basis of this review, no firm conclusions can be drawn about the association between iSUA and aneuploidy. More large-scale, prospective cohort studies are necessary to clarify these associations and identify appropriate management protocols for iSUA fetuses.