Search

Objective: To report the diagnostic accuracy of cell-free fetal DNA (cfDNA) in detecting fetal chromosomal anomalies in women experiencing miscarriage., Methods: PubMed, MEDLINE, EMBASE and Cochrane databases were searched from inception to June 2024. The inclusion criteria were women experiencing miscarriage (defined as pregnancy loss before 20 weeks of gestation) who underwent cfDNA screening for trisomies 21, 18 and 13, other autosomal aneuploidies, sex-chromosome aneuploidies and/or copy-number variants (CNVs). The index test was cfDNA screening for each of the chromosomal anomalies listed. The reference standard was cytogenetic analysis of pregnancy tissue. The quality of the studies was assessed using the revised tool for the quality assessment of diagnostic accuracy studies. Summary estimates of sensitivity, specificity, positive and negative likelihood ratios, and diagnostic odds ratio were computed using the hierarchical summary receiver-operating-characteristics model., Results: Seven studies (887 women) were included in the systematic review and meta-analysis. cfDNA had a sensitivity and specificity of 100% (95% CI, 81.5-100%) and 100% (95% CI, 99.1-100%), respectively, for trisomy 21, 100% (95% CI, 54.1-100%) and 100% (95% CI, 99.0-100%), respectively, for trisomy 18, and 88.9% (95% CI, 51.8-99.7%) and 100% (95% CI, 99.1-100%), respectively, for trisomy 13. The respective values for other autosomal trisomies were 75.8% (95% CI, 65.7-84.2%) and 99.4% (95% CI, 97.9-99.9%), while those for CNVs were 60.0% (95% CI, 14.7-94.7%) and 100% (95% CI, 97.4-100%). Failure of cfDNA testing was reported in 7.3% (95% CI, 5.7-9.2%) of cases., Conclusion: cfDNA has high diagnostic accuracy in detecting fetal trisomies 21, 18 and 13 in women experiencing miscarriage, while its accuracy for other autosomal aneuploidies and CNVs is only moderate. © 2024 International Society of Ultrasound in Obstetrics and Gynecology., (© 2024 International Society of Ultrasound in Obstetrics and Gynecology.)

Objective: In screening for small-for-gestational age (SGA) using third-trimester antenatal ultrasound, there are concerns about the low detection rates and potential for harm caused by both false-negative and false-positive screening results. Using a selective third-trimester ultrasound screening program, this study aimed to investigate the incidence of adverse perinatal outcomes among cases with (i) false-negative compared with true-positive SGA diagnosis and (ii) false-positive compared with true-negative SGA diagnosis., Methods: This prospective cohort study was nested within the UK-based DESiGN trial, a prospective multicenter cohort study of singleton pregnancies without antenatally detected fetal anomalies, born at > 24 + 0 to < 43 + 0 weeks' gestation. We included women recruited to the baseline period, or control arm, of the trial who were not exposed to the Growth Assessment Protocol intervention and whose birth outcomes were known. Stillbirth and major neonatal morbidity were the two primary outcomes. Minor neonatal morbidity was considered a secondary outcome. Suspected SGA was defined as an estimated fetal weight (EFW) < 10 th percentile, based on the Hadlock formula and fetal growth charts. Similarly, SGA at birth was defined as birth weight (BW) < 10 th percentile, based on UK population references. Maternal and pregnancy characteristics and perinatal outcomes were reported according to whether SGA was suspected antenatally or not. Unadjusted and adjusted logistic regression models were used to quantify the differences in adverse perinatal outcomes between the screening results (false negative vs true positive and false positive vs true negative)., Results: In total, 165 321 pregnancies were included in the analysis. Fetuses with a false-negative SGA screening result, compared to those with a true-positive result, were at a significantly higher risk of stillbirth (adjusted odds ratio (aOR), 1.18 (95% CI, 1.07-1.31)), but at lower risk of major (aOR, 0.87 (95% CI, 0.83-0.91)) and minor (aOR, 0.56, (95% CI, 0.54-0.59)) neonatal morbidity. Compared with a true-negative screening result, a false-positive result was associated with a lower BW percentile (median, 18.1 (interquartile range (IQR), 13.3-26.9) vs 49.9 (IQR, 30.3-71.7)). A false-positive result was also associated with a significantly increased risk of stillbirth (aOR, 2.24 (95% CI, 1.88-2.68)) and minor neonatal morbidity (aOR, 1.60 (95% CI, 1.51-1.71)), but not major neonatal morbidity (aOR, 1.04 (95% CI, 0.98-1.09))., Conclusions: In selective third-trimester ultrasound screening for SGA, both false-negative and false-positive results were associated with a significantly higher risk of stillbirth, when compared with true-positive and true-negative results, respectively. Improved SGA detection is needed to address false-negative results. It should be acknowledged that cases with a false-positive SGA screening result also constitute a high-risk population of small fetuses that warrant surveillance and timely birth. © 2024 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2024 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: Parental counseling for fetal malformations of cortical development (MCD) is based on data from studies in children and adults undergoing imaging investigation for abnormal neurodevelopment. However, such postnatal findings may not be applicable to prenatally diagnosed cases. The aim of this study was to review the existing data on postnatal neurodevelopmental outcome for fetuses diagnosed with MCD., Methods: A literature search was conducted in PubMed, Web of Science and EMBASE for articles published between 2013 and 2023, using standardized keywords to describe fetal cortical malformations. Full-text articles were accessed for the retrieved citations and data on participant characteristics, imaging findings, and pregnancy and neonatal outcomes were extracted. Fetal MCD was defined as either complex or isolated, according to the presence or absence, respectively, of additional brain or extracranial defects., Results: Overall, 30 articles including 371 cases of fetal MCD were reviewed. The cases were classified as complex (n = 324), isolated (n = 21) or unknown (n = 26). There were 144 terminations and four stillbirths, with pregnancy outcome unreported in 149 cases. A total of 108 cases had postnatal magnetic resonance imaging or postmortem examination data available. In nine of these cases, a diagnosis of complex fetal MCD was changed to isolated MCD after birth, and one case was found not to have MCD. There were 74 live births, for which postnatal neurodevelopment data were available in only 30 cases. Normal neurodevelopmental outcome was reported in seven (23.3% (95% CI, 9.9-42.2%)) infants, with the remaining 23 exhibiting various levels of neurodevelopmental delay (three mild, seven moderate and 13 severe) from 6 months to 7 years of age., Conclusions: Most reviewed cases of fetal MCD were complex in nature and underwent termination of pregnancy. There is a paucity of data on postnatal neurological development in fetuses diagnosed with MCD. The available data suggest antenatal overdiagnosis of case severity in about 5% of cases with known outcome, and either normal neurodevelopment or mild neurodevelopmental delay in approximately one-third of liveborn cases with neurological follow-up. © 2024 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2024 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

Objectives: To reach an international expert consensus on the diagnosis, prognosis and management of fetal lower urinary tract obstruction (LUTO) by means of a Delphi procedure, and to use this to define a core outcome set (COS)., Methods: A three-round Delphi procedure was conducted among an international panel of experts in fetal LUTO. The panel was provided with a list of literature-based parameters to consider for the diagnosis, prognosis, management and outcomes of LUTO. A parallel procedure was conducted with patient groups during the development of the COS., Results: A total of 168 experts were approached, of whom 99 completed the first round and 80/99 (80.8%) completed all three rounds of the study questionnaires. Consensus was reached that, in the first trimester, an objective measurement of longitudinal bladder diameter of ≥ 7 mm should be used to suspect LUTO. In the second trimester, imaging parameters suggestive of LUTO could include enlarged bladder, keyhole sign, bladder wall thickening, bilateral hydronephrosis, bilateral hydroureteronephrosis and male sex. There was 79% agreement that the current prognostic scoring systems in the literature should not be used clinically. However, experts agreed on the value of amniotic fluid volume (at < 24 weeks) to predict survival and that the value of fetal intervention is to improve the chance of neonatal survival. Experts endorsed sonographic parameters suggestive of renal dysplasia, at least one vesicocentesis, and renal biochemistry for prognosis and counseling, but these items did not reach a consensus for determining candidacy for fetal intervention. On the other hand, imaging parameters suggestive of LUTO, absence of life-limiting structural or genetic anomalies, gestational age of ≥ 16 weeks and oligohydramnios (defined as deepest vertical pocket < 2 cm) should be used as candidacy criteria for fetal intervention based on expert consensus. If bladder refill was evaluated, it should be assessed subjectively. Vesicoamniotic shunt should be the first line of fetal intervention. In the presence of suspected fetal renal failure, serial amnioinfusion should be offered only as an experimental procedure under research protocols. A COS for future LUTO studies was agreed upon., Conclusion: International consensus on the diagnosis, prognosis and management of fetal LUTO, as well as the COS, should inform clinical care and research to optimize perinatal outcomes. © 2024 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2024 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

Objectives: Twin pregnancies are at higher risk of stillbirth compared to singletons. Fetal growth restriction (FGR) is a major cause of perinatal mortality, but its impact on twins vs singletons remains unclear. The primary objective of this study was to investigate the association of FGR and small-for-gestational age (SGA) with stillbirth in twin compared with singleton pregnancies. A secondary objective was to assess these associations stratified by gestational age at delivery. Furthermore, we aimed to compare the associations of FGR and SGA with stillbirth in twin pregnancies using twin-specific vs singleton birth-weight charts, stratified by chorionicity., Methods: This was a retrospective cross-sectional study of pregnancies receiving obstetric care and giving birth between 1999 and 2022 at St George's Hospital, London, UK. The exclusion criteria included triplet and higher-order pregnancies, those resulting in miscarriage or live birth at ≤ 23 + 6 weeks, termination of pregnancy and missing data regarding birth weight or gestational age at birth. Birth-weight data were collected and FGR and SGA were defined as birth weight <5 th and <10 th centiles, respectively. While standard logistic regression was used for singleton pregnancies, the association of FGR and SGA with stillbirth in twin pregnancies was investigated using mixed-effects logistic regression models. For twin pregnancies, intercepts were allowed to vary for twin pairs to account for intertwin dependency. Analyses were stratified by gestational age at delivery and chorionicity. Statistical significance was set at P ≤ 0.001., Results: The study included 95 342 singleton and 3576 twin pregnancies. There were 494 (0.52%) stillbirths in singleton and 41 (1.15%) stillbirths in twin pregnancies (17 dichorionic and 24 monochorionic). SGA and FGR were associated significantly with stillbirth in singleton pregnancies across all gestational ages at delivery: the odds ratios (ORs) for SGA and FGR were 2.36 ((95% CI, 1.78-3.13), P < 0.001) and 2.67 ((95% CI, 2.02-3.55), P < 0.001), respectively, for delivery before 32 weeks; 2.70 ((95% CI, 1.71-4.31), P < 0.001) and 2.82 ((95% CI, 1.78-4.47), P < 0.001), respectively, for delivery between 32 and 36 weeks; and 3.85 ((95% CI, 2.83-5.21), P < 0.001) and 4.43 ((95% CI, 3.16-6.12), P < 0.001), respectively, for delivery after 36 weeks. In twin pregnancies, when stratified by gestational age at delivery, both SGA and FGR determined by twin-specific birth-weight charts were associated with increased odds of stillbirth for those delivered before 32 weeks (SGA: OR, 3.87 (95% CI, 1.56-9.50), P = 0.003 and FGR: OR, 5.26 (95% CI, 2.11-13.01), P = 0.001), those delivered between 32 and 36 weeks (SGA: OR, 6.67 (95% CI, 2.11-20.41), P = 0.001 and FGR: OR, 9.54 (95% CI, 3.01-29.40), P < 0.001) and those delivered beyond 36 weeks (SGA: OR, 12.68 (95% CI, 2.47-58.15), P = 0.001 and FGR: OR, 23.84 (95% CI, 4.62-110.25), P < 0.001). However, the association of stillbirth with SGA and FGR in twin pregnancies was non-significant when diagnosis was based on singleton charts (before 32 weeks: SGA, P = 0.014 and FGR, P = 0.005; 32-36 weeks: SGA, P = 0.036 and FGR, P = 0.008; after 36 weeks: SGA, P = 0.080 and FGR, P = 0.063)., Conclusion: Our study demonstrates that SGA and, especially, FGR are associated significantly with an increased risk of stillbirth across all gestational ages in singleton pregnancies, and in twin pregnancies when twin-specific birth-weight charts are used. © 2024 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2024 The Authors. 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 relative importance of ethnicity and socioeconomic deprivation in determining the likelihood and prevalence of placentally derived composite of adverse pregnancy outcomes (CAPO) and composite of severe adverse pregnancy outcomes (CAPO-S)., Methods: This was a single-center retrospective cohort study of data obtained in a tertiary maternity unit. Data regarding ethnicity and socioeconomic deprivation (as measured with indices of multiple deprivation) were collected for 13 165 singleton pregnancies screened routinely in the first trimester for pre-eclampsia using the Fetal Medicine Foundation combined risk-assessment algorithm. CAPO was defined as the presence of one or more interrelated outcomes associated with placental dysfunction, namely, hypertensive disorders of pregnancy, preterm birth, birth weight ≤ 10 th centile and stillbirth. CAPO-S was defined as the presence of one or more of the following: hypertensive disorders of pregnancy at < 37 + 0 weeks, preterm birth at < 34 + 0 weeks, birth weight ≤ 5 th centile and stillbirth at < 37 + 0 weeks., Results: The prevalence of CAPO was 16.3% in white women, 29.3% in black women and 29.3% in South Asian women. However, half (51.7%) of all CAPO cases occurred in white women. There was a strong interaction between ethnicity and socioeconomic deprivation, with a correlation coefficient of -0.223. Both ethnicity and socioeconomic deprivation influenced the prevalence of CAPO and CAPO-S, with the contribution of ethnicity being the strongest., Conclusions: Black and Asian ethnicity, as well as socioeconomic deprivation, influence the prevalence of placenta-mediated adverse pregnancy outcomes. Despite this, most adverse pregnancy outcomes occur in white women, who represent the majority of the population and are also affected by socioeconomic deprivation. For these reasons, inclusion of socioeconomic deprivation should be considered in early pregnancy risk assessment for placenta-mediated CAPO. © 2024 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2024 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

Objective: Antenatal growth assessment using ultrasound aims to identify small fetuses that are at higher risk of perinatal morbidity and mortality. This study explored whether the association between suboptimal fetal growth and adverse perinatal outcome varies with different definitions of fetal growth restriction (FGR) and different weight charts/standards., Methods: This was a retrospective cohort study of 17 261 singleton non-anomalous pregnancies at ≥ 24 + 0 weeks' gestation that underwent routine ultrasound at a tertiary referral hospital. Estimated fetal weight (EFW) and Doppler indices were converted into percentiles using a reference standard (INTERGROWTH-21 st (IG-21)) and various reference charts (Hadlock, Fetal Medicine Foundation (FMF) and Swedish). Test characteristics were assessed using the consensus definition, Society for Maternal-Fetal Medicine (SMFM) definition and Swedish criteria for FGR. Adverse perinatal outcome was defined as perinatal death, admission to the neonatal intensive care unit at term, 5-min Apgar score < 7 and therapeutic cooling for neonatal encephalopathy. The association between FGR according to each definition and adverse perinatal outcome was compared. Multivariate logistic regression analysis was used to test the strength of association between ultrasound parameters and adverse perinatal outcome. Ultrasound parameters were also tested for correlation., Results: IG-21, Hadlock and FMF fetal size references classified as growth-restricted 1.5%, 3.6% and 4.6% of fetuses, respectively, using the consensus definition and 2.9%, 8.8% and 10.6% of fetuses, respectively, using the SMFM definition. The sensitivity of the definition/chart combinations for adverse perinatal outcome varied from 4.4% (consensus definition with IG-21 charts) to 13.2% (SMFM definition with FMF charts). Specificity varied from 89.4% (SMFM definition with FMF charts) to 98.6% (consensus definition with IG-21 charts). The consensus definition and Swedish criteria showed the highest specificity, positive predictive value and positive likelihood ratio in detecting adverse outcome, irrespective of the reference chart/standard used. Conversely, the SMFM definition had the highest sensitivity across all investigated growth charts. Low EFW, abnormal mean uterine artery pulsatility index (UtA-PI) and abnormal cerebroplacental ratio were significantly associated with adverse perinatal outcome and there was a positive correlation between the covariates. Multivariate logistic regression showed that UtA-PI > 95 th percentile and EFW < 5 th percentile were the only parameters consistently associated with adverse outcome, irrespective of the definitions or fetal growth chart/standard used., Conclusions: The apparent prevalence of FGR varies according to the definition and fetal size reference chart/standard used. Irrespective of the method of classification, the sensitivity for the identification of adverse perinatal outcome remains low. EFW, UtA-PI and fetal Doppler parameters are significant predictors of adverse perinatal outcome. As these indices are correlated with one other, a prediction algorithm is advocated to overcome the limitations of using these parameters in isolation. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

Objective: Pregnancies with fetal growth restriction (FGR) are at increased risk for pre-eclampsia. Angiogenic markers including soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) are altered in pregnancies complicated by FGR, but their utility for predicting pre-eclampsia in growth-restricted pregnancies is uncertain. This study aimed to evaluate the prognostic value of angiogenic markers for predicting the development of pre-eclampsia in pregnancies with FGR and suspected pre-eclampsia., Methods: This was a retrospective study of singleton pregnancies with FGR, defined according to Delphi consensus criteria, which underwent sampling of sFlt-1 and PlGF for suspicion of pre-eclampsia at the Medical University of Vienna, Vienna, Austria, between 2013 and 2020. Women with an established diagnosis of pre-eclampsia at sampling were excluded. Cox regression analysis and logistic regression analysis were performed to evaluate the association of angiogenic markers with the development of pre-eclampsia at various timepoints., Results: In this cohort of 93 women, pre-eclampsia was diagnosed in 14 (15.1%) women within 1 week after sampling, 21 (22.6%) within 2 weeks after sampling and 38 (40.9%) at any time after assessment. The sFlt-1/PlGF ratio consistently showed a stronger association with the development of pre-eclampsia compared to sFlt-1 or PlGF alone (pre-eclampsia within 1 week: area under the receiver-operating-characteristics curve, 0.87 vs 0.82 vs 0.72). Models including the sFlt-1/PlGF ratio were associated more strongly with pre-eclampsia hazard compared to models including sFlt-1 or PlGF alone (concordance index, 0.790 vs 0.759 vs 0.755). The risk classification capability of the sFlt-1/PlGF ratio decreased after the 2-week timepoint. The established cut-off value for the sFlt-1/PlGF ratio of < 38 was effective for ruling out pre-eclampsia within 2 weeks, with a negative predictive value of 0.933 and sensitivity of 0.952., Conclusions: Use of the sFlt-1/PlGF ratio is preferrable to the use of PlGF alone for the prediction of pre-eclampsia in pregnancies with FGR. Established cut-offs for ruling out the development of pre-eclampsia in the short term seem to be effective in these patients. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

Objective: Fetoscopic laser photocoagulation (FLP) is a well-established treatment for twin-twin transfusion syndrome (TTTS) between 16 and 26 weeks' gestation. High-quality evidence and guidelines regarding the optimal clinical management of very early (prior to 16 weeks), early (between 16 and 18 weeks) and late (after 26 weeks) TTTS are lacking. The aim of this study was to construct a structured expert-based clinical consensus for the management of early and late TTTS., Methods: A Delphi procedure was conducted among an international panel of experts. Participants were chosen based on their clinical expertise, affiliation and relevant publications. A four-round Delphi survey was conducted using an online platform and responses were collected anonymously. In the first round, a core group of experts was asked to answer open-ended questions regarding the indications, timing and modes of treatment for early and late TTTS. In the second and third rounds, participants were asked to grade each statement on a Likert scale (1, completely disagree; 5, completely agree) and to add any suggestions or modifications. At the end of each round, the median score for each statement was calculated. Statements with a median grade of 5 without suggestions for change were accepted as the consensus. Statements with a median grade of 3 or less were excluded from the Delphi process. Statements with a median grade of 4 were modified according to suggestions and reconsidered in the next round. In the last round, participants were asked to agree or disagree with the statements, and those with more than 70% agreement without suggestions for change were considered the consensus., Results: A total of 122 experts met the inclusion criteria and were invited to participate, of whom 53 (43.4%) agreed to take part in the study. Of those, 75.5% completed all four rounds. A consensus on the optimal management of early and late TTTS was obtained. FLP can be offered as early as 15 weeks' gestation for selected cases, and can be considered up to 28 weeks. Between 16 and 18 weeks, management should be tailored according to Doppler findings., Conclusions: A consensus-based treatment protocol for early and late TTTS was agreed upon by a panel of experts. This protocol should be modified at the discretion of the operator, according to their experience and the specific demands of each case. This should advance the quality of future studies, guide clinical practice and improve patient care. © 2023 International Society of Ultrasound in Obstetrics and Gynecology., (© 2023 International Society of Ultrasound in Obstetrics and Gynecology.)

Objectives: To determine the incremental diagnostic yield of exome sequencing (ES) after negative chromosomal microarray analysis (CMA) in cases of prenatally diagnosed agenesis of the corpus callosum (ACC) and to identify the associated genes and variants., Methods: A systematic search was performed to identify relevant studies published up until June 2022 using four databases: PubMed, SCOPUS, Web of Science and The Cochrane Library. Studies in English reporting on the diagnostic yield of ES following negative CMA in prenatally diagnosed partial or complete ACC were included. Authors of cohort studies were contacted for individual participant data and extended cohorts were provided for two of them. The increase in diagnostic yield with ES for pathogenic/likely pathogenic (P/LP) variants was assessed in all cases of ACC, isolated ACC, ACC with other cranial anomalies and ACC with extracranial anomalies. To identify all reported genetic variants, the systematic review included all ACC cases; however, for the meta-analysis, only studies with ≥ three ACC cases were included. Meta-analysis of proportions was employed using a random-effects model. Quality assessment of the included studies was performed using modified Standards for Reporting of Diagnostic Accuracy criteria., Results: A total of 28 studies, encompassing 288 prenatally diagnosed ACC cases that underwent ES following negative CMA, met the inclusion criteria of the systematic review. We classified 116 genetic variants in 83 genes associated with prenatal ACC with a full phenotypic description. There were 15 studies, encompassing 268 cases, that reported on ≥ three ACC cases and were included in the meta-analysis. Of all the included cases, 43% had a P/LP variant on ES. The highest yield was for ACC with extracranial anomalies (55% (95% CI, 35-73%)), followed by ACC with other cranial anomalies (43% (95% CI, 30-57%)) and isolated ACC (32% (95% CI, 18-51%))., Conclusions: ES demonstrated an incremental diagnostic yield in cases of prenatally diagnosed ACC following negative CMA. While the greatest diagnostic yield was observed in ACC with extracranial anomalies and ACC with other central nervous system anomalies, ES should also be considered in cases of isolated ACC. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

Objective: The maternal cardiovascular system of women with hypertensive disorders of pregnancy (HDP) can be impaired, with higher rates of left ventricular (LV) remodeling and diastolic dysfunction compared to those with normotensive pregnancy. The primary objective of this prospective study was to correlate cardiac indices obtained by transthoracic echocardiography (TTE) and circulating angiogenic markers, such as soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF)., Methods: In this study, 95 women with a pregnancy complicated by HDP and a group of 25 with an uncomplicated pregnancy at term underwent TTE and blood tests to measure sFlt-1 and PlGF during the peripartum period (before delivery or within a week of giving birth). Spearman's rank correlation was used to derive correlation coefficients between biomarkers and cardiac indices in the HDP and control populations., Results: The HDP group included 61 (64.2%) pre-eclamptic patients and, among them, 42 (68.9%) delivered before 37 weeks' gestation. Twelve women with HDP (12.6%) underwent blood sampling and TTE after delivery, and, as they showed significantly lower levels of angiogenic markers, they were excluded from the analysis. There was a correlation between sFlt-1 and LV mass index (LVMI) (r = 0.246; P = 0.026) and early diastolic mitral inflow velocity (E) and early diastolic mitral annular velocity (e') ratio (r = 0.272; P = 0.014) in the HDP group (n = 83), while in the controls, sFlt-1 showed a correlation with relative wall thickness (r = 0.409; P = 0.043), lateral e' (r = -0.562; P = 0.004) and E/e' ratio (r = 0.417; P = 0.042). PlGF correlated with LVMI (r = -0.238; P = 0.031) in HDP patients and with lateral e' (r = 0.466; P = 0.022) in controls. sFlt-1/PlGF ratio correlated with lateral e' (r = -0.568; P = 0.004) and E/e' ratio (r = 0.428; P = 0.037) in controls and with LVMI (r = 0.252; P = 0.022) and E/e' ratio (r = 0.269; P = 0.014) in HDP., Conclusions: Although the current data are not able to infer causality, they confirm the intimate relationship between the maternal cardiovascular system and angiogenic markers that are used both to diagnose and indicate the severity of HDP. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

Objective: Most of the published literature on selective fetal growth restriction (sFGR) has focused on monochorionic twin pregnancies. The aim of this systematic review was to report on the outcome of dichorionic diamniotic (DCDA) twin pregnancies complicated by sFGR., Methods: MEDLINE, EMBASE and The Cochrane Library databases were searched. The inclusion criteria were DCDA twin pregnancies complicated by sFGR. The outcomes explored were intrauterine death (IUD), neonatal death and perinatal death (PND), survival of at least one and both twins, preterm birth (PTB) (either spontaneous or iatrogenic) prior to 37, 34, 32 and 28 weeks' gestation, pre-eclampsia (PE) or gestational hypertension, neurological, respiratory and infectious morbidity, Apgar score < 7 at 5 min, necrotizing enterocolitis, retinopathy of prematurity and admission to the neonatal intensive care unit (NICU). A composite outcome of neonatal morbidity, defined as the occurrence of respiratory, neurological or infectious morbidity, was also evaluated. Random-effects meta-analysis was used to analyze the data, and results are reported as pooled proportion or odds ratio (OR) with 95% CI., Results: Thirteen studies reporting on 1339 pregnancies with sFGR and 6316 pregnancies without sFGR were included. IUD occurred in 2.6% (95% CI, 1.1-4.7%) of fetuses from DCDA pregnancies with sFGR and 0.6% (95% CI, 0.3-9.7%) of those from DCDA pregnancies without sFGR, while the respective values for PND were 5.2% (95% CI, 3.5-7.3%) and 1.7% (95% CI, 0.1-5.7%). Spontaneous or iatrogenic PTB before 37 weeks complicated 84.1% (95% CI, 55.6-99.2%) of pregnancies with sFGR and 69.1% (95% CI, 45.4-88.4%) of those without sFGR. The respective values for PTB before 34, 32 and 28 weeks were 18.4% (95% CI, 4.4-38.9%), 13.0% (95% CI, 9.5-17.1%) and 1.5% (95% CI, 0.6-2.3%) in pregnancies with sFGR and 10.2% (95% CI, 3.1-20.7%), 7.8% (95% CI, 6.8-9.0%) and 1.8% (95% CI, 1.3-2.4%) in those without sFGR. PE or gestational hypertension complicated 19.9% (95% CI, 12.4-28.6%) of pregnancies with sFGR and 12.8% (95% CI, 10.4-15.4%) of those without sFGR. Composite morbidity occurred in 28.2% (95% CI, 7.8-55.1%) of fetuses from pregnancies with sFGR and 13.9% (95% CI, 6.5-23.5%) of those from pregnancies without sFGR. When stratified according to the sFGR status within a twin pair, composite morbidity occurred in 39.0% (95% CI, 11.1-71.5%) of growth-restricted fetuses and 29.9% (95% CI, 3.5-65.0%) of appropriately grown fetuses (OR, 1.9 (95% CI, 1.7-3.1)), while the respective values for PND were 3.0% (95% CI, 1.8-4.5%) and 1.6% (95% CI, 0.9-2.6%) (OR, 2.1 (95% CI, 1.0-4.1)). On risk analysis, DCDA pregnancies complicated by sFGR had a significantly higher risk of IUD (OR, 5.2 (95% CI, 3.2-8.6)) and composite morbidity or admission to the NICU (OR, 3.2 (95% CI, 1.9-5.6)) compared to those without sFGR, while there was no difference in the risk of PTB before 34 weeks (P = 0.220) or PE/gestational hypertension (P = 0.210)., Conclusions: DCDA twin pregnancies complicated by sFGR are at high risk of perinatal morbidity and mortality. The findings of this systematic review are relevant for counseling and management of complicated DCDA twin pregnancies, in which twin-specific, rather than singleton, outcome data should be used. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

Objective: Twin pregnancy is associated with increased perinatal mortality and morbidity, but long-term neurodevelopmental outcome remains underinvestigated. The primary objective of this study was to investigate the incidence of adverse neurodevelopment after 1 year of age in complicated monochorionic diamniotic (MCDA) twin pregnancies compared with uncomplicated twin pregnancies., Methods: This was a prospective cohort study conducted at St George's University Hospital NHS Foundation Trust, London, UK. Women with a twin pregnancy culminating in at least one surviving child, aged between 12 and 60 months (corrected for prematurity) at the time of assessment, were invited to complete the relevant Ages and Stages Questionnaire® version 3 (ASQ-3) test. The two study groups were: (1) complicated MCDA twin pregnancies, including those with twin-twin transfusion syndrome, twin anemia-polycythemia sequence, selective fetal growth restriction, twin reversed arterial perfusion sequence and/or single intrauterine demise; and (2) uncomplicated MCDA and dichorionic diamniotic twin pregnancies. The primary outcome measure was an abnormal ASQ-3 score, defined as a score of more than 2 SD below the mean in any one of the five domains. Mixed-effects multivariable logistic regression analysis was performed to determine whether a complicated MCDA twin pregnancy was associated independently with an abnormal ASQ-3 score., Results: The study included 174 parents who completed the questionnaire for one or both twins; therefore, 327 ASQ-3 questionnaires were available for analysis. Of those, 117 (35.8%) were complicated MCDA twin pregnancies and 210 (64.2%) were controls. The overall rate of an abnormal ASQ-3 score in children born of a complicated MCDA twin pregnancy was nearly double that of those from uncomplicated twin pregnancies (14.5% vs 7.6%; P = 0.056). Children born of a complicated MCDA twin pregnancy had a significantly higher rate of impairment in the gross-motor domain compared with the control group (8.5% vs 2.9%; P = 0.031). Complicated MCDA twin pregnancies that underwent prenatal intervention had a significantly higher rate of abnormal ASQ-3 score compared with those that did not undergo prenatal intervention (28.1% vs 1.7%; P < 0.001). On multilevel logistic regression analysis, complicated MCDA twin pregnancy was an independent predictor of abnormal ASQ-3 score (adjusted odds ratio, 3.28 (95% CI, 3.27-3.29); P < 0.001)., Conclusions: This study demonstrates that survivors of complicated MCDA twin pregnancies have a higher rate of adverse neurodevelopmental outcome, independently of prematurity. Long-term neurodevelopmental follow-up in these pregnancies can ensure timely and optimal management of those affected. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

Objective: Maternal cardiac function plays a crucial role in placental function and development. The maternal hemodynamic changes in twin pregnancy are more pronounced than those in singleton pregnancy, presumably due to a greater plasma volume expansion. In view of the correlation between maternal cardiac and placental function, it is plausible that chorionicity could influence maternal cardiac function. The aim of this study was to compare the longitudinal maternal hemodynamic changes between uncomplicated dichorionic (DC) and monochorionic (MC) twin pregnancies and in comparison to singleton pregnancies., Methods: Included in the study were 40 MC diamniotic and 35 DC diamniotic uncomplicated twin pregnancies. These were compared with a group of 294 healthy singleton pregnancies from a previous cross-sectional study. All participants underwent a hemodynamic evaluation using an Ultrasound Cardiac Output Monitor (USCOM®), at three different stages in pregnancy (11-15 weeks, 20-24 weeks and 29-33 weeks). The following parameters were recorded: mean arterial pressure (MAP), stroke volume (SV), stroke volume index (SVI), heart rate, cardiac output (CO), cardiac index (CI), systemic vascular resistance (SVR), systemic vascular resistance index (SVRI), stroke volume variation, Smith-Madigan inotropy index (INO) and potential-to-kinetic-energy ratio (PKR)., Results: In the first trimester, DC and MC twin pregnancies showed lower MAP, SVR and PKR and higher CO and SV in comparison to singleton pregnancy. In the second trimester, maternal CO (8.33 vs 7.30 L/min, P = 0.03) and CI (4.52 vs 4.00 L/min/m 2 , P = 0.02) were significantly higher in MC compared with DC twin pregnancy. In the third trimester, compared with in singleton pregnancy, women with MC twin pregnancy showed significantly higher PKR (24.06 vs 20.13, P = 0.03) and SVRI (1837.20 vs 1698.48 dynes × s/cm 5 /m 2 , P = 0.03), and significantly lower SV (78.80 vs 88.80 mL, P = 0.01), SVI (42.79 vs 50.31 mL/m 2 , P < 0.01) and INO (1.70 vs 1.87 W/m 2 , P = 0.03); these differences were not observed between DC twin and singleton pregnancies., Conclusions: Maternal cardiovascular function undergoes significant change during uncomplicated twin pregnancy and chorionicity influences maternal hemodynamics. In both MC and DC twin pregnancy, hemodynamic changes are detectable as early as the first trimester, showing higher maternal CO and lower SVR compared with singleton pregnancy. In DC twin pregnancy, the maternal hemodynamics remain stable during the rest of pregnancy. In contrast, in MC twin pregnancy, the rise in maternal CO continues in the second trimester in order to sustain the greater placental growth. There is a subsequent crossover, with a reduction in cardiovascular performance during the third trimester. © 2023 International Society of Ultrasound in Obstetrics and Gynecology., (© 2023 International Society of Ultrasound in Obstetrics and Gynecology.)

Objective: Low-dose aspirin (LDA) has been shown to reduce the risk of preterm pre-eclampsia and it has been suggested that it should be recommended for all pregnancies. However, some studies have reported an association between LDA and an increased risk of bleeding complications in pregnancy. Our aim was to evaluate the risk of placental abruption and postpartum hemorrhage (PPH) in patients for whom their healthcare provider had recommended prophylactic aspirin., Methods: This multicenter cohort study included 72 598 singleton births at 19 hospitals in the USA, between January 2019 and December 2021. Pregnancies complicated by placenta previa/accreta, birth occurring at less than 24 weeks' gestation, multiple pregnancy or those with data missing for aspirin recommendation were excluded. Propensity scores were calculated using 20 features spanning sociodemographic factors, medical history, year and hospital providing care. The association between LDA recommendation and placental abruption or PPH was estimated by inverse-probability treatment weighting using the propensity scores., Results: We included 71 627 pregnancies in the final analysis. Aspirin was recommended to 6677 (9.3%) and was more likely to be recommended for pregnant individuals who were 35 years or older (P < 0.001), had a body mass index of 30 kg/m 2 or higher (P < 0.001), had prepregnancy hypertension (P < 0.001) and who had a Cesarean delivery (P < 0.001). Overall, 1.7% of the study cohort (1205 pregnancies) developed preterm pre-eclampsia: 1.3% in the no-aspirin and 5.8% in the aspirin group. After inverse-probability weighting with propensity scores, aspirin was associated with increased risk of placental abruption (adjusted odds ratio (aOR), 1.44 (95% CI, 1.04-2.00)) and PPH (aOR, 1.21 (95% CI, 1.05-1.39)). The aOR translated to a number needed to harm with LDA of 79 (95% CI, 43-330) for PPH and 287 (95% CI, 127-3151) for placental abruption., Conclusions: LDA recommendation in pregnancy was associated with increased risk for placental abruption and for PPH. Our results support the need for more research into aspirin use and bleeding complications in pregnancy before recommending it beyond the highest-risk pregnancies. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

Objective: Pre-eclampsia (PE) is a pregnancy complication associated with premature cardiovascular disease morbidity and mortality (i.e. before 60 years of age or in the first year postpartum). PE is associated with adverse left ventricular (LV) remodeling in the peri- and postpartum periods, an independent risk factor for cardiovascular disease. This study aimed to compare LV geometry by LV mass (LVM) and LVM index (LVMI) between participants with a high vs low screening risk for preterm PE in the first trimester., Methods: This was a prospective cohort study of singleton pregnancies between 11 + 0 and 13 + 6 weeks' gestation that underwent screening for preterm PE as part of their routine first-trimester ultrasound assessment at a tertiary center in London, UK, from February 2019 until March 2020. Screening for preterm PE was performed using the Fetal Medicine Foundation algorithm. Participants with a screening risk of ≥ 1 in 50 for preterm PE were classified as high risk and those with a screening risk of ≤ 1 in 500 were classified as low risk. All participants underwent two-dimensional and M-mode transthoracic echocardiography., Results: A total of 128 participants in the first trimester of pregnancy were included in the analysis, with 57 (44.5%) participants screened as low risk and 71 (55.5%) participants as high risk for PE. The risk groups did not vary in maternal age and gestational age at assessment. Maternal body surface area and body mass index were significantly higher in the high-risk group (all P < 0.05). The high-risk participants were significantly more likely to be Afro-Caribbean, nulliparous and have a family history of hypertensive disease in pregnancy as well as other cardiovascular disease (all P < 0.05). In addition, mean arterial blood pressure (P < 0.001), mean heart rate (P < 0.001), median LVM (130.06 (interquartile range, 113.62-150.50) g vs 97.44 (81.68-114.16) g; P < 0.001) and mean LVMI (72.87 ± 12.2 g/m 2 vs 57.54 ± 12.72 g/m 2 ; P < 0.001) were significantly higher in the high-risk group. Consequently, those in the high-risk group were more likely to have abnormal LV geometry (37.1% vs 7.0%; P < 0.001)., Conclusions: Early echocardiographic assessment in participants at high risk of preterm PE may unmask clinically healthy individuals who are at increased risk for future cardiovascular disease. Adverse cardiac remodeling in the first trimester of pregnancy may be an indicator of decreased cardiovascular reserve and subsequent dysfunctional cardiovascular adaptation in pregnancy. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

Objectives: Angiogenic marker assessment, such as the ratio of soluble fms-like tyrosine kinase-1 (sFlt-1) to placental growth factor (PlGF), is known to be a useful tool in the prediction of pre-eclampsia (PE). However, evidence from surveillance strategies in pregnancies with a PE diagnosis is lacking. Therefore, we aimed to assess the predictive performance of longitudinal maternal serum angiogenic marker assessment for both maternal and perinatal adverse outcomes when compared to standard laboratory parameters in pregnancies with confirmed PE., Methods: This was a retrospective analysis of prospectively collected data from January 2013 to December 2020 at the Medical University of Vienna. The inclusion criteria were singleton pregnancy with confirmed PE and post-diagnosis maternal serum angiogenic marker assessment at a minimum of two timepoints. The primary outcome was the predictive performance of longitudinal sFlt-1 and PlGF assessment for adverse maternal and perinatal outcomes compared to conventional laboratory monitoring at the same time in pregnancies with confirmed PE. Composite adverse maternal outcome included intensive care unit admission, pulmonary edema, eclampsia and/or death. Composite adverse perinatal outcome included stillbirth, neonatal death, placental abruption, neonatal intensive care unit admission, intraventricular hemorrhage, necrotizing enterocolitis, respiratory distress syndrome and/or mechanical ventilator support., Results: In total, 885 post-diagnosis sFlt-1/PlGF ratio measurements were obtained from 323 pregnant women with confirmed PE. For composite adverse maternal outcome, the highest standalone predictive accuracy was obtained using maternal serum sFlt-1/PlGF ratio (area under the receiver-operating-characteristics curve (AUC), 0.72 (95% CI, 0.62-0.81)), creatinine (AUC, 0.71 (95% CI, 0.62-0.81)) and lactate dehydrogenase (LDH) levels (AUC, 0.73 (95% CI, 0.65-0.81)). Maternal platelet levels (AUC, 0.65 (95% CI, 0.55-0.74)), serum alanine aminotransferase (ALT) (AUC, 0.59 (95% CI, 0.49-0.69)) and aspartate aminotransferase (AST) (AUC, 0.61 (95% CI, 0.51-0.71) levels had poor standalone predictive accuracy. The best prediction model consisted of a combination of maternal serum LDH, creatinine levels and sFlt-1/PlGF ratio, which had an AUC of 0.77 (95% CI, 0.68-0.85), significantly higher than sFlt-1/PlGF ratio alone (P = 0.037). For composite adverse perinatal outcome, the highest standalone predictive accuracy was obtained using maternal serum sFlt-1/PlGF ratio (AUC, 0.82 (95% CI, 0.75-0.89)) and creatinine (AUC, 0.74 (95% CI, 0.67-0.80)) levels, sFlt-1/PlGF ratio being superior to creatinine alone (P < 0.001). Maternal serum LDH levels (AUC, 0.65 (95% CI, 0.53-0.74)), platelet count (AUC, 0.57 (95% CI, 0.44-0.67)), ALT (AUC, 0.58 (95% CI, 0.48-0.67)) and AST (AUC, 0.58 (95% CI, 0.48-0.67)) levels had poor standalone predictive accuracy. No combination of biomarkers was superior to maternal serum sFlt-1/PlGF ratio alone for prediction of composite adverse perinatal outcome (P > 0.05 for all)., Conclusions: In pregnancies with confirmed PE, longitudinal maternal serum angiogenic marker assessment is a good predictor of adverse maternal and perinatal outcomes and superior to some conventional laboratory parameters. Further studies should focus on optimal surveillance following diagnosis of PE. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

Objectives: To determine the rate of emergency delivery for presumed fetal compromise after epidural analgesia (EDA) compared with that after alternative analgesia or no analgesia, and to assess whether this rate is increased in pregnancies with reduced placental reserve., Methods: This was a nationwide registry-based cohort study of 629 951 singleton pregnancies delivered at 36 + 0 to 42 + 0 weeks of gestation that were recorded in the Dutch national birth registry between 2014 and 2018, including 120 426 cases that received EDA, 86 957 that received alternative analgesia and 422 568 that received no analgesia during labor. Pregnancies with congenital anomaly, chromosomal abnormality, fetal demise, planned Cesarean delivery, non-cephalic presentation at delivery and use of multiple forms of analgesia were excluded. The primary outcome was emergency delivery for presumed fetal compromise. Secondary outcomes included delivery characteristics and neonatal outcome. Negative binomial regression analysis was stratified by parity and results are presented according to birth-weight centile, after adjusting for confounding., Results: Among women who received EDA, 13.2% underwent emergency delivery for presumed fetal compromise, compared with 4.1% of women who had no analgesia (relative risk (RR), 3.23 (95% CI, 3.16-3.31)) and 7.0% of women who received alternative analgesia (RR, 1.72 (95% CI, 1.67-1.77)). Independent of birth weight, the RR of presumed fetal compromise after EDA vs no analgesia was higher in parous women (adjusted RR (aRR), 2.15 (95% CI, 2.04-2.27)) compared with nulliparous women (RR, 1.88 (95% CI, 1.84-1.94)). Stratified for parity, the effect of EDA was modified significantly by birth-weight centile (interaction P-value, < 0.001 for nulliparous and 0.004 for parous women). The emergency delivery rate following EDA was highest in those with a birth weight < 5 th centile (25.2% of nulliparous and 16.6% of parous women), falling with each increasing birth-weight centile category up to the 91 st -95 th centile (11.8% of nulliparous and 7.2% of parous women)., Conclusions: Intrapartum EDA is associated with a higher risk of emergency delivery for presumed fetal compromise compared with no analgesia and alternative analgesia, after adjusting for relevant confounding. The highest rate of emergency delivery for presumed fetal compromise was observed at the lowest birth-weight centiles. RRs of emergency delivery for presumed fetal compromise after EDA were modestly but consistently modified by birth-weight centile, supporting the hypothesis that the adverse effects of EDA are exacerbated by reduced placental function. While EDA provides effective pain relief during labor, alternative strategies for pain management may be preferable in pregnancies with a high background risk of fetal compromise. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

Objective: Monochorionic (MC) triplet pregnancies are extremely rare and information on these pregnancies and their complications is limited. We aimed to investigate the risk of early and late pregnancy complications, perinatal outcome and the timing and methods of fetal intervention in these pregnancies., Methods: This was a multicenter retrospective cohort study of MC triamniotic (TA) triplet pregnancies managed in 21 participating centers around the world from 2007 onwards. Data on maternal age, mode of conception, diagnosis of major fetal structural anomalies or aneuploidy, gestational age (GA) at diagnosis of anomalies, twin-to-twin transfusion syndrome (TTTS), twin anemia-polycythemia sequence (TAPS), twin reversed arterial perfusion (TRAP) sequence and or selective fetal growth restriction (sFGR) were retrieved from patient records. Data on antenatal interventions were collected, including data on selective fetal reduction (three to two or three to one), laser surgery and any other active fetal intervention (including amniodrainage). Data on perinatal outcome were collected, including numbers of live birth, intrauterine demise, neonatal death, perinatal death and termination of fetus or pregnancy (TOP). Neonatal data such as GA at birth, birth weight, admission to neonatal intensive care unit and neonatal morbidity were also collected. Perinatal outcomes were assessed according to whether the pregnancy was managed expectantly or underwent fetal intervention., Results: Of an initial cohort of 174 MCTA triplet pregnancies, 11 underwent early TOP, three had an early miscarriage, six were lost to follow-up and one was ongoing at the time of writing. Thus, the study cohort included 153 pregnancies, of which the majority (92.8%) were managed expectantly. The incidence of pregnancy affected by one or more fetal structural abnormality was 13.7% (21/153) and that of TRAP sequence was 5.2% (8/153). The most common antenatal complication related to chorionicity was TTTS, which affected just over one quarter (27.6%; 42/152, after removing a pregnancy with TOP < 24 weeks for fetal anomalies) of the pregnancies, followed by sFGR (16.4%; 25/152), while TAPS (spontaneous or post TTTS with or without laser treatment) occurred in only 4.6% (7/152) of pregnancies. No monochorionicity-related antenatal complication was recorded in 49.3% (75/152) of pregnancies. Survival was apparently associated largely with the development of these complications: there was at least one survivor beyond the neonatal period in 85.1% (57/67) of pregnancies without antenatal complications, in 100% (25/25) of those complicated by sFGR and in 47.6% (20/42) of those complicated by TTTS. The overall rate of preterm birth prior to 28 weeks was 14.5% (18/124) and that prior to 32 weeks' gestation was 49.2% (61/124)., Conclusion: Monochorionicity-related complications, which can impact adversely perinatal outcome, occur in almost half of MCTA triplet pregnancies, creating a challenge with regard to counseling, surveillance and management. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

Objective: The published literature reports mostly on the outcome of twin pregnancies complicated by twin-twin transfusion syndrome (TTTS) without considering whether the pregnancy is also complicated by another pathology, such as selective fetal growth restriction (sFGR). The aim of this systematic review was to report on the outcome of monochorionic diamniotic (MCDA) twin pregnancies undergoing laser surgery for TTTS that were complicated by sFGR and those not complicated by sFGR., Methods: MEDLINE, EMBASE and Cochrane databases were searched. The inclusion criteria were studies reporting on MCDA twin pregnancies with TTTS undergoing laser therapy that were complicated by sFGR and those not complicated by sFGR. The primary outcome was the overall fetal loss following laser surgery, defined as miscarriage and intrauterine death. The secondary outcomes included fetal loss within 24 h after laser surgery, survival at birth, preterm birth (PTB) prior to 32 weeks of gestation, PTB prior to 28 weeks, composite neonatal morbidity, neurological and respiratory morbidity, and survival free from neurological impairment. All outcomes were explored in the overall population of twin pregnancies complicated by sFGR vs those not complicated by sFGR in the setting of TTTS and in the donor and recipient twins separately. Random-effects meta-analysis was used to combine data and the results are reported as pooled odds ratios (OR) with 95% CI., Results: Five studies (1710 MCDA twin pregnancies) were included in the qualitative synthesis and four in the meta-analysis. The overall risk of fetal loss after laser surgery was significantly higher in MCDA twin pregnancies with TTTS complicated by sFGR (20.90% vs 14.42%), with a pooled OR of 1.6 (95% CI, 1.3-1.9) (P < 0.001). The risk of fetal loss was significantly higher in MCDA twin pregnancies with TTTS and sFGR for the donor but not for the recipient twin. The rate of live twins was 79.1% (95% CI, 72.6-84.9%) in TTTS pregnancies with sFGR and 85.6% (95% CI, 81.0-89.6%) in those without sFGR (pooled OR, 0.6 (95% CI, 0.5-0.8)) (P < 0.001). There was no significant difference in the risk of PTB prior to 32 weeks of gestation (P = 0.308) or prior to 28 weeks (P = 0.310). Assessment of short- and long-term morbidity was affected by the small number of cases. There was no significant difference in the risk of composite (P = 0.506) or respiratory (P = 0.531) morbidity between twins complicated by TTTS with vs those without sFGR, while the risk of neurological morbidity was significantly higher in those with TTTS and sFGR (pooled OR, 1.8 (95% CI, 1.1-2.9)) (P = 0.034). The risk of neurological morbidity was significantly higher for the donor twin (pooled OR, 2.4 (95% CI, 1.1-5.2)) (P = 0.029) but not for the recipient twin (P = 0.361). Survival free from neurological impairment was observed in 70.8% (95% CI, 45.0-91.0%) of twin pregnancies with TTTS complicated by sFGR and in 75.8% (95% CI, 51.9-93.3%) of those not complicated by sFGR, with no difference between the two groups., Conclusions: sFGR in MCDA pregnancies with TTTS represents an additional risk factor for fetal loss following laser surgery. The findings of this meta-analysis may be useful for individualized risk assessment of twin pregnancy complicated by TTTS and tailored counseling of the parents prior to laser surgery. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

Objective: To investigate whether arterial stiffness (AS) differs between healthy women and women with gestational diabetes mellitus (GDM) managed by different treatment modalities., Methods: This was a prospective longitudinal cohort study comparing AS in pregnancies complicated by GDM and low-risk controls. AS was assessed by recording aortic pulse-wave velocity (AoPWV), brachial augmentation index (BrAIx) and aortic augmentation index (AoAIx) using the Arteriograph® at four gestational-age windows: 24 + 0 to 27 + 6 weeks (W1); 28 + 0 to 31 + 6 weeks (W2); 32 + 0 to 35 + 6 weeks (W3) and ≥ 36 + 0 weeks (W4). Women with GDM were considered both as a single group and as subgroups stratified by treatment modality. Data were analyzed using a linear mixed model on each AS variable (log-transformed) with group, gestational-age window, maternal age, ethnicity, parity, body mass index, mean arterial pressure and heart rate as fixed effects and individual as a random effect. We compared the group means including relevant contrasts and adjusted the P-values using Bonferroni correction., Results: The study population comprised 155 low-risk controls and 127 women with GDM, of whom 59 were treated with dietary intervention, 47 were treated with metformin only and 21 were treated with metformin + insulin. The two-way interaction term of study group and gestational age was significant for BrAIx and AoAIx (P < 0.001), but there was no evidence that mean AoPWV was different between the study groups (P = 0.729). Women in the control group demonstrated significantly lower BrAIx and AoAIx compared with the combined GDM group at W1-W3, but not at W4. The mean difference in log-transformed BrAIx was -0.37 (95% CI, -0.52 to -0.22), -0.23 (95% CI, -0.35 to -0.12) and -0.29 (95% CI, -0.40 to -0.18) at W1, W2 and W3, respectively. The mean difference in log-transformed AoAIx was -0.49 (95% CI, -0.69 to -0.30), -0.32 (95% CI, -0.47 to -0.18) and -0.38 (95% CI -0.52 to -0.24) at W1, W2 and W3, respectively. Similarly, women in the control group also demonstrated significantly lower BrAIx and AoAIx compared with each of the GDM treatment subgroups (diet, metformin only and metformin + insulin) at W1-W3. The increase in mean BrAIx and AoAIx seen between W2 and W3 in women with GDM treated with dietary management was attenuated in the metformin-only and metformin + insulin groups. However, the mean differences in BrAIx and AoAIx between these treatment groups were not statistically significant at any gestational-age window., Conclusions: Pregnancies complicated by GDM demonstrate significantly higher AS compared with low-risk pregnancies regardless of treatment modality. Our data provide the basis for further investigation into the association of metformin therapy with changes in AS and risk of placenta-mediated diseases. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

Objective: Ventriculomegaly can be associated with long-term neurodevelopmental impairment. Prenatal diagnosis of ventriculomegaly is most commonly made at the routine second-trimester anomaly scan. The value of first-trimester ultrasound has expanded to early diagnosis and screening of fetal abnormalities. The objective of this study was to assess the predictive accuracy of first-trimester choroid-plexus-to-lateral-ventricle-or-head ratios for development of ventriculomegaly at a later gestational age., Methods: This was a case-control study of fetuses with isolated ventriculomegaly diagnosed after 16 weeks' gestation and a control group of normal fetuses (without ventriculomegaly). The exclusion criteria included aneuploidy, genetic syndrome and/or other brain abnormality. Stored two-dimensional first-trimester ultrasound images were analyzed blindly offline and fetal biometry was performed in the axial view of the fetal head. The ratios of choroid plexus area (PA) to lateral ventricular area (VA), choroid plexus length (PL) to lateral ventricular length (VL), choroid plexus diameter (PD) to lateral ventricular diameter (VD) and PA to biparietal diameter (BPD) were measured at 11 + 0 to 13 + 6 weeks' gestation. Intra- and interobserver variability of measurement of these fetal head biometric parameters at 11 + 0 to 13 + 6 weeks' gestation were assessed in 20 normal fetuses using intraclass correlation coefficients with 95% CI. The accuracy of first-trimester biometric measurements for prediction of ventriculomegaly was assessed using the area under the receiver-operating-characteristics curves (AUC)., Results: The analysis included 683 singleton pregnancies, of which 102 fetuses were diagnosed with ventriculomegaly. Ventriculomegaly was mild in 86 (84.3%) cases and severe in the other 16 (15.7%). All first-trimester fetal choroid-plexus-to-lateral-ventricle/head ratios were significantly lower in cases with ventriculomegaly compared with controls (P < 0.001), with good inter- and intraobserver agreement (≥ 0.95) for the majority of the fetal head biometric parameters assessed. On adjusting for crown-rump length, optimism-adjusted AUC values obtained after cross-validation showed that both PL/VL ratio (AUC, 0.87 (95% CI, 0.73-0.98)) and PA/VA ratio (AUC, 0.90 (95% CI, 0.82-0.98)) had good predictive accuracy for severe ventriculomegaly. The PA/BPD ratio (AUC, 0.73 (95% CI, 0.54-0.90)) had modest predictive ability, which was significantly lower compared with that of the PA/VA ratio and PL/VL ratio (P = 0.003 and P = 0.001, respectively). The predictive accuracy of PD/VD ratio was low with an AUC of 0.65 (95% CI, 0.47-0.84). Optimism-adjusted AUC values obtained after cross-validation showed that PA/VA ratio offered the highest predictive accuracy for mild ventriculomegaly with an AUC of 0.84 (95% CI, 0.79-0.89), followed by PL/VL ratio (AUC, 0.82 (95% CI, 0.76-0.88)), PA/BPD ratio (AUC, 0.76 (95% CI, 0.69-0.82)) and PD/VD ratio (AUC, 0.75 (95% CI, 0.67-0.81)). Calibration plots showed that both PA/VA and PL/VL ratios had good calibration., Conclusion: First-trimester prediction of ventriculomegaly using ratios of fetal choroid plexus to lateral ventricle/head appears promising. Future prospective studies are needed to validate the predictive accuracy of these ultrasound markers as a screening tool for ventriculomegaly. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

Objectives: To evaluate the prenatal characteristics of double aortic arch (DAA), assess the relative size of the arches and their growth during pregnancy, describe associated cardiac, extracardiac and chromosomal/genetic abnormalities and review postnatal presentation and clinical outcome., Methods: This was a retrospective cohort study of all fetuses with a confirmed diagnosis of DAA seen in five specialized referral centers in London, UK, between October 2012 and November 2019. Cases were identified from the hospitals' fetal databases. Fetal echocardiographic findings, intracardiac and extracardiac abnormalities, genetic defects, computed tomography (CT) findings and postnatal clinical presentation and outcome were evaluated., Results: A total of 79 fetuses with DAA were included. Of those assessed postnatally, 48.6% had an atretic left aortic arch (LAA), while 5.1% had an atretic LAA at the first fetal scan and were misdiagnosed antenatally with right aortic arch (RAA). The LAA was atretic in 55.8% of those who underwent CT. DAA was an isolated abnormality in 91.1% of cases; 8.9% of patients had an additional intracardiac abnormality and 2.5% had both intra- and extracardiac abnormalities. Among the 52 cases that underwent genetic testing, 11.5% had genetic abnormalities and, specifically, the 22q11 microdeletion was identified in 3.8% of patients. At a median follow-up of 993.5 days, 42.5% of patients had developed symptoms of tracheoesophageal compression (5.5% during the first month after birth) and 56.2% had undergone intervention. Statistical analysis using the χ-square test showed no significant relationship between morphology of DAA (patency of both aortic arches vs atretic LAA) and the need for intervention (P = 0.134), development of vascular ring symptoms (P = 0.350) or evidence of airway compression on CT (P = 0.193)., Conclusions: Most cases of DAA can be diagnosed easily at midgestation, as typically both arches are patent with a dominant RAA at this stage. However, we found that the LAA had become atretic in approximately half of the cases postnatally, supporting the theory of differential growth of the arches during pregnancy. DAA is usually an isolated abnormality; however, thorough assessment is required to exclude associated intra- and extracardiac anomalies and to determine the need for invasive prenatal genetic testing. Postnatally, early clinical assessment is needed and CT scan should be considered, irrespective of the presence of symptoms. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

Objectives: To establish the correlation between phase-rectified signal averaging (PRSA) outputs obtained from a novel self-applicable non-invasive fetal electrocardiography (NIFECG) monitor with those from computerized cardiotocography (cCTG). A secondary objective was to evaluate the potential for remote assessment of fetal wellbeing by determining the relationship between PRSA and short-term variation (STV)., Methods: This was a prospective observational study of women with a singleton pregnancy over 28 + 0 weeks' gestation attending a London teaching hospital for cCTG assessment. Participants underwent concurrent cCTG and NIFECG monitoring for up to 60 min. Averaged accelerative (AAC) and decelerative (ADC) capacities and STV were derived by postprocessing and filtration of signals, generating fully (F) and partially (P) filtered results. Linear correlation and accuracy and precision analysis were performed to assess the relationship between PRSA outputs from cCTG and NIFECG, using varying anchor thresholds, and their association with STV., Results: A total of 306 concurrent cCTG and NIFECG traces were collected from 285 women. F-filtered NIFECG PRSA (eAAC/eADC) results were generated from 65% of traces, whereas cCTG PRSA (cAAC/cADC) outputs were generated from all. Strong correlations were observed between cAAC and F-filtered eAAC (r = 0.879, P < 0.001) and between cADC and F-filtered eADC (r = 0.895, P < 0.001). NIFECG anchor detection decreased significantly with increasing signal loss, and NIFECG PRSA indices showed considerable deviation from those of cCTG when derived from traces in which fewer than 100 anchors were detected. Removing anchor filters from NIFECG traces to generate P-filtered PRSA outputs weakened the correlation (AAC: r = 0.505, P < 0.001; ADC: r = 0.560, P < 0.001). Lowering the anchor threshold to 100 increased the yield of eAAC and eADC outputs to approximately 74%, whilst maintaining strong correlation with cAAC (r = 0.839, P < 0.001) and cADC (r = 0.815, P < 0.001), respectively. Both cAAC and cADC showed a very strong linear relationship with cCTG STV (r = 0.928, P < 0.001 and r = 0.911, P < 0.001, respectively). Similar findings were observed with eAAC (r = 0.825, P < 0.001) and eADC (r = 0.827, P < 0.001)., Conclusions: PRSA appears to be a method of fetal assessment equivalent to STV, but, due to its innate ability to eliminate artifacts, it generates interpretable NIFECG traces with high accuracy at a higher rate. These findings raise the possibility of self-applied at-home or remote fetal heart-rate monitoring with automated reporting, thus enabling increased surveillance in high-risk women without impacting on service demand. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

Objectives: To compare short-term variation (STV) outputs from a novel self-applied non-invasive fetal electrocardiography (NIFECG) device with those obtained on computerized cardiotocography (cCTG). Technological and algorithmic limitations and mitigation strategies were also evaluated., Methods: This was a prospective cohort study of women with a singleton pregnancy over 28 + 0 weeks' gestation attending a tertiary London hospital for cCTG assessment between June 2021 and June 2022. Women underwent concurrent monitoring with both NIFECG and cCTG for up to 1 h. Postprocessing of NIFECG data using various filtering methods produced NIFECG-STV (eSTV) values, which were compared with cCTG-STV (cSTV) outputs. Linear correlation, mean bias, precision and limits of agreement were assessed for STV derived by the different methods of computation and mathematical correction., Results: Overall, 306 concurrent NIFECG and cCTG traces were collected from 285 women. Fully filtered eSTV was correlated very strongly with cSTV (r = 0.911, P < 0.001), but generated results only in 142/306 (46.4%) 1-h traces owing to the removal of traces with lower-quality signals. Partial filtering generated more eSTV data (98.4%), but with a weak correlation with cSTV (r = 0.337, P < 0.001). The difference in STV between the monitors (eSTV - cSTV) increased with signal loss; in traces with > 60% signal loss, the values became highly discrepant. Removal of traces with > 60% signal loss resulted in a stronger correlation with cSTV, while still generating eSTV results for 65% of traces. Correcting these remaining eSTV values for signal loss using linear regression analysis further improved correlation with cSTV (r = 0.839, P < 0.001)., Conclusions: The discrepancy between STV computed by NIFECG and cCTG necessitates signal filtering, exclusion of poor-quality traces and eSTV correction. This study demonstrates that, with such correction, NIFECG is able to produce STV values that are strongly correlated with those of cCTG. This evidence base for NIFECG monitoring and interpretation is a promising step forward in the development of safe and effective at-home fetal heart-rate monitoring. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

Objective: To evaluate outcomes of dichorionic twin pregnancies undergoing early vs late selective termination of pregnancy (ST)., Methods: MEDLINE, EMBASE, CINAHL and the Web of Science databases were searched electronically up to March 2022. The primary outcome of this study was pregnancy loss prior to 24 weeks' gestation. The secondary outcomes included preterm birth (PTB) before 37, 34, and 32 weeks, preterm prelabor rupture of membranes (PPROM), gestational age (GA) at delivery, Cesarean delivery, mean birth weight, 5-min Apgar score < 7, overall neonatal morbidity and neonatal survival. Only prospective or retrospective studies reporting data on the outcome of early (before 18 weeks) vs late (at or after 18 weeks) ST in dichorionic twin pregnancies were considered suitable for inclusion. Quality assessment of the included studies was performed using the Newcastle-Ottawa scale for cohort studies. Random-effects head-to-head meta-analysis was used to analyze the data., Results: Seven studies reporting on 649 dichorionic twin pregnancies were included in this systematic review. The risk of pregnancy loss prior to 24 weeks was significantly lower in dichorionic twin pregnancies undergoing early compared with late ST (1% vs 8%; odds ratio (OR), 0.25 (95% CI, 0.10-0.65); P = 0.004). The risk of PTB was significantly lower in dichorionic twin pregnancies undergoing early compared with late ST when considering PTB before 37 weeks (19% vs 45%; OR, 0.36 (95% CI, 0.23-0.57); P < 0.00001), before 34 weeks (4% vs 19%; OR, 0.24 (95% CI, 0.11-0.54); P = 0.0005) and before 32 weeks (4% vs 20%; OR, 0.21 (95% CI, 0.05-0.85); P = 0.03). The mean birth weight was significantly greater in the early-ST group (mean difference (MD), 392.2 g (95% CI, 59.1-726.7 g); P = 0.02), as was the mean GA at delivery (MD, 2.47 weeks (95% CI, 0.04-4.91 weeks); P = 0.049). There was no significant difference between dichorionic twin pregnancies undergoing early compared with late ST in terms of PPROM (P = 0.27), Cesarean delivery (P = 0.38), 5-min Apgar score < 7 (P = 0.35) and neonatal survival of the non-reduced twin (P = 0.54)., Conclusions: The risk of pregnancy loss prior to 24 weeks and the rate of PTB before 37, 34 and 32 weeks were significantly higher in dichorionic twin pregnancies undergoing late vs early ST, thus highlighting the importance of early diagnosis of fetal anomalies in twin pregnancies. © 2022 International Society of Ultrasound in Obstetrics and Gynecology., (© 2022 International Society of Ultrasound in Obstetrics and Gynecology.)

Objective: Universal screening for cytomegalovirus (CMV) infection in pregnancy is not recommended in most countries. One of the major deterrents is the lack of effective prenatal therapy. The role of valacyclovir therapy in reducing the risk of vertical transmission, symptomatic congenital CMV infection and adverse outcome is controversial. The main aim of this systematic review and meta-analysis was to investigate the safety and effectiveness of prenatal valacyclovir therapy in pregnancies with maternal CMV infection., Methods: MEDLINE, EMBASE and Cochrane databases and ClinicalTrials.gov were searched. The inclusion criteria were pregnancy with confirmed maternal CMV infection, treated or untreated with valacyclovir. The primary outcome was the incidence of congenital CMV infection confirmed by a positive CMV polymerase chain reaction result of the amniotic fluid. The secondary outcomes were symptomatic and asymptomatic infection, perinatal death, termination of pregnancy, anomalies detected on follow-up ultrasound, on fetal magnetic resonance imaging or at birth, severe and mild-to-moderate symptoms due to congenital CMV infection, neurological, visual and hearing symptoms, and adverse events related to valacyclovir. Risk of bias was assessed using the revised Cochrane risk-of-bias tool for randomized trials (RoB 2) or Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool, as appropriate. Head-to-head meta-analyses were used to compare the risk of each of the explored outcomes according to whether pregnancies with maternal CMV infection were treated with prenatal valacyclovir therapy., Results: Eight studies (620 women) were included. Pregnancies treated with valacyclovir had a significantly lower risk of congenital CMV infection compared with those not receiving valacyclovir (three studies; 325 fetuses; pooled odds ratio (OR), 0.37 (95% CI, 0.21-0.64); I 2  = 0%; P < 0.001). When stratifying the analysis according to gestational age at maternal infection, the risk of vertical transmission was significantly lower in pregnancies receiving valacyclovir following first-trimester maternal infection (three studies; 184 fetuses; pooled OR, 0.34 (95% CI, 0.15-0.74); I 2  = 20.9%; P = 0.001), while there was no significant difference between the two groups in those acquiring CMV infection in the periconceptional period or in the third trimester of pregnancy. Only one study reported on the risk of vertical transmission in women infected in the second trimester, demonstrating a lower risk of congenital infection in women taking valacyclovir, although this was based on a small number of cases. Pregnancies treated with valacyclovir therapy had an increased likelihood of asymptomatic congenital CMV infection compared with those not receiving valacyclovir (two studies; 132 fetuses; pooled OR, 2.98 (95% CI, 1.18-7.55); I 2  = 0%; P = 0.021), while there was no significant difference between the two groups in the risk of perinatal death (P = 0.923), termination of pregnancy (P = 0.089), anomalies detected at follow-up imaging assessment during pregnancy or at birth (P = 0.934) and symptoms due to CMV infection in the newborn (P = 0.092). The occurrence of all adverse events in pregnant individuals taking valacyclovir was 3.17% (95% CI, 1.24-5.93%) (six studies; 210 women), with 1.71% (95% CI, 0.41-3.39%) experiencing acute renal failure, which resolved after discontinuation of the drug. On GRADE assessment, the quality of evidence showing that valacyclovir reduced the risk of congenital CMV infection and adverse perinatal outcome was very low., Conclusions: Prenatal valacyclovir administration in pregnancies with maternal CMV infection reduces the risk of congenital CMV infection. Further evidence is needed to elucidate whether valacyclovir can affect the course of infection in the fetus and the risk of symptomatic fetal or neonatal infection. © 2022 International Society of Ultrasound in Obstetrics and Gynecology., (© 2022 International Society of Ultrasound in Obstetrics and Gynecology.)

Objectives: First, to determine the uptake of prenatal exome sequencing (pES) and the diagnostic yield of pathogenic (causative) variants in a UK tertiary fetal medicine unit following the introduction of the NHS England Rapid Exome Sequencing Service for fetal anomalies testing (R21 pathway). Second, to identify how the decision to proceed with pES and identification of a causative variant affect perinatal outcomes, specifically late termination of pregnancy (TOP) at or beyond 22 weeks' gestation., Methods: This was a retrospective cohort study of anomalous fetuses referred to the Liverpool Women's Hospital Fetal Medicine Unit between 1 March 2021 and 28 February 2022. pES was performed as part of the R21 pathway. Trio exome sequencing was performed using an Illumina next-generation sequencing platform assessing coding and splice regions of a panel of 974 prenatally relevant genes and 231 expert reviewed genes. Data on demographics, phenotype, pES result and perinatal outcome were extracted and compared. Descriptive statistics and the χ-square or Fisher's exact test were performed using IBM SPSS version 28.0.1.0., Results: In total, 72 cases were identified and two-thirds of eligible women (n = 48) consented to trio pES. pES was not feasible in one case owing to a low DNA yield and, therefore, was performed in 47 cases. In one-third of cases (n = 24), pES was not proposed or agreed. In 58.3% (14/24) of these cases, this was because invasive testing was declined and, in 41.7% (10/24) of cases, women opted for testing and underwent chromosomal microarray analysis only. The diagnostic yield of pES was 23.4% (11/47). There was no overall difference in the proportion of women who decided to have late TOP in the group in which pES was agreed compared with the group in which pES was not proposed or agreed (25.0% (12/48) vs 25.0% (6/24); P = 1.0). However, the decision to have late TOP was significantly more frequent when a causative variant was detected compared with when pES was uninformative (63.6% (7/11) vs 13.9% (5/36); P < 0.0009). The median turnaround time for results was longer in cases in which a causative variant was identified than in those in which pES was uninformative (22 days (interquartile range (IQR), 19-34) days vs 14 days (IQR, 10-15 days); P < 0.0001)., Conclusions: This study demonstrates the potential impact of identification of a causative variant by pES on decision to have late TOP. As the R21 pathway continues to evolve, we urge clinicians and policymakers to consider introducing earlier screening for anomalies, developing robust guidance for late TOP and ensuring optimized support for couples. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

Objective: To identify the clinical characteristics and patterns of ultrasound use amongst pregnancies with an antenatally unidentified small-for-gestational-age (SGA) fetus, compared with those in which SGA is identified, to understand how to design interventions that improve antenatal SGA identification., Methods: This was a prospective cohort study of singleton, non-anomalous SGA (birth weight < 10 th centile) neonates born after 24 + 0 gestational weeks at 13 UK sites, recruited for the baseline period and control arm of the DESiGN trial. Pregnancy with antenatally unidentified SGA was defined if there was no scan or if the final scan showed estimated fetal weight (EFW) at the 10 th centile or above. Identified SGA was defined if EFW was below the 10 th centile at the last scan. Maternal and fetal sociodemographic and clinical characteristics were studied for associations with unidentified SGA using unadjusted and adjusted logistic regression models. Ultrasound parameters (gestational age at first growth scan, number and frequency of ultrasound scans) were described, stratified by presence of indication for serial ultrasound. Associations of unidentified SGA with absolute centile and percentage weight difference between the last scan and birth were also studied on unadjusted and adjusted logistic regression, according to time between the last scan and birth., Results: Of the 15 784 SGA babies included, SGA was not identified antenatally in 78.7% of cases. Of pregnancies with unidentified SGA, 47.1% had no recorded growth scan. Amongst 9410 pregnancies with complete data on key maternal comorbidities and antenatal complications, the risk of unidentified SGA was lower for women with any indication for serial scans (adjusted odds ratio (aOR), 0.56 (95% CI, 0.49-0.64)), for Asian compared with white women (aOR, 0.80 (95% CI, 0.69-0.93)) and for those with non-cephalic presentation at birth (aOR, 0.58 (95% CI, 0.46-0.73)). The risk of unidentified SGA was highest among women with a body mass index (BMI) of 25.0-29.9 kg/m 2 (aOR, 1.15 (95% CI, 1.01-1.32)) and lowest in those with underweight BMI (aOR, 0.61 (95% CI, 0.48-0.76)) compared to women with BMI of 18.5-24.9 kg/m 2 . Compared to women with identified SGA, those with unidentified SGA had fetuses of higher SGA birth-weight centile (adjusted odds for unidentified SGA increased by 1.21 (95% CI, 1.18-1.23) per one-centile increase between the 0 th and 10 th centiles). Duration between the last scan and birth increased with advancing gestation in pregnancies with unidentified SGA. SGA babies born within a week of the last growth scan had a mean difference between EFW and birth-weight centiles of 19.5 (SD, 13.8) centiles for the unidentified-SGA group and 0.2 (SD, 3.3) centiles for the identified-SGA group (adjusted mean difference between groups, 19.0 (95% CI, 17.8-20.1) centiles)., Conclusions: Unidentified SGA was more common amongst women without an indication for serial ultrasound, and in those with cephalic presentation at birth, BMI of 25.0-29.9 kg/m 2 and less severe SGA. Ultrasound EFW was overestimated in women with unidentified SGA. This demonstrates the importance of improving the accuracy of SGA screening strategies in low-risk populations and continuing performance of ultrasound scans for term pregnancies. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

Objective: To investigate the role of fetal brain magnetic resonance imaging (MRI) in detecting associated anomalies in fetuses with congenital cytomegalovirus (CMV) infection and normal neurosonography., Methods: This was a multicenter, retrospective cohort study of patients examined between 2012 and 2021 in 11 referral fetal medicine centers in Italy. Inclusion criteria were fetuses with congenital CMV infection diagnosed by polymerase chain reaction analysis of amniotic fluid, pregnancies that underwent detailed multiplanar ultrasound assessment of the fetal brain as recommended by the International Society of Ultrasound in Obstetrics and Gynecology, maternal age ≥ 18 years, normal fetal karyotype and MRI performed within 3 weeks after the last ultrasound examination. The primary outcome was the rate of central nervous system (CNS) anomalies detected exclusively on MRI and confirmed after birth or autopsy in fetuses with a prenatal diagnosis of congenital CMV infection and normal neurosonography at diagnosis. Additional CNS anomalies were classified into anomalies of the ventricular and the periventricular zone, intracranial calcifications in the basal ganglia or germinal matrix, destructive encephalopathy in the white matter, malformations of cortical development, midline anomalies, posterior fossa anomalies and complex brain anomalies. We evaluated the relationship between the incidence of structural CNS malformations diagnosed exclusively on fetal MRI and a number of maternal and gestational characteristics. Univariate and multivariate logistic regression analyses were used to identify and adjust for potential independent predictors of the MRI diagnosis of fetal anomalies., Results: The analysis included 95 fetuses with a prenatal diagnosis of congenital CMV infection and normal neurosonography referred for prenatal MRI. The rate of structural anomalies detected exclusively at fetal MRI was 10.5% (10/95). When considering the type of anomaly, malformations of cortical development were detected on MRI in 40.0% (4/10) of fetuses, destructive encephalopathy in 20.0% (2/10), intracranial calcifications in the germinal matrix in 10.0% (1/10) and complex CNS anomalies in 30.0% (3/10). On multivariate logistic regression analysis, only CMV viral load in the amniotic fluid, expressed as a continuous variable (odds ratio (OR), 1.16 (95% CI, 1.02-1.21); P = 0.02) or categorical variable (> 100 000 copies/mL) (OR, 12.0 (95% CI, 1.2-124.7); P = 0.04), was independently associated with the likelihood of detecting fetal anomalies on MRI. Associated anomalies were detected exclusively at birth and missed by both prenatal neurosonography and fetal MRI in 3.8% (3/80) of fetuses with congenital CMV infection., Conclusions: Fetal brain MRI can detect additional anomalies in a significant proportion of fetuses with congenital CMV infection and negative neurosonography. Viral load in the amniotic fluid was an independent predictor of the risk of associated anomalies in these fetuses. The findings of this study support a longitudinal evaluation using fetal MRI in congenital CMV infection, even in cases with negative neurosonography at diagnosis. © 2022 International Society of Ultrasound in Obstetrics and Gynecology., (© 2022 International Society of Ultrasound in Obstetrics and Gynecology.)

Introduction: There are few randomized clinical trials in vascular cognitive impairment (VCI). This trial tested the hypothesis that the PDE5 inhibitor tadalafil, a widely used vasodilator, increases cerebral blood flow (CBF) in older people with symptomatic small vessel disease, the main cause of VCI., Methods: In a double-blind, placebo-controlled, cross-over trial, participants received tadalafil (20 mg) and placebo on two visits ≥7 days apart (randomized to order of treatment). The primary endpoint, change in subcortical CBF, was measured by arterial spin labelling., Results: Tadalafil increased CBF non-significantly in all subcortical areas (N = 55, age: 66.8 (8.6) years) with greatest treatment effect within white matter hyperintensities (+9.8%, P = .0960). There were incidental treatment effects on systolic and diastolic blood pressure (-7.8, -4.9 mmHg; P < .001). No serious adverse events were observed., Discussion: This trial did not identify a significant treatment effect of single-administration tadalafil on subcortical CBF. To detect treatment effects may require different dosing regimens., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Objective: To ascertain maternal and perinatal outcomes of monochorionic twin pregnancies complicated by twin-twin transfusion syndrome (TTTS) treated with the Solomon technique compared with selective fetoscopic laser photocoagulation (SFLP) of placental anastomoses., Methods: MEDLINE, EMBASE and The Cochrane Library were searched to identify relevant studies. The outcomes observed were perinatal loss and survival, preterm prelabor rupture of membranes (PPROM), preterm birth (PTB), gestational age (GA) at delivery, interval between laser treatment and delivery, maternal bleeding, septostomy or chorioamniotic separation, placental abruption, twin anemia-polycythemia sequence (TAPS), recurrence of TTTS, neonatal morbidity and neurological morbidity. Random-effects head-to-head meta-analyses were used to analyze the data. Pooled odds ratios (OR) and mean differences (MD) and their 95% CIs were calculated., Results: Nine studies were included in the systematic review. There was generally no difference in the main maternal and pregnancy characteristics between pregnancies treated using the Solomon technique and those treated using SFLP of placental anastomoses. The risks of fetal loss (pooled OR, 0.69 (95% CI, 0.50-0.95); P = 0.023), neonatal death (pooled OR, 0.37 (95% CI, 0.16-0.84); P = 0.018) and perinatal loss (pooled OR, 0.56 (95% CI, 0.38-0.83); P = 0.004) were significantly lower in pregnancies treated using the Solomon technique than in those treated with SFLP. Likewise, pregnancies treated using the Solomon technique had a significantly higher chance of survival of at least one twin (pooled OR, 2.31 (95% CI, 1.03-5.19); P = 0.004) and double survival (pooled OR, 2.18 (95% CI, 1.29-3.70); P = 0.001). There was no difference in the risk of PPROM (P = 0.603), PPROM within 10 days from laser surgery (P = 0.982), PTB (P = 0.207), maternal bleeding (P = 0.219), septostomy or chorioamniotic separation (P = 0.224) or chorioamnionitis (P = 0.135) between the two groups, while the risk of placental abruption was higher in pregnancies treated using the Solomon technique (pooled OR, 2.90 (95% CI, 1.55-5.44); P = 0.001). In the Solomon technique group, pregnancies delivered at a significantly earlier GA than did those treated with SFLP (pooled MD, -0.625 weeks (95% CI, -0.90 to -0.35 weeks); P < 0.001), while there was no difference in the interval between laser treatment and delivery (P = 0.589). The rate of recurrence of TTTS was significantly lower in pregnancies undergoing the Solomon technique (pooled OR, 0.43 (95% CI, 0.22-0.81); P < 0.001), while there was no difference in the risk of TAPS between the two groups (P = 0.792). Finally, there was no difference in the overall risk of neonatal morbidity (P = 0.382) or neurological morbidity (P = 0.247) between the two groups., Conclusions: Monochorionic twin pregnancies complicated by TTTS undergoing laser treatment using the Solomon technique had a significantly higher survival rate and lower recurrence rate of TTTS but were associated with an increased risk of placental abruption and earlier GA at delivery compared to those treated with SFLP. © 2022 International Society of Ultrasound in Obstetrics and Gynecology., (© 2022 International Society of Ultrasound in Obstetrics and Gynecology.)

Objectives: To describe the associated cardiac and extracardiac findings and estimate the prevalence of single left superior vena cava (LSVC) among fetuses referred for fetal echocardiography., Methods: This was a retrospective case series of fetuses diagnosed with situs solitus and single LSVC at the Brompton Centre for Fetal Cardiology, London, UK, from October 2006 to December 2020. Prenatal and postnatal outcome data were collected. Prenatal diagnosis was based on abnormal vessel alignment at the three-vessel view and/or three-vessel-and-trachea view, showing a vessel to the left of the pulmonary artery (i.e. the LSVC) and absence of the usual vessel to the right of the ascending aorta (i.e. the right superior vena cava), and further visualization of the LSVC draining into the coronary sinus., Results: Of 19 968 fetal echocardiograms performed during the study period, 34 cases of single LSVC were identified (a prevalence of 0.17%). Of these, 32 pregnancies had a live birth, one was lost to follow-up and one resulted in intrauterine demise. Single LSVC was isolated in 79.4% of cases. No major congenital heart disease was identified. One fetus showed mild isthmus hypoplasia, with no aortic coarctation postnatally. Two fetuses had umbilical vessel abnormalities. A genetic abnormality was found in one case (15q24.1-q24.2 deletion)., Conclusions: Antenatal diagnosis of single LSVC in the setting of situs solitus is usually a benign isolated finding. Nevertheless, investigation of other cardiac, extracardiac and genetic disorders should be considered. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

Objective: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in pregnancy is associated with increased risk of adverse maternal and perinatal outcomes. Vaccines are highly effective at preventing severe coronavirus disease 2019 (COVID-19), but there are limited data on COVID-19 vaccines in pregnancy. This study aimed to investigate the reactogenicity and immunogenicity of COVID-19 vaccines in pregnant women when administered according to the 12-week-interval dosing schedule recommended in the UK., Methods: This was a cohort study of pregnant women receiving COVID-19 vaccination between April and September 2021. The outcomes were immunogenicity and reactogenicity after COVID-19 vaccination. Pregnant women were recruited by phone, e-mail and/or text and were vaccinated according to vaccine availability at their local vaccination center. For immunogenicity assessment, blood samples were taken at specific timepoints after each dose to evaluate nucleocapsid protein (N) and spike protein (S) antibody titers. The comparator group comprised non-pregnant female healthcare workers in the same age group who were vaccinated as part of the national immunization program in a contemporaneous longitudinal cohort study. Longitudinal changes in serum antibody titers and association with pregnancy status were assessed using a two-step regression approach. Reactogenicity assessment in pregnant women was undertaken using an online questionnaire. The comparator group comprised non-pregnant women aged 18-49 years who had received two vaccine doses in primary care. The association of pregnancy status with reactogenicity was assessed using logistic regression analysis., Results: Overall, 67 pregnant women, of whom 66 had received a mRNA vaccine, and 79 non-pregnant women, of whom 50 had received a mRNA vaccine, were included in the immunogenicity study. Most (61.2%) pregnant women received their first vaccine dose in the third trimester, while 3.0% received it in the first trimester and 35.8% in the second trimester. SARS-CoV-2 S-antibody geometric mean concentrations after mRNA vaccination were not significantly different at 2-6 weeks after the first dose but were significantly lower at 2-6 weeks after the second dose in infection-naïve pregnant compared with non-pregnant women. In pregnant women, prior infection was associated with higher antibody levels at 2-6 weeks after the second vaccine dose. Reactogenicity analysis included 108 pregnant women and 116 non-pregnant women. After the first dose, tiredness and chills were reported less commonly in pregnant compared with non-pregnant women (P = 0.043 and P = 0.029, respectively). After the second dose, feeling generally unwell was reported less commonly (P = 0.046) in pregnant compared with non-pregnant women., Conclusions: Using an extended 12-week interval between vaccine doses, antibody responses after two doses of mRNA COVID-19 vaccine were found to be lower in pregnant compared with non-pregnant women. Strong antibody responses were achieved after one dose in previously infected women, regardless of pregnancy status. Pregnant women reported fewer adverse events after both the first and second dose of vaccine. These findings should now be addressed in larger controlled studies. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

Objective: To determine whether the Growth Assessment Protocol (GAP), as implemented in the DESiGN trial, is cost-effective in terms of antenatal detection of small-for-gestational-age (SGA) neonate, when compared with standard care., Methods: This was an incremental cost-effectiveness analysis undertaken from the perspective of a UK National Health Service hospital provider. Thirteen maternity units from England, UK, were recruited to the DESiGN (DEtection of Small for GestatioNal age fetus) trial, a cluster randomized controlled trial. Singleton, non-anomalous pregnancies which delivered after 24 + 0 gestational weeks between November 2015 and February 2019 were analyzed. Probabilistic decision modeling using clinical trial data was undertaken. The main outcomes of the study were the expected incremental cost, the additional number of SGA neonates identified antenatally and the incremental cost-effectiveness ratio (ICER) (cost per additional SGA neonate identified) of implementing GAP. Secondary analysis focused on the ICER per infant quality-adjusted life year (QALY) gained., Results: The expected incremental cost (including hospital care and implementation costs) of GAP over standard care was £34 559 per 1000 births, with a 68% probability that implementation of GAP would be associated with increased costs to sustain program delivery. GAP identified an additional 1.77 SGA neonates per 1000 births (55% probability of it being more clinically effective). The ICER for GAP was £19 525 per additional SGA neonate identified, with a 44% probability that GAP would both increase cost and identify more SGA neonates compared with standard care. The probability of GAP being the dominant clinical strategy was low (11%). The expected incremental cost per infant QALY gained ranged from £68 242 to £545 940, depending on assumptions regarding the QALY value of detection of SGA., Conclusion: The economic case for replacing standard care with GAP is weak based on the analysis reported in our study. However, this conclusion should be viewed taking into account that cost-effectiveness analyses are always limited by the assumptions made. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)