Fionnuala Mone

Objective: To determine the efficacy and safety of different pharmacological and non‐pharmacological methods of feticide to induce fetal asystole prior to termination of pregnancy (TOP). Methods: MEDLINE, EMBASE, CINAHL, SCOPUS, PubMed and Cochrane Library databases were searched electronically from January 1991 to June 2025. Observational and randomized studies of feticides using pharmacological or non‐pharmacological methods prior to TOP in the second or third trimester were included. The primary outcome was failure to achieve fetal asystole prior to TOP. Secondary outcomes included the total dose of feticidal agent, maternal complications and influence of feticide method on feasibility and quality of postmortem evaluation. Quality assessment of the included studies was performed using the Risk Of Bias In Non‐randomized Studies of Interventions tool, Revised Cochrane Risk‐of‐Bias‐2 tool and National Institutes of Health Quality Assessment Tools. A meta‐analysis of the proportions of failed procedures was conducted using random‐effects models. Results: Twenty‐five studies with a total of 10 683 cases were included in the systematic review. Pooled proportions of failed procedures were 0.4% (95% CI, 0.1–2.4%) ( I ² = 0%) for intracardiac potassium chloride (KCl), 3.2% (95% CI, 1.2–8.2%) ( I ² = 0%) for intrafunic KCl, 4.8% (95% CI, 3.9–5.9%) ( I ² = 19.0%) for intrafetal digoxin and 10.6% (95% CI, 6.4–17.1%) ( I ² = 0%) for intra‐amniotic digoxin. A range of doses were reported for KCl, lidocaine and digoxin by all routes of injection. There were four cases of postprocedure chorioamnionitis across all studies, but no other significant adverse events related directly to feticidal procedures. There was limited assessment of the impact of feticidal agent on postmortem examinations, but fetal intravascular lidocaine and KCl were associated consistently with cell lysis. Conclusions: Feticide is an important procedure to induce asystole prior to TOP. Point estimates from the meta‐analysis indicate that the most effective feticidal method is intracardiac KCl. Effectiveness should be considered alongside safety and feasibility when deciding on appropriate methods for different settings. © 2026 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Objective: To determine the retrospective yield of prenatal exome sequencing (PES) by establishing the proportion of children with a postnatal monogenic diagnosis that could have been diagnosed prenatally if PES had been available. Methods: The study cohort comprised a sample of children in Northern Ireland, born between January 2010 and January 2018 (predating routine availability of PES), who received a monogenic diagnosis postnatally via next generation sequencing as part of either of two UK‐wide studies (the 100 000 Genomes Project (2015–2018) or the Deciphering Developmental Disorders study (2011–2015)). Clinical data were collected retrospectively and correlated with the current UK National Health Service PES protocol, including the phenotypic eligibility criteria for PES and the associated fetal anomalies gene panel. Cases were considered retrospective diagnoses if the fetal phenotype would have been eligible for PES and the diagnostic gene was included on the test panel, meaning prenatal diagnosis in this current era could have been feasible. Results: Of 101 children, 17.8% (95% CI, 10.3–25.3%) had both an eligible fetal structural anomaly (FSA) (i.e. high‐risk FSA) and a diagnostic gene on the associated test panel, meaning that they could have been diagnosed prenatally in the current clinical landscape. The median length of the diagnostic odyssey for this subgroup of children was 3.7 years (1354 (range, 822–2450) days). Moreover, 58.4% ( n = 59) of cases had no anomalies detected prenatally and 19.8% ( n = 20) had a FSA that would not meet the eligibility criteria for PES (low‐risk FSA). Although these cases would have been ineligible for PES under the current clinical pathway, 89.9% ( n = 71/79) were affected by severe or profound syndromes. Postnatally, the most common functional anomalies were neurodevelopmental delay/intellectual disability and/or behavioral abnormality, which were observed in 80.2% ( n = 81) of the included children. However, 80.2% ( n = 65/81) of these affected children did not present with fetal anomalies eligible for PES. Conclusions: Almost one‐fifth of children with a monogenic condition included in this study could have received a diagnosis via modern PES, avoiding a diagnostic odyssey lasting almost 4 years. However, despite having a monogenic condition, over half of the children did not present with any structural anomalies in utero . This demonstrates the degree to which fetal imaging is limited in its ability to reassure parents of the absence of a fetal genetic syndrome. © 2026 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Objective: To evaluate the performance of the genomic analytics applied to the Northern Ireland cohort recruited to the 100,000 Genomes Project, focusing on diagnostic yields in first‐line analysis and revisiting inconclusive cases with rare diseases. Methods: Whole genome sequencing (WGS) and initial data processing were performed centrally by Genomics England (GEL), consistent with a national protocol. A novel internal approach to variant selection and interpretation was designed using a two‐pronged pathway; with initial prioritisation using GEL virtual panels and subsequent Exomiser‐mediated reanalysis of remaining undiagnosed cases. Retrospective collection of genomic records was completed for service evaluation. Results: Of 440 patients recruited 20.2% ( n = 89/440) received a monogenic diagnosis; 69.7% ( n = 62/89) via the initial interpretation pathway (analysed between 2019 and 2021) and 30.3% ( n = 27/89) via the secondary pathway (analysed between 2019 and 2025). The majority of variants missed by the initial analysis were because the diagnostic gene was not included as a target on the applied panel(s) at the time of analysis. The median turnaround time for the initial approach was 644.5 days (range: 315–1342) and for the secondary approach was 1766.5 days (range: 862–2311). The secondary approach was found to be more effective in prioritising pathogenic variants; 69.7% ( n = 62/89) versus 89.9% ( n = 80/89) p = 0.0008. Conclusion: Pre‐classification variant selection and reanalysis of undiagnosed cases are critical to optimise quality improvement in the clinical delivery of WGS. Variant selection via virtual panels can expedite interpretation but may miss clinically relevant findings, leaving cases undiagnosed. Revisiting these cases gave an additional ~6% yield. For efficient variant selection in both initial and follow‐up analysis, a multi‐disciplinary approach is required.

Objectives: To evaluate: (i) the performance of the National Health Service (NHS) phenotypic eligibility criteria for prenatal exome sequencing (pES); (ii) the diagnostic yield of individual NHS criteria; (iii) the diagnostic yield when one or multiple NHS criteria were met; and (iv) the performance of the NHS criteria compared with that of phenotypic eligibility criteria used in other countries/regions. Methods: An online survey was circulated to healthcare professionals in 120 countries to gather information on whether pES is offered in their country and how case selection is performed. Five predefined sets of phenotypic eligibility criteria from England, Greece, Canada (British Columbia and Ontario) and Spain were tested on a virtual historical cohort of 1054 ‘unselected’ structurally abnormal fetuses undergoing pES, derived from a published systematic review. The performance of the current and previous gene panels used in the NHS pES service was assessed in the unselected cohort. The sensitivity and specificity with 95% CI for each set of criteria in relation to diagnostic yield for pathogenic and likely pathogenic variants were calculated, along with the area under the summary receiver‐operating‐characteristics curve (AUC). Results: The electronic survey received 261 responses from 63/120 countries. Where deducible, 81.8% (45/55) of the countries surveyed offered pES. Where stated, most (90.3% (28/31)) cases were selected for pES on a case‐by‐case basis, according to fetal phenotype and the likelihood of an association with a monogenic condition, rather than on the basis of predetermined phenotypic criteria. The total diagnostic yield of the NHS criteria when applied to all relevant cases for pES was 27.8% (69/248), with pooled sensitivity, pooled specificity and AUC of 49.8% (95% CI, 31.7–67.9%), 80.7% (95% CI, 59.6–92.2%) and 0.66 (95% CI, 0.53–0.74), respectively. The diagnostic yield was highest for isolated short long bones (58.3% (7/12)). The likelihood of a monogenic diagnosis did not increase significantly as the number of NHS criteria met increased. There was a significant increase in the diagnostic yield of the current (2024) vs original (2020) gene panel adopted by the NHS (129/135 (95.6%) vs 118/135 (87.4%); P = 0.017). The four other sets of phenotypic criteria used in other countries/regions performed moderately well, with the best performance seen for the British Columbia criteria, which had a pooled sensitivity of 70.5% (95% CI, 43.7–88.1%), pooled specificity of 68.9% (95% CI, 37.5–89.1%) and AUC of 0.73 (95% CI, 0.58–0.79). Conclusions: In the majority of countries for which there was a survey response, pES was offered on a case‐by‐case basis, according to fetal phenotype and the likelihood of an underlying monogenic condition. Existing phenotypic eligibility criteria for pES performed modestly. © 2025 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Key content: Cell‐free fetal DNA (cffDNA) screening test performance for sex chromosome aneuploidies (SCAs), copy number variants (CNVs), rare autosomal trisomies (RATs) and single gene disorders. cffDNA screening for detection of pre‐eclampsia and malignancy. Investigation of recurrent miscarriage using cffDNA. Alternative approaches to interrogating free fetal DNA. Learning objectives: To appreciate there is a lack of robust evidence regarding cffDNA screening test performance for expanded applications. To understand that some but not all countries endorse SCA screening and screening for some CNVs such as 22q.11.2 microdeletion syndrome. To be aware that expanded applications of cffDNA screening pose interpretational and ethical challenges. To be aware that the diagnostic confirmatory test of choice following a high‐chance screening result for the aforementioned conditions is an amniocentesis. Ethical issues: Indirect sex determination may occur with SCA screening. Expanded applications for cffDNA screening in the UK fall outside recommendations.

Objective: To critically review the literature and synthesize evidence on the incremental yield of prenatal exome sequencing (PES) in fetuses with an apparently normal phenotype with a normal G‐banded karyotype or chromosomal microarray (CMA).Methods: This systematic review and meta‐analysis was conducted using a predetermined protocol and registered with PROSPERO (ID: CRD42024593349). We included observational cohort studies reporting on the incremental yield of PES in fetuses with an apparently normal phenotype and a previously normal G‐banded karyotype/CMA. The risk of bias of the included studies was assessed using the Newcastle–Ottawa Scale. The pooled proportion of events was calculated using generalized linear mixed models, using the metaprop function in R version 2.15.1.Results: Four studies (1916 fetuses) were included in this systematic review and meta‐analysis, of which 32 cases had a pathogenic or likely pathogenic variant. The pooled incremental yield of PES in fetuses with an apparently normal phenotype was 1.6% (95% CI, 1.0–2.6%); the majority of variants were de novo within genes associated with autosomal dominant inherited conditions (pooled incremental yield, 0.9% (95% CI, 0.5–1.7%)). Based on the expected severity of the associated disease, the pooled incremental yield was 0.5% (95% CI, 0.1–1.5%) for severe disease and 0.5% (95% CI, 0.2–1.5%) for moderate disease. There were insufficient data to conduct the predefined secondary analyses according to normality of phenotype at birth, variants of uncertain significance and expected age of disease onset.Conclusion: Pooling data from four studies, we found that 1.6% of phenotypically normal fetuses with a normal G‐banded karyotype or CMA may have a pathogenic or likely pathogenic variant identified on PES, most of which occur de novo. The likelihood of a variant being associated with severe disease in such fetuses is 0.5%. However, more research is needed regarding the development of a universal classification of disease severity and the utilization of this evidence in clinical practice. © 2025 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Objective: In the West Midlands regional genetics service, cases of perinatal death with a possible genetic diagnosis are evaluated by the perinatal pathology genetic multidisciplinary team (MDT). The MDT assesses autopsy findings and suggests appropriate genomic assessment. The objective of this retrospective service evaluation was to determine the clinical utility of the MDT in assessing perinatal deaths associated with structural anomaly. This is the first evaluation since the introduction of whole‐genome and whole‐exome sequencing in routine clinical care.Methods: This was a retrospective service evaluation including all cases of perinatal death with an associated structural anomaly and suspected genetic etiology that underwent perinatal MDT assessment between January and December 2021. All cases received a full or partial postmortem examination and at least a chromosomal microarray analysis. Demographic characteristics, phenotype, genotype, MDT recommendations, diagnoses, outcomes and impact of postmortem analysis and genetic testing data were collected from patient case notes.Results: Overall, 123 cases were discussed at the MDT meetings in 2021. Genetic evaluation was recommended in 84 cases and accepted in 64 cases. A range of genetic tests were requested according to indication and availability. Thirty diagnoses were made in 29 cases from 26 unrelated families. The diagnostic yield was 24% (29/123) in all cases or 45% (29/64) in cases with a suspected genetic diagnosis who underwent genetic testing. Postmortem examination provided clinically actionable phenotypic data in 79% of cases. A genetic diagnosis enabled accurate recurrence risk counseling and provision of appropriate follow‐up, including prenatal testing and preimplantation diagnosis for patients with inherited conditions.Conclusions: Genomic testing was a clinically useful addition to (but not a substitute for) postmortem examination in cases of perinatal death associated with structural anomaly. The MDT approach helped assess cases and plan appropriate follow‐up. Expedited whole‐genome sequencing or panel‐agnostic analysis were most appropriate for heterogeneous presentations. This broad approach can also expand knowledge of prenatal phenotypes and detect novel disease genes, and should be a priority in future research. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.

Background: Fetal growth restriction is associated with perinatal morbidity and mortality. Early identification of women having at-risk fetuses can reduce perinatal adverse outcomes. Objectives: To assess the predictive performance of existing models predicting fetal growth restriction and birthweight, and if needed, to develop and validate new multivariable models using individual participant data. Design: Individual participant data meta-analyses of cohorts in International Prediction of Pregnancy Complications network, decision curve analysis and health economics analysis. Participants: Pregnant women at booking. External validation of existing models (9 cohorts, 441,415 pregnancies); International Prediction of Pregnancy Complications model development and validation (4 cohorts, 237,228 pregnancies). Predictors: Maternal clinical characteristics, biochemical and ultrasound markers. Primary outcomes: fetal growth restriction defined as birthweight c-statistic, calibration slope, calibration-in-the-large) for each model and pooled using random-effects meta-analysis. Heterogeneity was quantified using τ² and 95% prediction intervals. We assessed the clinical utility of the fetal growth restriction model using decision curve analysis, and health economics analysis based on National Institute for Health and Care Excellence 2008 model. Results: Of the 119 published models, one birthweight model (Poon) could be validated. None reported fetal growth restriction using our definition. Across all cohorts, the Poon model had good summary calibration slope of 0.93 (95% confidence interval 0.90 to 0.96) with slight overfitting, and underpredicted birthweight by 90.4 g on average (95% confidence interval 37.9 g to 142.9 g). The newly developed International Prediction of Pregnancy Complications-fetal growth restriction model included maternal age, height, parity, smoking status, ethnicity, and any history of hypertension, pre-eclampsia, previous stillbirth or small for gestational age baby and gestational age at delivery. This allowed predictions conditional on a range of assumed gestational ages at delivery. The pooled apparent c-statistic and calibration were 0.96 (95% confidence interval 0.51 to 1.0), and 0.95 (95% confidence interval 0.67 to 1.23), respectively. The model showed positive net benefit for predicted probability thresholds between 1% and 90%. In addition to the predictors in the International Prediction of Pregnancy Complications-fetal growth restriction model, the International Prediction of Pregnancy Complications-birthweight model included maternal weight, history of diabetes and mode of conception. Average calibration slope across cohorts in the internal-external cross-validation was 1.00 (95% confidence interval 0.78 to 1.23) with no evidence of overfitting. Birthweight was underestimated by 9.7 g on average (95% confidence interval −154.3 g to 173.8 g). Limitations: We could not externally validate most of the published models due to variations in the definitions of outcomes. Internal-external cross-validation of our International Prediction of Pregnancy Complications-fetal growth restriction model was limited by the paucity of events in the included cohorts. The economic evaluation using the published National Institute for Health and Care Excellence 2008 model may not reflect current practice, and full economic evaluation was not possible due to paucity of data. Future work: International Prediction of Pregnancy Complications models’ performance needs to be assessed in routine practice, and their impact on decision-making and clinical outcomes needs evaluation. Conclusion: The International Prediction of Pregnancy Complications-fetal growth restriction and International Prediction of Pregnancy Complications-birthweight models accurately predict fetal growth restriction and birthweight for various assumed gestational ages at delivery. These can be used to stratify the risk status at booking, plan monitoring and management. Study registration: This study is registered as PROSPERO CRD42019135045. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/148/07) and is published in full in Health Technology Assessment; Vol. 28, No. 14. See the NIHR Funding and Awards website for further award information.