Authors' objectives: 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. 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. In the UK, all pregnant women are currently offered second-trimester ultrasound screening at 18–20+6 weeks of gestation for the detection of congenital fetal anomalies. However, many severe and lethal anomalies can be detected earlier and routine first-trimester anomaly screening at 11–14 weeks may be a valuable addition to prenatal care. The objectives of this study were: To assess the diagnostic accuracy of first-trimester ultrasound for major structural anomalies through systematic reviews and meta-analyses of the literature and to understand how this screening should be optimally performed (i.e. anatomical protocol, anomalies to be targeted, gestational age window, ultrasound modality used and referral pathways). To undertake a survey of the current first-trimester screening environment in England. To perform an analysis of UK-based data currently held by the National Congenital Anomaly Disease Registry (NCARDRS) to determine the impact of performing a routine first-trimester anomaly scan on the timing of fetal congenital anomaly diagnosis. To conduct a Delphi consensus procedure for the development of a protocol including technical and logistical aspects of first-trimester anomaly screening, based on expert opinions of healthcare providers from across the UK (sonographers, midwives, obstetricians and fetal medicine specialists). To determine the acceptability of the early anomaly scan among women and their partners. To conduct an economic analysis to estimate the expected costs and outcomes associated with current practice and with prospective first-trimester anomaly screening protocols identified by the work described above. To undertake a value-of-information (VoI) analysis to determine whether there is economic value in undertaking additional future research. To draw together the findings and recommendations from the project, and, if appropriate, outline the design of plausible studies or clinical trials.

Authors' results and conclusions: 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. 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. Based on systematic review of low-risk and unselected pregnancies (416,877 fetuses in 40 studies), for the group of major anomalies prioritised by FASP and the consensus procedure, a first-trimester anomaly scan will detect 93.29% [95% confidence interval (CI) 90.37% to 95.71%] of anomalies with a specificity of 99.99% (95% CI 99.98% to 99.99%) and a positive predictive value (PPV) of 96.54% (95% CI 93.27 to 98.76). False-positive (FP) rates are low, and this is consistent with findings from several individual studies examining this issue. Within our review, there were 49 reported FP cases identified, of which 47 were described as findings of bowel-only exomphalos on first-trimester ultrasound in euploid fetuses which were labelled as having subsequently ‘spontaneously resolved’. It should be noted that FP screening will result in additional referrals for fetal medicine assessment, and this has been taken into account within the health economic analysis. For major cardiac anomalies (306,872 fetuses, 45 studies), a first-trimester anomaly scan will detect 55.80% (95% CI 45.87% to 65.50%) of anomalies with a specificity of 99.98% (95% CI 99.97% to 99.99%) and a PPV of 94.85% (95% CI 91.63% to 97.32%). Individually, the first-trimester detection rates for seven of the non-cardiac anomalies in question (acrania, exomphalos, gastroschisis, body stalk anomaly, holoprosencephaly and ectopia cordis) exceed 85% of cases, with fetuses affected by LUTO identified in 65% of cases. We compared studies using a formal anatomical protocol to those not doing so. This showed no statistically significant differences in the detection rates for these eight anomalies combined, nor in the detection of the anomalies individually, with the exception of screening for holoprosencephaly. For major cardiac anomalies, we found strong evidence that the imaging protocol used for examination impacts screening performance (p 

Authors' methods: 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. United Kingdom National Health Service. Pregnant women and partners. Detailed anomaly ultrasound at 11–14 weeks’ gestation, in addition to usual practice. Diagnostic accuracy, protocol development, health economic modelling and value-of-information analysis. 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). Systematic review and meta-analysis for diagnostic accuracy. 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. The systematic reviews and meta-analyses of studies were designed to evaluate the diagnostic accuracy of two-dimensional ultrasound for the detection of a pre-selected group of major anomalies at 11–14 weeks’ gestation, based on Fetal Anomaly Screening Program (FASP) priorities and the consensus group: anencephaly, holoprosencephaly, encephalocele, body stalk anomaly, ectopia cordis, exomphalos, gastroschisis, lower urinary tract obstruction (LUTO) and major cardiac anomalies. The protocols for the reviews were developed and registered with the International Prospective Register of Systematic Reviews prior to undertaking the search, selection of studies and data extraction (PROSPERO, CRD42018111781 and CRD42018112434). A systematic electronic search strategy was designed with the help of a specialist librarian using free-text terms and subject headings related to prenatal screening, early pregnancy and congenital abnormalities and conducted using four databases (MEDLINE, EMBASE, Web of Science Core Collection and Cochrane Library) for studies published between January 1998 and July 2020. Prospective and retrospective studies evaluating pregnancies of low, mixed or uncertain a priori risk and in any healthcare setting were eligible for inclusion. We excluded studies only evaluating high-risk pregnancies. The reference standard used was the detection of a major abnormality on postnatal or post-mortem examination. Data were extracted from the included studies to populate 2 × 2 tables. Meta-analysis was performed using a random-effects model to determine the performance of first-trimester ultrasound for the detection of the individual pre-selected congenital anomalies, for major cardiac abnormalities overall and for the major non-cardiac anomalies overall (n = 7). Pre-planned secondary analyses were conducted to assess factors that may impact screening performance, including the imaging protocol used for assessment, ultrasound modality, year of publication, and the index of sonographer suspicion at the time of the scan. Risk of bias and quality assessment were undertaken for all included studies using the quality assessment of diagnostic accuracy studies (QUADAS-2) tool. The nationwide survey of NHS practice was developed and undertaken in collaboration with the FASP. Thirty-six questions covered domains including current first-trimester ultrasound protocols; local policies regarding screening logistics (e.g. time allocated for scan, mode of scan, equipment) and referral pathways; inclusions of a routine early fetal anomaly scan and resource availability. After validation and piloting, the survey was distributed electronically in January 2019 to all NHS maternity trusts in England (n = 132). Anonymised data were analysed using descriptive statistics for the group of responding trusts; survey responses from trusts in different regions [as defined by Public Health England (PHE) at that time] were compared using chi-squared tests. Data obtained from the nationwide survey of NHS practice regarding the first-trimester anomaly screening protocols of different NHS trusts were linked to retrospective data held by the NCARDRS from pregnancies with estimated delivery dates between April 2017 and 2019. Ethics approval for this work was obtained after full review by the North West – Preston Research Ethics committee (21/NW/0173) in March 2021 and by the National Disease Registry Project Review Panel on behalf of PHE. Data from NHS Hospital trusts who responded to the nationwide survey were aggregated into one of four groups based on the reported type of first-trimester anomaly screening protocol used routinely: (1) no formal assessment; (2) basic anatomical assessment (routine evaluation of fetal head, limbs and/or cord insertion only); (3) advanced anatomical protocol (basic + either stomach and/or bladder); (4) extended anatomical protocol (advanced + fetal heart, spine and/or face). The primary objective of the study was to determine the proportion of anomalies (a pre-designated group) which are currently identified prior to 16 weeks in England and to compare the early detection rates of these anomalies based on the first-trimester screening protocol used (Group a vs. Group b vs. Group c vs. Group d). The pre-designated anomalies of interest were based on current FASP second-trimester guidance and on several anomalies of interest in the first trimester which included anencephaly, alobar holoprosencephaly, encephalocele, exomphalos, gastroschisis, spina bifida, facial clefts, congenital diaphragmatic hernia, bilateral renal agenesis, megacystis, lethal skeletal dysplasias, limb reduction defects, hypoplastic left heart syndrome (HLHS), atrioventricular septal defect (AVSD), tetralogy of Fallot (TOF) and transposition of great arteries. Pre-specified subanalysis of each type of anomaly by ultrasound protocol was also assessed. Analysis of data at individual trust level was not undertaken. The Delphi consensus procedure took place entirely online over two rounds using RedCap software (Vanderbilt, Nashville, TN, USA). The study was open to all UK healthcare professionals with an interest in this area of research, with invitations to participate circulated to a list of UK-based sonographers, midwives and doctors with known interests in this area, and to the membership of the British Medical Ultrasound Society and the British Maternal Fetal Medicine Society. All data collected from participants were kept confidential, analysed anonymously and in aggregate form. A literature search conducted from 1991 to 2021 identified (1) all published first-trimester ultrasound protocols evaluating fetal anatomy; (2) a list of anomalies detectable at 11–14 weeks; and (3) relevant screening factors; this formed the basis for round one of the Delphi questionnaire. Participants were asked to identify those fetal anomalies and anatomical views which should be routinely evaluated in the first trimester, and determine logistical aspects. Items receiving ≥ 80% support and < 60% support were included and excluded, respectively, from the protocol. In round two, results were fed back to the participants for confirmation, and items receiving between 60% and 80% support were reconsidered. Subgroup analysis was performed to determine whether responses differed by stakeholder group. The ACceptability of the first trimester Anomaly Scan (ACAS) Study was a multicentre prospective, questionnaire-based study designed to explore parental views towards routine anomaly screening at 11–14 weeks in the UK. It included two distinct study cohorts. In Cohort A, parents attending routine antenatal ultrasound at 1 of 10 participating NHS hospitals in England and Wales were eligible for recruitment. In Cohort B, parents with a previous pregnancy or child with a congenital anomaly were invited to participate via two national charities: Antenatal Results and Choices and Spina Bifida, Hydrocephalus, Information, Networking, Equality Charity. All participants received a briefing guide explaining the potential benefits and risks of an 11–14 week anatomy assessment and were asked to complete a validated, structured questionnaire on their views regarding screening for anomalies. For the health economic evaluation, a detailed decision-analytic model was developed to simulate the impact upon healthcare costs and maternal quality-adjusted life-years (QALYs) of a policy to add a first-trimester anomaly scan to the current antenatal screening pathway. Assessments of the impact of the screening policy upon pregnancy outcomes and infant costs and QALYs were also made and are reported separately. Costs included additional time for consent and scanning, sonographer training, as well as additional fetal medicine and echocardiographic scans, and other follow-up investigations offered following an initial screen-positive scan. The implications for maternal quality of life of screening outcomes, further investigations, pregnancy continuation decisions, and fetal losses during the first and second trimesters were also modelled. The model was run for a period of 20 years using an NHS perspective, and populated using data from the project’s systematic reviews and surveys, administrative databases, the National Schedule of NHS Costs (2019–20) and the published literature. Parameters were entered using distributions to facilitate probabilistic sensitivity analysis. VoI analysis, conducted on the cost-effectiveness results generated using maternal healthcare costs and QALYs, was used to identify uncertainty present in groups of key model parameters and whether investments in further research are needed to reduce such uncertainty before a policy decision can be made about the implementation of first-trimester anomaly screening.

Project Status: Completed

URL for project: https://www.journalslibrary.nihr.ac.uk/programmes/hta/17/19/10

Year Published: 2025

URL for published report: https://www.journalslibrary.nihr.ac.uk/hta/NLTP7102

URL for additional information: English

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: England, United Kingdom

DOI: 10.3310/NLTP7102

Organisation Name: NIHR Health Technology Assessment programme

Contact Address: NIHR Journals Library, National Institute for Health and Care Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK

Contact Name: journals.library@nihr.ac.uk

Contact Email: journals.library@nihr.ac.uk