ABSTRACT Cell-free DNA (cfDNA) screens are now widely used for trisomy 21, 18, and 13 (and less often for sex-chromosome aberrations). In 2017, the Netherlands became the first country to implement genome-wide cfDNA as a first-tier screening test for chromosomal abnormalities. The use of this test for first-trimester screening subsequently increased from 32% to 45%, with 2% of women still choosing to have the combined test. Although the official purpose of these tests is for aneuploidy screening, studies demonstrate that at least one-fourth of structural abnormalities in fetuses can be detected during nuchal translucency (NT) measurement. Whether the routine addition of first-trimester anatomy screening (FTAS) would be effective in detecting severe fetal structural anomalies with low rates of false-positive results was felt to be important to address, to determine whether this should be an integral component of prenatal screening program. This study aimed to determine the gestational age at which fetal anomalies were detected and which anomalies detected by second-trimester anatomical screening could have theoretically been diagnosed via FTAS had this been performed on all women in the cohort. The data for this retrospective observational study were collected from pregnant women referred to the University Medical Center of Groningen Fetal Medicine Unit from 2017 through 2020. Women in the cohort were referred based on suspicion of fetal structural abnormalities following a dating ultrasound, or first- or second-trimester anatomy survey. First-trimester anatomy surveys were performed only in women with high-risk indications, including monochorionic twin pregnancy (or greater multiple pregnancy), first-degree relative of the fetus with structural abnormalities, more than 1 more distant relative with similar abnormalities, preexisting diabetes mellitus or first-trimester diagnosis of diabetes mellitus, high-titer thyroid-stimulating hormone receptor antibodies, or high radiation exposure of >0.50 Gy. In the study, all information was collected regarding additional examinations, invasive testing, and pregnancy outcomes, including postpartum follow-up to confirm the diagnosis. Cases with an abnormal cfDNA result or increased risk for aneuploidy based on serum screening were not included, nor were “soft markers” for aneuploidy or variations of normal anatomy such as persistent left superior vena cava. In all, 547 pregnancies had second-trimester anomalies and were included in the analysis. A total of 13 pregnancies underwent FTAS, whereas the other 534 (97.6%) underwent only the dating ultrasound scan and second-trimester anatomy scanning. Average maternal age was 29 years, with a median body mass index of 25.1 kg/m2, and the mean gestational age at the time of the anatomical survey of 21.4 weeks. Of the 13 pregnancies that underwent FTAS, anomalies were confirmed in 12 fetuses, whereas 1 had edema that resolved. Overall, 492 fetuses (92.1%) had structural anomalies that were confirmed, and analysis was done to determine whether these would have been diagnosable in the first trimester. In all, 66 (13.4%) were classified as “always detectable” in the first trimester, 303 (61.6%) as “sometimes detectable,” and 123 (25.0%) as “never detectable.” The mean gestational age at diagnosis was 22.8 weeks. Limitations of the study include its hypothetical classification of abnormalities as “always,” “sometimes,” and “never,” based on the literature. However, the authors concluded that the introduction of an early anatomical survey together with noninvasive screening for aneuploidies is appropriate based on these results.