BACKGROUND: In the United Kingdom, pregnant women are offered two scans: at 11-14 and 18-20 weeks' gestation. Current guidance supports fetal anatomical screening at the second scan, but evidence suggests earlier detection is possible. OBJECTIVES: To determine clinical and cost-effectiveness of a detailed two-dimensional ultrasound scan in the first trimester for detection of fetal anomalies, in addition to usual practice. DESIGN: Systematic review and meta-analysis. Nationwide survey. Analysis of National Congenital Anomaly Disease Registry data. Consensus procedure. Prospective survey of parental opinions. Probabilistic decision-analytic model for cost-effectiveness. Value-of-information analysis. SETTING: United Kingdom National Health Service. PARTICIPANTS: Pregnant women and partners. INTERVENTIONS: Detailed anomaly ultrasound at 11-14 weeks' gestation, in addition to usual practice. MAIN OUTCOME MEASURES: Diagnostic accuracy, protocol development, health economic modelling and value-of-information analysis. DATA SOURCES: MEDLINE (OvidSP), EMBASE (OvidSP), Science Citation Index and Conference Proceedings Citation Index-Science (Web of Science Core Collection); National Congenital Anomaly Disease Registry; European Congenital Anomalies Registry; Surveys of National Health Service Trusts; screening sonographers, midwives and doctors; and parents; National Schedule of National Health Service Costs (2019-20). REVIEW METHODS: Systematic review and meta-analysis for diagnostic accuracy. RESULTS: First-trimester ultrasound detects 93.3% (95% confidence interval 90.4% to 95.7%) of a pre-selected group of eight major anomalies with specificity of 99.99% (95% confidence interval 99.98% to 99.99%) and positive predictive value of 96.5% (95% confidence interval 93.3 to 98.8, 416,877 fetuses, 40 studies). For major cardiac anomalies, the respective data are 55.8% (95% confidence interval 45.9% to 65.5%), 99.98% (95% confidence interval 99.97% to 99.99%) and 94.85% (95% confidence interval 91.63% to 97.32%, 306,872 fetuses, 45 studies). Of NHS trusts surveyed, 77% currently perform first-trimester anatomy assessment, with evidence of inequity of care; earlier screening resulted in more diagnoses before 16 weeks' gestation. A consensus procedure (n = 172) developed an anatomical protocol and minimum targets for diagnosis. Parental survey (n = 1374) indicated that over 90% would opt for such screening. Modelling of singleton pregnancies undergoing earlier anomaly screening using two-dimensional ultrasound was associated with increased mean healthcare costs per woman (£11, 95% confidence interval £1 to £29) and maternal quality-adjusted life-years (0.002065, 95% confidence interval 0.000565 to 0.00358), an incremental cost per quality-adjusted life-year of £5270, with likelihood of being cost-effective at £20,000 per quality-adjusted life-year of over 95%. Additional modelling predicted reductions in infant healthcare costs and quality-adjusted life-years. Decision uncertainty was low. Value-of-information analysis of cost-effectiveness results showed no groups of parameters for which further research to reduce uncertainty would likely prove cost-effective. LIMITATIONS: Study heterogeneity; the lack of a universal reference standard; simplifying assumptions relating to economic model structure; and estimation of some parameters are documented and justified. The rarity of the conditions made estimation of longer-term maternal and infant costs and quality-adjusted life-years challenging, resulting in likely under-estimation of healthcare costs. CONCLUSIONS: With standardisation and training, first-trimester ultrasound screening for fetal anomalies is clinically effective with over 90% detection for eight major conditions and low false-positive rates. Decision uncertainty around implementation is low and a prospective study would not be an efficient investment. Adding first-trimester anomaly screening to the current screening likely represents a cost-effective use of resources and is acceptable to parents. FUTURE WORK: Focus on developing an implementation framework to modify the current United Kingdom Fetal Anomaly Screening Programme. STUDY REGISTRATION: This study is registered as PROSPERO CRD42018111781 and CRD42018112434. FUNDING: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/19/10) and is published in full in Health Technology Assessment; Vol. 29, No. 22. See the NIHR Funding and Awards website for further award information.