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Charlotte Kvist Ekelund,1 Tine Iskov Kopp,2 Ann Tabor,1 Olav Bjørn Petersen3 1Department of Obstetrics, Center of Fetal Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; 2Registry Support Centre (East) – Epidemiology and Biostatistics, Research Centre for Prevention and Health, Glostrup, Denmark; 3Fetal Medicine Unit, Aarhus University Hospital, Aarhus Nord, Denmark Aim: The aim of this study is to set up a database in order to monitor the detection rates and false-positive rates of first-trimester screening for chromosomal abnormalities and prenatal detection rates of fetal malformations in Denmark. Study population: Pregnant women with a first or second trimester ultrasound scan performed at all public hospitals in Denmark are registered in the database. Main variables/descriptive data: Data on maternal characteristics, ultrasonic, and biochemical variables are continuously sent from the fetal medicine units' Astraia databases to the central database via web service. Information about outcome of pregnancy (miscarriage, termination, live birth, or stillbirth) is received from the National Patient Register and National Birth Register and linked via the Danish unique personal registration number. Furthermore, results of all pre- and postnatal chromosome analyses are sent to the database. Conclusion: It has been possible to establish a fetal medicine database, which monitors first-trimester screening for chromosomal abnormalities and second-trimester screening for major fetal malformations with the input from already collected data. The database is valuable to assess the performance at a regional level and to compare Danish performance with international results at a national level. Keywords: prenatal screening, nuchal translucency, fetal malformations, chromosomal abnormalities

Lars H Pedersen,1,2 Olav B Petersen,1,2 Mette Nørgaard,3 Charlotte Ekelund,4 Lars Pedersen,3 Ann Tabor,4 Henrik T Sørensen3 1Department of Clinical Medicine, Aarhus University, 2Department of Obstetrics and Gynecology, 3Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, 4Department of Fetal Medicine, Rigshospitalet, Copenhagen, Denmark Abstract: A linked population-based database is being created in Denmark for research on drug safety during pregnancy. It combines information from the Danish National Health Service Prescription Database (with information on all prescriptions reimbursed in Denmark since 2004), the Danish Fetal Medicine Database, the Danish National Registry of Patients, and the Medical Birth Registry. The new linked database will provide validated information on malformations diagnosed both prenatally and postnatally. The cohort from 2008 to 2014 will comprise 589,000 pregnancies with information on 424,000 pregnancies resulting in live-born children, ~420,000 pregnancies undergoing prenatal ultrasound scans, 65,000 miscarriages, and 92,000 terminations. It will be updated yearly with information on ~80,000 pregnancies. The cohort will enable identification of drug exposures associated with severe malformations, not only based on malformations diagnosed after birth but also including those having led to termination of pregnancy or miscarriage. Such combined data will provide a unique source of information for research on the safety of medications used during pregnancy. Keywords: malformations, teratology, therapeutic drug monitoring, epidemiological methods, registries

Maria Rasmussen,1 Morten Smærup Olsen,2 Lone Sunde,1,3 Lars Pedersen,2 Olav Bjørn Petersen4 1Department of Clinical Genetics, Aarhus University Hospital, Skejby, 2Department of Clinical Epidemiology, Aarhus University Hospital, Skejby, 3Department of Biomedicine, Aarhus University, Aarhus, 4Department of Gynecology and Obstetrics, Aarhus University Hospital, Skejby, Denmark Objective: Restricting studies of severe congenital malformations to live-born children may introduce substantial bias. In this study, we estimated the attendance to the second-trimester fetal malformation screening program. We also estimated the positive predictive value (PPV) of prenatally assigned International Classification of Disease-10 diagnoses recorded in the Danish National Patient Registry (DNPR) and the completeness of case registration. We used kidney anomalies as an example. Methods: We identified the proportion of all Danish live-born children from January 1, 2007 to December 31, 2012, who were scanned during the second trimester using the DNPR and the Civil Registration System. Details of all fetuses with specific kidney anomaly diagnoses according to the DNPR were retrieved. The PPV was estimated using the nationwide Astraia database of pregnancy medical charts or traditional medical charts, as gold standard. The completeness was assessed using the total number of cases estimated by the capture–recapture method. Results: Of 372,263 live born infants, 97.3% were scanned during the second trimester. We identified 172 fetuses in the DNPR. Of these, 149 had kidney anomalies according to Astraia or medical chart review, corresponding to a PPV of 87% (95% CI: 81%–91%). The estimated completeness was 43% (95% CI: 38%–49%) for the DNPR and 75% (95% CI: 70%–79%) for Astraia. Conclusion: Almost all live-born children were scanned during the second trimester in Denmark. However, low completeness may hamper the use of the DNPR for studies of prenatally detected severe malformations, and use of the Astraia database may preferably be considered. Keywords: Danish National Patient Registry, International Classification of Disease, validation study, prenatal diagnosis, Astraia, kidney anomaly, Danish Fetal Medicine Database

Objective To evaluate the influence of chorionicity on outcome in twin pregnancies with two live fetuses at the nuchal translucency scan in the first trimester. Design Population-based register study. Setting Denmark. Population A cohort of 3621 twin pregnancies, 84.3% dichorionic ( DC) pregnancies and 15.7% monochorionic ( MC) pregnancies (15% diamniotic [ MCDA] and 0.7% monoamniotic [ MCMA]). Methods A cohort study based on data collected from the Danish Fetal Medicine Database from July 2008 to July 2011. Main outcome measures Fetal loss rate before week 22, intrauterine death rate from week 22 to birth, and neonatal mortality. Results Significantly more DC than MC pregnancies resulted in at least one live born infant-98.2% versus 92.3% in MCDA ( P < 0.05) and 66.7% in MCMA pregnancies ( P < 0.05). The rates of spontaneous loss of both fetuses before week 22 were 0.9, 2.4, and 20.8% for DC, MCDA and MCMA twins, respectively ( P < 0.05). The rate of intrauterine death of one fetus after week 22 was higher in MCDA twins than DC twins 1.7% versus 0.6% ( P < 0.05). We found no significant difference in the rate of neonatal death. Conclusions The risk of spontaneous loss of both fetuses before week 22 of gestation was significantly higher in MCMA and MCDA pregnancies than in DC pregnancies, and significantly higher in MCMA pregnancies than in MCDA pregnancies. After week 22 the risk of loss of one fetus after week 22 was significantly higher in MCDA pregnancies than in DC pregnancies. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The aim of this study was to investigate gestational age-dependent effects of racial origin, smoking status and mode of conception on maternal serum levels of free [beta]-human chorionic gonadotropin ([beta]-hCG) and pregnancy-associated plasma protein-A (PAPP-A) at 7-14 weeks' gestation. METHODS: This was an analysis of data from prospective first-trimester combined screening for aneuploidies in singleton pregnancies, with [beta]-hCG and PAPP-A measured at 7 + 1 to 14 + 3 weeks' gestation. We included 27,908 pregnancies from three centers in the U.K. and 125,461 pregnancies from 22 centers in Denmark, all with known normal fetal karyotype or resulting in the birth of a phenotypically normal neonate. Multiple regression modelling of log10 -transformed marker concentrations was used to produce log10 multiple of the median (MoM) values for free [beta]-hCG and PAPP-A and to examine pregnancy characteristics that have significant effects on marker concentrations. RESULTS: Serum free [beta]-hCG and PAPP-A concentrations were significantly affected by gestational age, maternal weight, racial origin, parity, smoking and mode of conception. There were significant gestational age-dependent effects attributed to Afro-Caribbean race, smoking and conception through in-vitro fertilization (IVF) on PAPP-A and free [beta]-hCG levels. In women of Afro-Caribbean race there was a weekly increase in PAPP-A of 5.3% and in free [beta]-hCG of 1.8%. In smokers there was a weekly decrease in PAPP-A of 2.4% and in free [beta]-hCG of 1.6%. In cases of IVF conceptions there was a weekly increase in PAPP-A of 4.5% and in free [beta]-hCG of 4.6%. CONCLUSIONS: Serum free [beta]-hCG and PAPP-A concentrations at 7-14 weeks' gestation are affected by several pregnancy characteristics. The effects of Afro-Caribbean race, smoking and IVF conception change with gestational age. [ABSTRACT FROM AUTHOR]

Objective: To prospectively evaluate the performance of first-trimester combined screening for trisomy 21 using the biochemical markers pregnancy-associated plasma protein-A (PAPP-A) and free beta-human chorionic gonadotropin (free β-hCG) obtained before and at the time of the nuchal translucency (NT) scan.Methods: Three fetal medicine departments in Denmark participated in the study. Screening for trisomy 21 was set up as a two-step approach with blood sampling performed before the NT scan (early sample) and again at the time of the NT scan (late sample). PAPP-A and free β-hCG were measured on both the early and late samples. Age-standardized detection and false-positive rates for different screening protocols were calculated.Results: We collected two blood samples in 27 pregnancies affected by trisomy 21 and in 3891 control pregnancies. The early samples were taken between gestational ages 8 + 0 and 13 + 6 weeks, and the late samples between 11 + 3 and 14 + 6 weeks. The median interval between the samples was 17 (range, 1-40) days. We found a significantly better estimated screening performance when using early sampling vs late sampling (P < 0.05). With a risk cut-off of 1 in 100, at the time of the risk assessment the estimated detection and false-positive rates when using the early sample were 91% (95% CI, 81-98%) and 1.6% (95% CI, 1.3-2.0%), respectively. For fixed false-positive rates the highest detection rates were achieved using both blood samples. When comparing early sampling vs double sampling there was no significant difference in screening performance.Conclusion: In combined first-trimester screening for trisomy 21, use of early sampling with measurement of PAPP-A and free β-hCG before the time of the NT scan can optimize screening performance. Using maternal serum markers obtained both before and at the time of the NT scan has the potential to further improve performance, but larger studies are needed to confirm this potential. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To investigate whether chromosomally normal fetuses with a nuchal translucency (NT) >= 99th percentile(3.5 mm) in the first trimester have an increased risk of delayed development at 2 years of age. METHODS: The study included children of women from 10 Danish hospitals who had fetal NT either >= 99th percentile (Group 1) or <95th percentile (Group 2) in the first trimester. The groups were matched by gender,gestational age at birth and maternal age. There were twice as many children in Group 2 as in Group 1. Follow-up was conducted at 2 years of age, infant development being assessed by the 'Ages and Stages Questionnaire'. The cutoff value for delayed development was defined as the 5th percentile from the first 100 questionnaires from Group 2. RESULTS: In a 1-year period 202 of 33 266 fetuses (0.6%)had NT >= 3.5 mm. Of these, 99 (49.0%) were liveborn with normal karyotype and normal ultrasound findings during pregnancy. The response rate to the ASQ was 83.3% in Group 1 and 71.4% in Group 2. A low ASQ score was found in 1.3% (1/80) and 4.4% (6/137)in Groups 1 and 2, respectively (P = 0.265), but no difference was found in the mean ASQ score between the two groups (P = 0.160). CONCLUSION: Fetuses with NT >= 99th percentile, normal karyotype and normal ultrasound findings during pregnancy had no increased risk of developmental delay at 2 years of age compared with fetuses with normal NT(<95th percentile). [ABSTRACT FROM AUTHOR]

OBJECTIVE: To evaluate early fetal growth and the biomarkers, pregnancy-associated plasma protein A (PAPP-A) and free [beta]-human chorionic gonadotrophin ([beta]-hCG), in relation to preterm delivery. METHODS: A cohort study of 9450 singleton pregnant women who attended the prenatal screening program at Aarhus University Hospital between January 2005 and December 2007, was conducted. PAPP-A and free [beta]-hCG were measured in the first trimester. Early fetal growth was estimated by (GA(20)- GA(12))/Days(calendar), where GA(12) reflects the gestational age in days calculated from the crown-rump length at a 12-week scan, GA(20) reflects the gestational age in days calculated from the biparietal diameter at a 20-week scan, and Days(calendar) is the number of calendar days between the two scans. RESULTS: Low PAPP-A and low free [beta]-hCG were significantly associated with preterm delivery (<37 weeks). The association was even stronger when low PAPP-A and slow early fetal growth were combined, resulting in an adjusted odds ratio of 3.8 (95% CI, 1.6-8.7). Fast early fetal growth, but neither high PAPP-A nor high free [beta]-hCG, was significantly associated with preterm delivery. CONCLUSION: Two different biological pathways leading to spontaneous preterm delivery are suggested: fast early fetal growth and the combination of low PAPP-A and slow early fetal growth. Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Advances in haemolytic disease of the fetus and newborn have led to numerous treatment options. We report practice variations in the management and outcomes of haemolytic disease of the fetus and newborn in at-risk pregnancies., Methods: In this international, retrospective, observational cohort study, data from cases with moderate or severe haemolytic disease of the fetus and newborn were retrieved from 31 centres in 22 countries. Eligible participants had pregnancies with haemolytic disease of the fetus that led to fetal death at 16 + 0 weeks or later, those treated antenatally with intrauterine transfusion or intravenous immunoglobulins, or neonates without antenatal treatment who were treated with intensive phototherapy, exchange transfusion, or red blood cell transfusions. All patients had confirmed maternal alloantibodies and an antigen-positive fetus incompatible with the maternal alloantibody. Patients with ABO-incompatibility only were excluded. We assessed serological diagnostics and referrals, antenatal treatment and timing, complications, delivery route, and gestational age at birth. Outcomes were analysed in all eligible participants who had complete data available., Findings: 2443 pregnancies with haemolytic disease of the fetus and newborn treated between Jan 1, 2006, and July 1, 2021, were shared by the centres and analysed between Dec 1, 2021, and March 1, 2023. 23 pregnancies were excluded due to missing information and we included 2420 for further analysis. 1764 (72·9%) of 2420 pregnancies were affected by D-antibodies. 95 (3·9%) of 2420 pregnancies resulted in fetal death. Of the 2325 liveborn neonates, 1349 (58·1%) received any form of antenatal treatment and 976 (41·9%) were only treated postnatally. Median gestational age at referral was 20·4 weeks (IQR 14·9-28·0) and ranged between medians of 10·0 and 26·3 weeks between centres. Severe hydrops at first intrauterine transfusion was present in 185 (14·5%) of 1276 pregnancies, with proportions ranging between 0 and 42% between centres. A median of two intrauterine transfusions (IQR 1-4) were done per pregnancy. The fetal access sites used in intrauterine transfusions varied widely between centres. Non-lethal complications in intrauterine transfusions by transfusion site occurred at a lower rate in intrahepatic approaches (2·0%, 95% CI 1·1-3·3) than in placental insertion (6·9%, 5·8-8·0) and free loop (13·3%, 8·9-18·9). The use and indication for intravenous immunoglobulin administration varied widely. Neonates with intrauterine transfusion were born at a median gestational age of 35·6 weeks (IQR 34·0-36·7), ranging between medians of 33·2 and 37·3 weeks between centres, while neonates without antenatal treatment were born at a median gestational age of 37·3 (IQR 36·3-38·1), ranging between medians of 34·9 and 38·9 weeks between centres., Interpretation: We found considerable variation in antenatal management and outcomes in haemolytic disease of the fetus and newborn between sites in different countries. Our study shows the capacity of the field to gather valuable data on a rare disease and to optimise care., Funding: None., Competing Interests: Declaration of interests DPdW is doing a PhD programme partly funded by Momenta Pharmaceuticals, which was acquired by Johnson & Johnson, and is an investigator for a phase 2 trial (NCT03842189) of a new drug for the treatment of haemolytic disease of the fetus and newborn. EL is a sub-investigator for a phase 2 trial (NCT03842189) of a new drug for the treatment of haemolytic disease of the fetus and newborn, which is sponsored by Janssen Pharmaceuticals. RD reports paid lectures and participation in studies for Janssen Pharmaceuticals. PM received payment for a lecture from CSL Behrin. PM and J-MJ reports participation in an advisory board for haemolytic disease of the fetus and newborn of Janssen Pharmaceuticals in December, 2023, and both report participation in a phase 3 trial (NCT05912517) of a new drug for the treatment of haemolytic disease of the fetus and newborn, which is sponsored by Janssen Pharmaceuticals. ET is the principal investigator for Janssen-sponsored trials Unity and Clarity in Sweden and an advisory Board Member and Steering Committee member for Janssen Pharmaceutical on haemolytic disease of the fetus and newborn and FNAIT programmes. TPS is a member of the board of the International Society of The Fetus as a Patient and member of the expert committee for Gynaecology and Obstetrics at Ministry of Health, Republic of Slovenia. EJTV is the principal investigator for a phase 2 trial (NCT03842189) and phase 3 trial (NCT05912517) of a new drug for the treatment of haemolytic disease of the fetus and newborn, which is sponsored by Janssen Pharmaceuticals. All other authors report no competing interests or financial disclosures., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Objective: To assess the validity of the Fetal Medicine Foundation (FMF) chorionicity-specific models for fetal growth in twin pregnancy., Methods: This was an external validation study of the FMF models using a nationwide Danish cohort of twin pregnancies. The cohort included all dichorionic (DC) and monochorionic diamniotic (MCDA) twin pregnancies with an estimated delivery date between 2008 and 2018, which satisfied the following inclusion criteria: two live fetuses at the first-trimester ultrasound scan (11-14 weeks' gestation); biometric measurements available for the calculation of estimated fetal weight (EFW) using the Hadlock-3 formula; and delivery of two liveborn infants. Validation involved assessing the distributional properties of the models and estimating the mean EFW Z-score deviations. Additionally, the models were applied to pregnancies that delivered preterm and attended non-scheduled visits (complicated pregnancies)., Results: Overall, 8542 DC and 1675 MCDA twin pregnancies met the inclusion criteria. In DC twins, 17 084 fetuses were evaluated at a total of 95 346 ultrasound scans, of which 44.5% were performed at scheduled visits in pregnancies carried to 37 + 0 weeks or later. The median number of growth scans per DC twin fetus from 20 + 0 weeks onwards was four. The model showed good agreement with the validation cohort for scheduled visits in DC twins delivered at 37 + 0 weeks or later (mean EFW Z-score, -0.14 ± 1.05). In MCDA twins, 3350 fetuses underwent 31 632 eligible ultrasound scans, of which 59.5% were performed at scheduled visits in pregnancies carried to 36 + 0 weeks or later. The median number of growth scans per MCDA twin fetus from 16 + 0 weeks onwards was 10. The model showed favorable agreement with the validation cohort for scheduled visits in MCDA twins delivered at 36 + 0 weeks or later (mean EFW Z-score, -0.09 ± 1.01). Non-scheduled visits and preterm delivery before 37 + 0 weeks for DC twins and before 36 + 0 weeks for MCDA twins corresponded with smaller weight estimates, which was consistent with the study's definition of complicated pregnancy., Conclusions: The FMF models provide a good fit for EFW measurements in our Danish national cohort of uncomplicated twin pregnancies assessed at routine scans. Therefore, the FMF models establish robust criteria for subsequent investigations and potential clinical applications. Future research should focus on exploring the consequences of clinical implementation, particularly regarding the identification of twins that are small-for-gestational age, as they are especially susceptible to adverse perinatal outcome. © 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: Prenatal exposure to maternal diabetes is associated with an increased risk of offspring heart defects. We evaluated associations with subtle infant cardiac changes., Research Design and Methods: In a cohort of 25,486 infants with transthoracic echocardiography within 60 days of birth, we investigated associations between maternal preexisting diabetes and gestational diabetes mellitus (GDM) and infant left ventricular (LV) structural and functional parameters, using linear regression to estimate adjusted mean differences (aMDs) between groups., Results: Infants exposed to maternal preexisting diabetes (n = 198) had thicker LV posterior walls (aMD 0.19 mm; 95% CI 0.11, 0.27), smaller LV internal diameters in systole (aMD -0.27 mm; 95% CI -0.45, -0.18) and diastole (aMD -0.37 mm; 95% CI -0.59, -0.09), reduced stroke volumes (aMD -0.36 mL; 95% CI -0.61, -0.11), and increased heart rates (aMD 3.14 bpm; 95% CI 1.10, 6.18) and mitral valve early peak velocities (aMD 2.17 cm/s; 95% CI 0.31, 4.04) than unexposed infants (n = 24,639). Infants born to mothers with GDM (n = 649) had significantly smaller LV internal diameters in systole (aMD -0.13 mm; 95% CI -0.22, -0.03) and similar structural and functional changes as children exposed to preexisting diabetes, albeit with smaller nonsignificant aMDs. Higher third-trimester HbA1c levels were associated with smaller LV internal diameters and stroke volumes in infants exposed to preexisting diabetes and with lower heart rates in infants exposed to GDM., Conclusions: Maternal preexisting diabetes and, to a lesser extent, GDM were associated with changes in infant LV structure and function., (© 2024 by the American Diabetes Association.)

Objectives: Our aim was to examine the prenatal profiles of pregnancies affected by an atypical chromosomal aberration, focusing on pathogenic copy-number variants (pCNVs). We also wanted to quantify the performance of combined first-trimester screening (cFTS) and a second-trimester anomaly scan in detecting these aberrations. Finally, we aimed to estimate the consequences of a policy of using non-invasive prenatal testing (NIPT) rather than invasive testing with chromosomal microarray analysis (CMA) to manage pregnancies identified as high risk by cFTS., Methods: This was a retrospective review of the Danish Fetal Medicine Database of all pregnant women who underwent cFTS and a risk assessment for trisomy 21 between 1 January 2008 and 31 December 2018. Chromosomal aberrations diagnosed prenatally, postnatally or from fetal tissue following pregnancy loss or termination of pregnancy were identified. Chromosomal aberrations were grouped into one of six categories: triploidy; common trisomy (13, 18 or 21); monosomy X; other sex-chromosome aberration (SCA); pCNV; and rare autosomal trisomy (RAT) or mosaicism. The prevalence of each aberration category was stratified by the individual cFTS markers and trisomy 21 risk estimate, and the size of each pCNV diagnosed by CMA was calculated., Results: We retrieved data on 565 708 pregnancies, of which 3982 (0.70%) were diagnosed with a fetal chromosomal aberration. cFTS identified 87% of the common trisomies, but it also performed well in identifying triploidies (86%), monosomy X (92%), atypical SCAs (58%) and RATs or mosaicisms (70%). pCNVs comprised 27% (n = 1091) of the chromosomal aberrations diagnosed overall, and the prevalence increased during the study period, as prenatal CMA was increasingly being performed. In pregnancies with a maternal age < 30 years, nuchal translucency (NT) thickness ≤ 95 th centile, pregnancy-associated plasma protein-A (PAPP-A) ≥ 1 multiple of the median, or trisomy 21 risk of ≤ 1 in 1000, the prevalence of pCNVs exceeded significantly the prevalence of trisomies 21, 18 and 13. Pregnancies affected by a pCNV had significantly increased NT and decreased levels of the maternal biomarkers PAPP-A and β-human chorionic gonadotropin compared with unaffected pregnancies. However, only 23% of these pregnancies screened positive on cFTS and 51% of pCNVs were not detected until after birth. Among high-risk pregnancies, pCNVs comprised 14% of diagnosed aberrations, and when other atypical aberrations were considered, conventional NIPT (screening for trisomies 21, 18 and 13 and monosomy X) would miss 27% of all pathogenic aberrations diagnosed from invasive testing following a high-risk cFTS result. Thus, 1 in 26 pregnancies at high risk following cFTS would be affected by a chromosomal aberration despite a normal result from conventional NIPT. In a contingent screening model using NIPT for the 'intermediate'-risk group (trisomy 21 risk of 1 in 100-299), 50% of the aberrations would be missed. In our cohort, 79% of the pCNVs diagnosed were < 5Mb and therefore not detectable using current forms of 'genome-wide' NIPT., Conclusions: As a by-product of screening for trisomies 21, 18 and 13, most triploidies and the majority of atypical SCAs, RATs and mosaicisms are detected before birth. However, only 23% of pCNVs are associated with a high-risk result according to cFTS and only half are diagnosed before birth. Replacing invasive testing with NIPT for high-risk pregnancies would substantially decrease the first-trimester detection of pathogenic chromosomal anomalies. © 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.)

Objectives: To compute a set of atypicality indices based on combined first-trimester screening (cFTS) markers and second-trimester estimated fetal weight (EFW), and to demonstrate their potential in identifying pregnancies at reduced or increased risk of chromosomal aberrations following a low-risk cFTS result., Methods: The atypicality index quantifies the unusualness of an individual set of measurements relative to a reference distribution and can be computed from any variables or measurements available. A score of 0% on the atypicality index represents the most typical profiles, while a score of 100% indicates the highest level of atypicality. From the Danish Fetal Medicine Database, we retrieved data on all pregnant women seen for cFTS in the Central Denmark Region between January 2008 and December 2018. All pregnancies with a cytogenetic or molecular analysis obtained prenatally, postnatally or following pregnancy loss or termination were identified. A first-trimester atypicality index (A cFTS ) was computed based on nuchal translucency (NT) thickness, maternal serum free β-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A). Furthermore, a second-trimester index (A cFTS + EFW ) was computed from cFTS markers and EFW from a routine second-trimester anomaly scan. All pregnancies were stratified into subgroups based on their atypicality levels and their cFTS risk estimates. The risk of chromosomal aberrations in each subgroup was then compared with the overall prevalence, and a graphical presentation of the multivariate measurement profiles was developed., Results: We retrieved data on 145 955 singleton pregnancies, of which 9824 (6.7%) were genetically examined. Overall, 1 in 122 (0.82% (95% CI, 0.77-0.87%)) of all pregnancies seen for cFTS were affected by a fetal chromosomal aberration, and in screen-negative pregnancies (cFTS trisomy 21 risk < 1 in 100 and/or trisomy 18/13 risk < 1 in 50), 0.41% (95% CI, 0.38-0.44%) were affected. In screen-negative pregnancies with a typical first-trimester profile (A cFTS < 80% ), the risk of chromosomal aberrations was significantly reduced (0.28%) compared with the overall risk. The risk of chromosomal aberrations increased with higher atypicality index to 0.49% (A cFTS [80-90%) ), 1.52% (A cFTS [90-99%) ) and 4.44% (A cFTS ≥ 99% ) and was significantly increased in the two most atypical subgroups. The same applied for the second-trimester atypicality index, with risks of chromosomal aberrations of 0.76% and 4.16% in the two most atypical subgroups (A cFTS + EFW [90-99%) and A cFTS + EFW ≥ 99% , respectively)., Conclusions: As an add-on to cFTS, the atypicality index identifies women with typical measurement profiles, which may provide reassurance, whereas atypical profiles may warrant specialist referral and further investigation. In pregnancies identified as low risk on cFTS but with a highly atypical distribution of NT, PAPP-A and β-hCG, the risk of a chromosomal aberration is substantially increased. The atypicality index optimizes the interpretation of pre-existing prenatal screening profiles and is not limited to cFTS markers or EFW. © 2023 International Society of Ultrasound in Obstetrics and Gynecology., (© 2023 International Society of Ultrasound in Obstetrics and Gynecology.)

Objective: To examine the feasibility and performance of implementing a standardized fetal cardiac scan at the time of a routine first-trimester ultrasound scan., Method: A retrospective, single-center study in an unselected population between March 2021 and July 2022. A standardized cardiac scan protocol consisting of a four-chamber and 3-vessel trachea view with color Doppler was implemented as part of the routine first-trimester scan. Sonographers were asked to categorize the fetal heart anatomy. Data were stratified into two groups based on the possibility of evaluating the fetal heart. The influence of maternal and fetal characteristics and the detection of major congenital heart disease were investigated., Results: A total of 5083 fetuses were included. The fetal heart evaluation was completed in 84.9%. The proportion of successful scans increased throughout the study period from 76% in the first month to 92% in the last month. High maternal body mass index and early gestational age at scan significantly decreased the feasibility. The first-trimester detection of major congenital heart defects was 7/16, of which four cases were identified by the cardiac scan protocol with no false-positive cases., Conclusion: First-trimester evaluation of the fetal heart by a standardized scan protocol is feasible to implement in daily practice. It can contribute to the earlier detection of congenital heart defects at a very low false positive rate., (© 2024 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Objective: To investigate the overall and type-specific prenatal detection rates (DRs) of orofacial clefts in a national cohort in Denmark., Methods: This study was based on data from the Danish Fetal Medicine Database and included all fetuses and children from singleton pregnancies diagnosed with an orofacial cleft prenatally and/or postnatally between 2009 and 2018. The types of cleft included unilateral, bilateral or median cleft lip (CL); unilateral, bilateral or median cleft lip with secondary cleft palate (CLP); and cleft palate (CP). The clefts were grouped as cleft lip with or without cleft palate (CL(P)) or as all clefts (including CP). All cases with discordance between prenatal and postnatal diagnoses were validated in the local patient files (Astraia). Cases without prenatal validation of the postnatal diagnosis were marked as undetected. Postnatally diagnosed cases with a strong prenatal suspicion of a cleft but without an International Classification of Diseases-10 code were registered as prenatally detected. Termination of pregnancy and intrauterine death were registered as true positives even if no autopsy could be performed. Liveborn cases with a prenatal diagnosis but without a postnatal validation were excluded., Results: A total of 994 cases were included in the study, of which 933 were liveborn. The prevalence of orofacial cleft was 1.6 per 1000 live births. There were no differences in the baseline characteristics between detected and undetected cases. The DR for CL(P) was 71.7% (95% CI, 64.8-78.9%), with an increase from 60.0% in 2009 to 73.0% in 2018 (P = 0.018). The type-specific DRs for the entire period were 56.4% (95% CI, 45.0-67.6%) for unilateral CL; 76.6% (95% CI, 71.7-82.9%) for unilateral CLP; 70.5% (95% CI, 52.1-87.6%) for bilateral CL; 82.3% (95% CI, 70.6-93.6%) for bilateral CLP; 0% (0/6) for median CL; 75.0% (3/4) for median CLP; and 3.3% (95% CI, 0.6-5.7%) for CP. A total of 20.9% (208/994) of the cases had associated findings, of which 33.2% (69/208) were genetic aberrations., Conclusions: The DR for CL(P) has improved in Denmark over the last decade. The DR for CLP is high, with the highest DR for bilateral CLP. However, prenatal detection of CP remains a challenge. © 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 perform a nationwide study of quadrichorionic quadriamniotic (QCQA) quadruplet pregnancies and to compare the pregnancy outcome in those undergoing fetal reduction with non-reduced quadruplets and dichorionic diamniotic (DCDA) twin pregnancies from the same time period., Methods: This was a retrospective Danish national register-based study performed using data from the national Danish Fetal Medicine Database, which included all QCQA quadruplets and all non-reduced DCDA twin pregnancies with an estimated due date between 2008 and 2018. The primary outcome measure was a composite of adverse pregnancy outcomes, including pregnancy loss or intrauterine death of one or more fetuses. Secondary outcomes included gestational age at delivery, the number of liveborn children, preterm delivery before 28, 32 and 37 gestational weeks and birth weight. Data on pregnancy complications and baseline characteristics were also recorded. Outcomes were compared between reduced and non-reduced quadruplet pregnancies, and between DCDA pregnancies and quadruplet pregnancies reduced to twins. A systematic literature search was performed to describe and compare previous results with our findings., Results: Included in the study were 33 QCQA quadruplet pregnancies, including three (9.1%) non-reduced pregnancies, 28 (84.8%) that were reduced to twin pregnancy and fewer than three (6.1%) that were reduced to singleton pregnancy, as well as 9563 DCDA twin pregnancies. Overall, the rate of adverse pregnancy outcome was highest in non-reduced quadruplets (66.7%); it was 50% in quadruplets reduced to singletons and 10.7% in quadruplets reduced to twins. The proportion of liveborn infants overall was 91.1% of the total number expected to be liveborn in quadruplet pregnancies reduced to twins. This was statistically significantly different from 97.6% in non-reduced dichorionic twins (P = 0.004), and considerably higher than 58.3% in non-reduced quadruplets. The rates of preterm delivery < 28, < 32 and < 37 weeks were decreased in quadruplets reduced to twins compared with those in non-reduced quadruplet pregnancies. Quadruplets reduced to twins did not achieve equivalent pregnancy outcomes to those of DCDA twins., Conclusion: This national study of QCQA quadruplets has shown that multifetal pregnancy reduction improves pregnancy outcome, including a decreased rate of preterm delivery and higher proportion of liveborn children. © 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.)

This study aimed to develop a deep learning model to assess the quality of fetal echocardiography and to perform prospective clinical validation. The model was trained on data from the 18-22-week anomaly scan conducted in seven hospitals from 2008 to 2018. Prospective validation involved 100 patients from two hospitals. A total of 5363 images from 2551 pregnancies were used for training and validation. The model's segmentation accuracy depended on image quality measured by a quality score (QS). It achieved an overall average accuracy of 0.91 (SD 0.09) across the test set, with images having above-average QS scoring 0.97 (SD 0.03). During prospective validation of 192 images, clinicians rated 44.8% (SD 9.8) of images as equal in quality, 18.69% (SD 5.7) favoring auto-captured images and 36.51% (SD 9.0) preferring manually captured ones. Images with above average QS showed better agreement on segmentations (p < 0.001) and QS (p < 0.001) with fetal medicine experts. Auto-capture saved additional planes beyond protocol requirements, resulting in more comprehensive echocardiographies. Low QS had adverse effect on both model performance and clinician's agreement with model feedback. The findings highlight the importance of developing and evaluating AI models based on 'noisy' real-life data rather than pursuing the highest accuracy possible with retrospective academic-grade data., (© 2024. The Author(s).)

Objective: To compare morbidity, as measured by length of stay in the neonatal intensive care unit (NICU), in twin and singleton gestations classified as small-for-gestational age (SGA) according to estimated fetal weight < 10 th percentile on twin or singleton growth charts., Methods: NICU length of stay was compared in 1150 twins and 29 035 singletons that underwent ultrasound assessment between 35 + 0 and 36 + 6 weeks' gestation. Estimated fetal weight was obtained from measurements of head circumference, abdominal circumference and femur length using the Hadlock formula. Gestational age was derived from the first-trimester crown-rump length measurement, using the larger of the two twins. Singletons and twins were compared in terms of NICU admission rate and length of stay according to classification as SGA by the Fetal Medicine Foundation singleton and twin reference distributions., Results: The overall proportions of twins and singletons admitted to NICU were similar (7.3% vs 7.4%), but twins tended to have longer lengths of stay in NICU (≥ 7 days: 2.4% vs 0.8%; relative risk (RR), 3.0 (95% CI, 1.6-4.4)). Using the singleton chart, a higher proportion of twins were classified as SGA compared with singletons (37.6% vs 7.0%). However, the proportion of SGA neonates entering NICU was similar (10.2% for twins and 10.1% for singletons) and the proportion of SGA neonates spending ≥ 7 days in NICU was substantially higher for twins compared with singletons (3.7% vs 1.4%; RR, 2.6 (95% CI, 1.4-4.7))., Conclusions: When singleton charts are used to define SGA in twins and in singletons, there is a greater degree of growth-related neonatal morbidity amongst SGA twins compared with SGA singletons. Consequently, singleton charts do not inappropriately overdiagnose fetal growth restriction in twins and they should be used for monitoring fetal growth in both twins and singletons. © 2023 International Society of Ultrasound in Obstetrics and Gynecology., (© 2023 International Society of Ultrasound in Obstetrics and Gynecology.)

Objective: To derive reference distributions of estimated fetal weight (EFW) in twins relative to singletons., Methods: Gestational-age- and chorionicity-specific reference distributions for singleton percentiles and EFW were fitted to data on 4391 twin pregnancies with two liveborn fetuses from four European centers, including 3323 dichorionic (DC) and 1068 monochorionic diamniotic (MCDA) twin pregnancies. Gestational age was derived using the larger of the two crown-rump length measurements obtained during the first trimester of pregnancy. EFW was obtained from ultrasound measurements of head circumference, abdominal circumference and femur length using the Hadlock formula. Singleton percentiles were obtained using the Fetal Medicine Foundation population weight charts for singleton pregnancies. Hierarchical models were fitted to singleton Z-scores with autoregressive terms for serial correlations within the same fetus and between twins from the same pregnancy. Separate models were fitted for DC and MCDA twins., Results: Fetuses from twin pregnancies tended to be smaller than singletons at the earliest gestational ages (16 weeks for MCDA and 20 weeks for DC twins). This was followed by a period of catch-up growth until around 24 weeks. After that, both DC and MCDA twins showed reduced growth. In DC twins, the EFW corresponding to the 50 th percentile was at the 50 th percentile of singleton pregnancies at 23 weeks, the 43 rd percentile at 28 weeks, the 32 nd percentile at 32 weeks and the 22 nd percentile at 36 weeks. In MCDA twins, the EFW corresponding to the 50 th percentile was at the 36 th percentile of singleton pregnancies at 24 weeks, the 29 th percentile at 28 weeks, the 19 th percentile at 32 weeks and the 12 th percentile at 36 weeks., Conclusions: In DC and, to a greater extent, MCDA twin pregnancies, fetal growth is reduced compared with that observed in singleton pregnancies. Furthermore, after 24 weeks, the divergence in growth trajectories between twin and singleton pregnancies becomes more pronounced as gestational age increases. © 2023 International Society of Ultrasound in Obstetrics and Gynecology., (© 2023 International Society of Ultrasound in Obstetrics and Gynecology.)

Introduction: In this register-based study of pregnancies in Denmark, we assessed the associations between maternal age and the risk of fetal aneuploidies (trisomy 21, trisomy 18, trisomy 13, triploidy, monosomy X and other sex chromosome aberrations). Additionally, we aimed to disentangle the maternal age-related effect on fetal aneuploidies by cases with translocation trisomies and mosaicisms., Material and Methods: We followed a nationwide cohort of 542 375 singleton-pregnant women attending first trimester screening in Denmark between 2008 and 2017 until delivery, miscarriage or termination of pregnancy. We used six maternal age categories and retrieved information on genetically confirmed aneuploidies of the fetus and infant from the national cytogenetic register., Results: We confirmed the known associations between advanced maternal age and higher risk of trisomy 21, 18, 13 and other sex chromosome aberrations, especially in women aged ≥35 years, whereas we found no age-related associations with triploidy or monosomy X. Cases with translocation trisomies and mosaicisms did not influence the overall reported association between maternal age and aneuploidies., Conclusion: This study provides insight into the accurate risk of fetal aneuploidies that pregnant women of advanced ages encounter., (© 2023 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Objectives: To examine the distribution of nuchal translucency thickness (NT), free β-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A) in pregnancies with a fetal 22q11.2 aberration. Furthermore, the performance of combined first-trimester screening (cFTS) and a new risk algorithm targeting 22q11.2 deletions in detecting affected pregnancies was evaluated. Finally, prenatal malformations and pregnancy outcome were assessed., Methods: This was a nationwide registry-based cohort study of all pregnancies that underwent prenatal screening with a due date between January 2008 and December 2018 in Denmark. All cases with a fetal 22q11.2 deletion or duplication (hg19 chr22:18.9mio-25.0mio) diagnosed pre- or postnatally or following pregnancy loss or termination of pregnancy were retrieved from the Danish Cytogenetic Central Register and linked with pregnancy data from the Danish Fetal Medicine Database. Fetal and maternal characteristics, including cFTS results and pregnancy outcome, of pregnancies with any 22q11.2 deletion or duplication (LCR22-A to -H) and pregnancies with a classic deletion or duplication (LCR22-A to -D) diagnosed by chromosomal microarray were compared with those of a chromosomally normal reference group. A risk algorithm was developed for assessing patient-specific risks for classic 22q11.2 deletions based on NT, PAPP-A and β-hCG. Detection rates and false-positive rates at different risk cut-offs were calculated., Results: We included data on 143 pregnancies with a fetal 22q11.2 aberration, of which 97 were deletions (54 classic) and 46 were duplications (32 classic). NT was significantly increased in fetuses with a classic deletion (mean, 1.89 mm), those with any deletion (mean, 1.78 mm) and those with any duplication (mean, 1.86 mm) compared to the reference group (mean, 1.65 mm). β-hCG multiples of the median (MoM) was decreased in all 22q11.2 subgroups compared with the reference group (mean, 1.02) and reached significance in pregnancies with a classic deletion and those with any deletion (mean, 0.77 and 0.71, respectively). PAPP-A MoM was significantly decreased in pregnancies with a classic duplication and those with any duplication (mean, 0.57 and 0.63, respectively), and was significantly increased in pregnancies with a classic deletion and those with any deletion (mean, 1.34 and 1.16, respectively), compared to reference pregnancies (mean, 1.01). The screen-positive rate by cFTS was significantly increased in pregnancies with a classic deletion (13.7%), any deletion (12.5%), a classic duplication (46.9%) or any duplication (37.8%) compared to the reference group (4.5%). A risk algorithm targeting classic 22q11.2 deletions more than doubled the prenatal detection rate of classic 22q11.2 deletions, but with a substantial increase in the false-positive rate. Structural malformations were detected in 41%, 35%, 17% and 25% of the pregnancies with a classic deletion, any deletion, classic duplication or any duplication, respectively. Pregnancy loss occurred in 40% of pregnancies with a classic deletion and 5% of those with a classic duplication diagnosed prenatally or following pregnancy loss., Conclusions: The distribution of cFTS markers in pregnancies with a classic 22q11.2 duplication resembles that of the common trisomies, with decreased levels of PAPP-A. However, classic 22q11.2 deletions are associated with increased levels of PAPP-A, which likely limits early prenatal detection using the current cFTS risk algorithm. The scope for improving early detection of classic 22q11.2 deletions using targeted risk algorithms based on NT, PAPP-A and β-hCG is limited. This demonstrates the capability, but also the limitations, of cFTS markers in detecting atypical chromosomal anomalies, which is important knowledge when designing new prenatal screening programs. © 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.)

Background: Artificial intelligence (AI) is becoming increasingly used in medical education, but our understanding of the validity of AI-based assessments (AIBA) as compared with traditional clinical expert-based assessments (EBA) is limited. In this study, the authors aimed to compare and contrast the validity evidence for the assessment of a complex clinical skill based on scores generated from an AI and trained clinical experts, respectively., Methods: The study was conducted between September 2020 to October 2022. The authors used Kane's validity framework to prioritise and organise their evidence according to the four inferences: scoring, generalisation, extrapolation and implications. The context of the study was chorionic villus sampling performed within the simulated setting. AIBA and EBA were used to evaluate performances of experts, intermediates and novice based on video recordings. The clinical experts used a scoring instrument developed in a previous international consensus study. The AI used convolutional neural networks for capturing features on video recordings, motion tracking and eye movements to arrive at a final composite score., Results: A total of 45 individuals participated in the study (22 novices, 12 intermediates and 11 experts). The authors demonstrated validity evidence for scoring, generalisation, extrapolation and implications for both EBA and AIBA. The plausibility of assumptions related to scoring, evidence of reproducibility and relation to different training levels was examined. Issues relating to construct underrepresentation, lack of explainability, and threats to robustness were identified as potential weak links in the AIBA validity argument compared with the EBA validity argument., Conclusion: There were weak links in the use of AIBA compared with EBA, mainly in their representation of the underlying construct but also regarding their explainability and ability to transfer to other datasets. However, combining AI and clinical expert-based assessments may offer complementary benefits, which is a promising subject for future research., (© 2023 The Authors. Medical Education published by Association for the Study of Medical Education and John Wiley & Sons Ltd.)

Objective: To examine the association of isolated single umbilical artery (iSUA) confirmed at the mid-trimester anomaly scan and adverse pregnancy outcome and congenital malformations with up to 10 years postnatal follow up., Methods: This retrospective cohort study included 116,501 singleton pregnancies consecutively enrolled in first trimester screening for aneuploidies and mid-trimester anomaly scan at three University Hospitals in the Capital Region of Copenhagen, Denmark.Data from the Danish Fetal Medicine Database (2008-2017) were verified by manually scrutinizing pre- and postnatal records. The main outcomes of interest were intrauterine fetal demise (IUFD), small for gestational age (SGA), preterm delivery, cesarean section and unrecognized pre- and postnatal congenital malformations., Results: In total, 775 pregnancies with iSUA were identified. Isolated SUA were associated with a significantly increased risk of IUFD (OR 4.16, 95% CI 2.06-8.44), SGA < 3 rd centile (aOR 2.41, 95% 1.85-3.14) and SGA < 10 th centile (aOR 1.84, 95% CI 1.53-2.21), but not with preterm delivery or cesarean section. The laterality of the missing artery was not associated with SGA. In total, 4.3% of pregnancies with iSUA had unrecognized congenital malformations. 1.5% with iSUA had congenital cardiovascular malformations, which were considered minor., Conclusion: Isolated SUA is associated with IUFD and SGA, supporting surveillance during third trimester. If, during the mid-trimester scan, the sonographer achieves thorough, extended cardiac views and finds no additional malformation other than SUA, fetal echocardiography seems not to be needed.

Introduction: In 2011, it was decided to implement chromosomal microarray in prenatal testing in the Central Denmark Region, mainly due to the expected higher diagnostic yield. Chromosomal microarray was introduced gradually for an increasing number of pregnancies and without a transition period where both karyotyping and chromosomal microarray were performed: first malformations (2011), then large nuchal translucency (2013), then high risk at combined first trimester risk screening (2016) and finally for all indications (2018). This retrospective study summarizes 11 years of using chromosomal microarray in invasive prenatal testing and presents the effect on diagnostic yield and turnaround time. Furthermore, the concerns when introducing chromosomal microarray are presented and discussed., Material and Methods: Registry data from the Danish Fetal Medicine Database, the regional fetal medicine database, the Danish Cytogenetic Central Register and the local laboratory database at Department of Clinical Genetics were all combined, and a cohort of 147 158 singleton pregnancies with at least one ultrasound examination was established RESULTS: Of the 147 158 pregnancies, invasive sampling was performed (chorionic villi or amniocytes) in 8456, corresponding to an overall invasive rate of 5.8%. Between 2016 and 2018, 3.4% (95% confidence interval [CI] 2.8-4.2%; n = 86) of the invasive samples (n = 2533) had a disease causing copy number variant and 5.3% (95% CI 4.4-6.2%; n = 133) had trisomies and other aneuploidies. The turnaround time more than halved from 14 days to an average of 5.5 days for chorionic villus sampling., Conclusions: Chromosomal microarray identified 5.3% trisomies and 3.4% copy number variants, thereby increased the diagnostic yield by more than 64% compared with karyotype only and it also more than halved the turnaround time. Some preliminary concerns proved real, eg prenatal counseling complexity, but these have been resolved over time in a clinical path with expert consultations., (© 2023 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Importance: As venous thromboembolism (VTE) remains one of the leading causes of maternal mortality, identifying women at increased risk of VTE is of great importance. Preeclampsia is a pregnancy-induced hypertensive disorder with generalized endothelial dysfunction. Some studies suggest that preeclampsia is associated with an increased risk of VTE, but much controversy exists., Objective: To examine the association between preeclampsia and the risk of VTE during pregnancy, during the puerperium, and after the puerperium., Design, Setting, and Participants: This observational cohort study used Danish nationwide registries to identify all eligible primiparous women who gave birth in Denmark from January 1, 1997, to December 31, 2016. The women were followed up from primiparous pregnancy to incident VTE, emigration, death, or the end of the study (December 31, 2016). Statistical analyses were carried out from January to May 2023., Exposure: Preeclampsia during primiparous pregnancy., Main Outcomes and Measure: The main outcome was incident VTE, and the secondary outcome was all-cause mortality., Results: A total of 522 545 primiparous women (median age, 28 years [IQR, 25-31 years]) were included, and 23 330 (4.5%) received a diagnosis of preeclampsia. Women with preeclampsia were of similar age to women without preeclampsia but had a higher burden of comorbidities. During a median follow-up of 10.2 years (IQR, 5.2-15.4 years), preeclampsia was associated with a higher incidence of VTE compared with no preeclampsia (incidence rate, 448.8 [95% CI, 399.9-503.5] vs 309.6 [95% CI, 300.6-319.9] per 1000 patient-years, corresponding to an unadjusted hazard ratio [HR] of 1.45 [95% CI, 1.29-1.63] and an adjusted HR of 1.43 [95% CI, 1.27-1.61]). When stratified according to the subcategories of VTE, preeclampsia was associated with an increased rate of deep vein thrombosis (unadjusted HR, 1.51 [95% CI, 1.32-1.72] and adjusted HR, 1.49 [95% CI, 1.31-1.70]) as well as pulmonary embolism (unadjusted HR, 1.39 [95% CI, 1.09-1.76]; adjusted HR, 1.36 [95% CI, 1.08-1.73]). These findings held true in landmark analyses during pregnancy, during the puerperium, and after the puerperium., Conclusions and Relevance: This cohort study suggests that preeclampsia was associated with a significantly increased risk of VTE during pregnancy, during the puerperium, and after the puerperium, even after thorough adjustment. Future studies should address how to improve the clinical management of women with a history of preeclampsia to prevent VTE.

Background: Triplet pregnancies are high risk for both the mother and the infants. The risks for infants include premature birth, low birthweight, and neonatal complications. Therefore, the management of triplet pregnancies involves close monitoring and may include interventions, such as fetal reduction, to prolong the pregnancy and improve outcomes. However, the evidence of benefits and risks associated with fetal reduction is inconsistent., Objective: This study aimed to compare the outcomes of trichorionic triplet pregnancies with and without fetal reduction and with nonreduced dichorionic twin pregnancies and primary singleton pregnancies., Study Design: All trichorionic triplet pregnancies in Denmark, including those with fetal reduction, were identified between 2008 and 2018. In Denmark, all couples expecting triplets are informed about and offered fetal reduction. Pregnancies with viable fetuses at the first-trimester ultrasound scan and pregnancies not terminated were included. Adverse pregnancy outcome was defined as a composite of miscarriage before 24 weeks of gestation, stillbirth at 24 weeks of gestation, or intrauterine fetal death of 1 or 2 fetuses., Results: The study cohort was composed of 317 trichorionic triplet pregnancies, of which 70.0% of pregnancies underwent fetal reduction to a twin pregnancy, 2.2% of pregnancies were reduced to singleton pregnancies, and 27.8% of pregnancies were not reduced. Nonreduced triplet pregnancies had high risks of adverse pregnancy outcomes (28.4%), which was significantly lower in triplets reduced to twins (9.0%; difference, 19.4%, 95% confidence interval, 8.5%-30.3%). Severe preterm deliveries were significantly higher in nonreduced triplet pregnancies (27.9%) than triplet pregnancies reduced to twin pregnancies (13.1%; difference, 14.9%, 95% confidence interval, 7.9%-21.9%). However, triplet pregnancies reduced to twin pregnancies had an insignificantly higher risk of miscarriage (6.8%) than nonreduced twin pregnancies (1.1%; difference, 5.6%; 95% confidence interval, 0.9%-10.4%)., Conclusion: Triplet pregnancies reduced to twin pregnancies had significantly lower risks of adverse pregnancy outcomes, severe preterm deliveries, and low birthweight than nonreduced triplet pregnancies. However, triplet pregnancies reduced to twin pregnancies were potentially associated with a 5.6% increased risk of miscarriage., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Twin pregnancies carry a higher risk of congenital and structural malformations, and pregnancy complications including miscarriage, stillbirth, and intrauterine fetal death, compared with singleton pregnancies. Carrying a fetus with severe malformations or abnormal karyotype places the remaining healthy fetus at an even higher risk of adverse outcome and pregnancy complications. Maternal medical conditions or complicated obstetrical history could, in combination with twin pregnancy, cause increased risks for both the woman and the fetuses. To our knowledge, no previous studies have evaluated and compared the outcomes of all dichorionic twin pregnancies and compared the results of reduced twins with those of nonreduced and primary singletons in a national cohort. These data are important for clinicians when counseling couples about fetal reduction and its implications., Objective: This study aimed to describe and compare the risks of adverse pregnancy outcomes, including the risk of pregnancy loss, in a national cohort of all dichorionic twins-reduced, nonreduced, and primary singletons. In addition, we examined the implications of gestational age at fetal reduction on gestational age at delivery., Study Design: This was a retrospective cohort study of all Danish dichorionic twin pregnancies, including pregnancies undergoing fetal reduction and a large proportion of randomly selected primary singleton pregnancies with due dates between January 2008 and December 2018. The primary outcome measures were adverse pregnancy outcomes (defined as miscarriage before 24 weeks, stillbirth from 24 weeks, or single intrauterine fetal death in nonreduced twin pregnancies), preterm delivery, and obstetrical pregnancy complications. Outcomes after fetal reduction were compared with those of nonreduced dichorionic twins and primary singletons., Results: In total, 9735 dichorionic twin pregnancies were included, of which 172 (1.8%) were reduced. In addition, 16,465 primary singletons were included. Fetal reductions were performed between 11 and 23 weeks by transabdominal needle-guided injection of potassium chloride, and outcome data were complete for all cases. Adverse pregnancy outcome was observed in 4.1% (95% confidence interval, 1.7%-8.2%) of reduced twin pregnancies, and 2.4% (95% confidence interval, 0.7%-6.1%) were delivered before 28 weeks, and 4.2% (95% confidence interval, 1.7%-8.5%) before 32 weeks. However, when fetal reduction was performed before 14 weeks, adverse pregnancy outcomes occurred in only 1.4% (95% confidence interval, 0.0%-7.4%), and delivery before 28 and 32 weeks diminished to 0% (95% confidence interval, 0.0%-5.0%) and 2.8% (95% confidence interval, 0.3%-9.7%), respectively. In contrast, 3.0% (95% confidence interval, 2.7%-3.4%) of nonreduced dichorionic twins had an adverse pregnancy outcome, and 1.9% (95% confidence interval, 1.7%-2.1%) were delivered before 28 weeks, and 7.3% (95% confidence interval, 6.9%-7.7%) before 32 weeks. Adverse pregnancy outcomes occurred in 0.9% (95% confidence interval, 0.7%-1.0%) of primary singletons, and 0.2% (95% confidence interval, 0.1%-0.3%) were delivered before 28 weeks, and 0.7% (95% confidence interval, 0.6%-0.9%) before 32 weeks. For reduced twins, after taking account of maternal factors and medical history, it was demonstrated that the later the fetal reduction was performed, the earlier the delivery occurred (P<.01). The overall risk of pregnancy complications was significantly lower among reduced twin pregnancies than among nonreduced dichorionic twin pregnancies (P=.02)., Conclusion: In a national 11-year cohort including all dichorionic twin pregnancies, transabdominal fetal reduction by needle guide for fetal or maternal indication was shown to be safe, with good outcomes for the remaining co-twin. Results were best when the procedure was performed before 14 weeks., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To examine early pregnancy risk factors for preterm prelabour rupture of membranes (PPROM) and develop a predictive model., Study Design: Retrospective analysis of a cohort of mixed-risk singleton pregnancies screened in the first and second trimesters in three Danish tertiary fetal medicine centres, including a cervical length measurement at 11-14 weeks, at 19-21 weeks and at 23-24 weeks of gestation. Univariable and multivariable logistic regression analyses were employed to identify predictive maternal characteristics, biochemical and sonographic factors. Receiver operating characteristic (ROC) curve analysis was used to determine predictors for the most accurate model., Results: Of 3477 screened women, 77 (2.2%) had PPROM. Maternal factors predictive of PPROM in univariable analysis were nulliparity (OR 2.0 (95% CI 1.2-3.3)), PAPP-A < 0.5 MoM (OR 2.6 (1.1-6.2)), previous preterm birth (OR 4.2 (1.9-8.9)), previous cervical conization (OR 3.6 (2.0-6.4)) and cervical length ≤ 25 mm on transvaginal imaging (first-trimester OR 15.9 (4.3-59.3)). These factors all remained statistically significant in a multivariable adjusted model with an AUC of 0.72 in the most discriminatory first-trimester model. The detection rate using this model would be approximately 30% at a false-positive rate of 10%. Potential predictors such as bleeding in early pregnancy and pre-existing diabetes mellitus affected very few cases and could not be formally assessed., Conclusions: Several maternal characteristics, placental biochemical and sonographic features are predictive of PPROM with moderate discrimination. Larger numbers are required to validate this algorithm and additional biomarkers, not currently used for first-trimester screening, may improve model performance., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To demonstrate the application of the atypicality index as an adjunct to first-trimester risk assessment for major trisomies by the combined test., Methods: This was a study of 123 998 Danish women with a singleton pregnancy who underwent routine first-trimester screening, including risk assessment for major trisomies. An atypicality index, which is a measure of the degree to which a profile is atypical, was produced for measurements of fetal nuchal translucency thickness and maternal serum free β-human chorionic gonadotropin and pregnancy-associated plasma protein-A. The incidence of adverse pregnancy outcome, including miscarriage, intrauterine death and termination of pregnancy, was tabulated according to the screening result and atypicality index., Results: In pregnancies with low risk and those with high risk for major trisomies according to the combined screening test, the incidence of adverse pregnancy outcome increased with increasing atypicality index. In pregnancies with a low risk for trisomies and atypicality index of ≥ 99%, the incidence of adverse outcome was 5.1 (95% CI, 3.4-7.6) times higher compared with that in low-risk pregnancies with a typical measurement profile, reflected by an atypicality index of < 80%. Similarly, in high-risk pregnancies, the incidence of adverse outcome was 7.9 (95% CI, 4.4-14.5) times higher in those with an atypicality index of ≥ 99% compared to those with an atypicality index of < 80%. Using individual profile plots, we were able to demonstrate a transparent and intuitive method for visualization of multiple variables, which can help interpret the individual combination of measurements and level of atypicality., Conclusions: In pregnancies undergoing first-trimester combined screening and classified as being at low risk for major trisomies, profiles that are typical of pregnancies with normal outcome provide additional reassurance, whereas those with an atypical profile may warrant further investigation. © 2022 International Society of Ultrasound in Obstetrics and Gynecology., (© 2022 International Society of Ultrasound in Obstetrics and Gynecology.)

Objective: To examine the extent to which sex chromosomes are included in current noninvasive prenatal testing (NIPT) and the reporting practices with respect to fetal chromosomal sex and sex chromosome aberrations (SCAs), in addition to an update on the general implementation of NIPT., Method: A questionnaire addressing the research objectives was distributed by email to fetal medicine and clinical genetics experts in Asia, Australia, Europe and the USA., Results: Guidelines on NIPT are available in the majority of the included countries. Not all existing guidelines address reporting of fetal chromosomal sex and SCAs. In most settings, NIPT frequently includes sex chromosomes (five Australian states, China, Hong Kong, Israel, Singapore, Thailand, USA and 23 of 31 European countries). This occurs most often by default or when parents wish to know fetal sex. In most settings, a potential SCA is reported by stating the risk hereof as "low" or "high" and/or by naming the SCA. Less than 50% of all pregnant women receive NIPT according to respondents from three Australian states, China, Israel, Singapore, Thailand and 24 of 31 European countries. However, this percentage, the genomic coverage of NIPT and its application as primary or secondary screening vary by setting., Conclusion: In most of the studied countries/states, NIPT commonly includes sex chromosomes. The reporting practices concerning fetal chromosomal sex and SCAs are diverse and most commonly not addressed by guidelines. In general, NIPT is variably implemented across countries/states., (© 2023 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Objective: To estimate the prevalence of chromosomal conditions in all fetuses and children with major congenital heart defect (CHD) in Denmark between 2008 and 2018., Methods: This was a national registry-based study including all singleton pregnancies with a prenatally or postnatally diagnosed major CHD usually requiring surgery within the first year after birth and a due date between July 2008 and December 2018 in Denmark. Data were retrieved from the Danish Fetal Medicine Database (DFMD) and the Danish Cytogenetic Central Register (DCCR) in October 2020. The DCCR contains information on all prenatal and postnatal genetic analyses, including karyotyping, chromosomal microarray, polymerase chain reaction, multiplex ligation-dependent probe amplification and fluorescence in-situ hybridization. All cases were reviewed by a clinical geneticist, and genetic changes were classified as pathogenic, likely pathogenic, variant of uncertain significance, likely benign or benign. Pathogenic and likely pathogenic variants were considered to be abnormal. Cases with CHD without any registered chromosomal analysis reported were considered genetically normal. Isolated CHD was defined as a case with major CHD without any other structural malformations detected prenatally or postnatally. Results are given as n (%). Comparisons between isolated and non-isolated cases were performed using logistic regression analysis, and data are presented as odds ratios (ORs) with 95% CIs., Results: A total of 8482 cases with any cardiovascular diagnosis were retrieved from the DFMD. Twins (n = 112) and minor CHD cases (n = 6921) were excluded, resulting in 1449 cases with major CHD. Of the included cases, 918 (63.4%) underwent chromosomal analysis. An abnormal test result was found in 187 cases, giving a prevalence of a chromosomal condition of 12.9% (95% CI, 11.2-14.7%) among all cases with major CHD. The highest prevalence of a chromosomal condition was found in cases with pulmonary atresia with intact ventricular septum and those with truncus arteriosus (both 28.6%), while the lowest prevalence was found in cases with transposition of the great arteries (2.2%) and congenitally corrected transposition of the great arteries (0%). In isolated cases of transposition of the great arteries, the prevalence of a chromosomal condition was 0.6%. The overall OR for a chromosomal condition in non-isolated cases compared with isolated cases was 2.72 (95% CI, 1.90-3.88)., Conclusions: We found an overall prevalence of a chromosomal condition of 12.9% among cases with major CHD in a national cohort with a high participation rate in first- and second-trimester screening, without employing whole genome and whole exome sequencing. The prevalence of a chromosomal condition varied considerably according to CHD diagnosis and presence of associated extracardiac malformations. These findings are important for prenatal counseling. © 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.)

Paracetamol (N-acetyl-p-aminophenol (APAP), also known as acetaminophen) is used to relieve mild to moderate pain and reduce fever. APAP is widely used during pregnancy as it is considered safe when used as directed by regulatory authorities. However, a significant amount of epidemiological and experimental research suggests that prenatal exposure potentially alters fetal development. In this paper, we summarize the potentially harmful adverse effects of APAP and the limitations of the current evidence. It highlights the urgent need for a clinical trial, and the aim of the presented qualitative pilot study on APAP use during pregnancy is the feasibility of a large-scale randomized controlled trial (RCT). In the qualitative study, we included 232 Danish women from three hospitals in the spring of 2021. After recognizing the pregnancy, 48% had taken any APAP, and 6% had taken it weekly or more than weekly. A total of 27% who had taken APAP in the first trimester of pregnancy (even rarely) would potentially participate in an RCT. In a potential clinical trial, the women would need to be included early in the 1st trimester as the suspected harmful effects of APAP lies within this early reproductive developmental window. A possible recruitment strategy was explored. These data suggest that the target population appears positive towards an RCT. As a negative attitude among users has been considered the major hindrance for such a study, we cannot see hindrances for performing an RCT., Competing Interests: The authors have declared that no competing interests exist.

Background: Intrauterine growth restriction is associated with an increased risk of cardiovascular changes neonatally. However, the underlying pathways are poorly understood, and it is not clear whether the dysfunction is already present in the fetus., Objective: This study aimed to investigate fetal cardiac dimensions assessed from images at the second trimester anatomy scan from fetuses classified postnatally as small for gestational age and intrauterine growth restricted and compare them with appropriate for gestational age fetuses., Study Design: This was a substudy from The Copenhagen Baby Heart Study, a prospective, multicenter cohort study including fetuses from the second trimester of pregnancy in Copenhagen from April 2016 to October 2018. The mothers were recruited at the second trimester anatomy scan that included extended cardiovascular image documentation followed by consecutively measured heart biometry by 2 investigators blinded for the pregnancy outcome. The fetuses were classified postnatally as small for gestational age and intrauterine growth restricted according to the International Society of Ultrasound in Obstetrics and Gynecology 2020 guidelines using birthweight and with a retrospective assessment of Doppler flow. The mean differences in the cardiovascular biometry were adjusted for gestational age at the time of the second trimester scan and the abdominal circumference. The z-scores were calculated, and the comparisons were Bonferroni corrected (significance level of P<.005). Receiver operating characteristic curves were computed after performing backward regression on several maternal characteristics and biomarkers., Results: We included 8278 fetuses, with 625 (7.6%) of them being small for gestational age and 289 (3.5%) being intrauterine growth restricted. Both small for gestational age and intrauterine growth restricted fetuses had smaller heart biometry, including the diameter at the location of the aortic valve (P<.005), the ascending aorta in the 3-vessel view (P<.005), and at the location of the pulmonary valve (P<.005). The intrauterine growth restricted group had significantly smaller hearts with respect to length and width (P<.005) and smaller right and left ventricles (P<.005). After adjusting for the abdominal circumference, the differences in the aortic valve and the pulmonary valve remained significant in the intrauterine growth restricted group. Achievement of an optimal receiver operating characteristic curve included the following parameters: head circumference, abdominal circumference, femur length, gestational age, pregnancy associated plasma protein-A multiples of median, nullipara, spontaneous conception, smoking, body mass index <18.5, heart width, and pulmonary valve with an area under the curve of 0.91 (0.88-0.93) for intrauterine growth restricted cases., Conclusion: Intrauterine growth restricted fetuses had smaller prenatal cardiovascular biometry, even when adjusting for abdominal circumference. Our findings support that growth restriction is already associated with altered cardiac growth at an early stage of pregnancy. The heart biometry alone did perform well as a screening test, but combined with other factors, it increased the sensitivity and specificity for intrauterine growth restriction., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The existing risk of procedure-related miscarriage following invasive sampling for prenatal diagnosis is higher for twin pregnancies and some women are reluctant to test these typically difficultly obtained pregnancies invasively. Therefore, there is a need for noninvasive testing options that can test twin pregnancies at an early gestational age and ideally test the twins individually. Case presentation: A pregnant woman opted for cell-based NIPT at GA 10 + 5. As cell-based NIPT is not established for use in twins, the test was provided in a research setting only, when an ultrasound scan showed that she carried dichorionic twins. Materials and Methods: Fifty mL of peripheral blood was sampled, and circulating fetal cells were enriched and isolated. Individual cells were subject to whole-genome amplification and STR analysis. Three fetal cells were analyzed by chromosomal microarray (aCGH). Results: We identified 20 fetal cells all sharing the same genetic profile, which increased the likelihood of monozygotic twins. aCGH of three fetal cells showed the presence of two X chromosomes and a gain of chromosome Y. CVS from both placentae confirmed the sex chromosomal anomaly, 47,XXY and that both fetuses were affected. Conclusion: NIPT options can provide valuable genetic information to twin pregnancies that help the couples in their decision-making on prenatal testing. Little has been published about the use of cell-based NIPT in twin pregnancies, but the method may offer the possibility to obtain individual cell-based NIPT results in dizygotic twins., Competing Interests: LJ, LH, RS, and PS were employed by the Danish biotech company ARCEDI Biotech that has launched a commercial cell-based noninvasive prenatal test (www.evitatest.com). JH was employed by Aagaard Fertility Clinic. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jeppesen, Hjortshøj, Hindkjær, Hatt, Petersen, Singh, Schelde, Andreasen, Christensen, Lildballe and Vogel.)

Introduction: Home management in general is considered to improve patient well-being, patient involvement and cost-effectiveness, for obstetric patients as well. But concerns regarding inclusion of intermediate- and high-risk pregnant women are an issue and a limitation for clinical implementation. This retrospective study evaluated the outcome and safety of extended remote self-monitoring of maternal and fetal health in intermediate- and high-risk pregnancies., Material and Methods: The study reports on 400 singleton pregnancies complicated by preterm premature rupture of membranes (PPROM), fetal growth restriction, preeclampsia, gestational diabetes mellitus, high-risk of preeclampsia, or a history of previous fetal or neonatal loss. Remote self-monitoring was performed by pregnant women and included C-reactive protein, non-stress test by cardiotocography, temperature, blood pressure, heart rate, and a questionnaire concerning maternal and fetal wellbeing. Data were transferred to the hospital using a mobile device platform and evaluated by healthcare professionals. In case of non-reassuring registrations, the pregnant women were invited for assessment at the hospital. Primary outcome was perinatal death. Secondary outcomes were other maternal and perinatal complications., Results: No severe maternal complications were observed. Nine fetal or neonatal deaths occurred, all secondary to malformations, severe fetal growth restriction, extreme prematurity or lung hypoplasia in cases of PPROM before 24 weeks. Even in the latter group, fetal and neonatal survival was 78% (18/23) and rose to 97% (60/62) when PPROM occurred after a gestational age 23+6 weeks. None of the fetal or neonatal deaths were attributable to the home-management setting., Conclusions: Home-monitoring including remote self-monitoring of fetal and maternal well-being in intermediate- and high-risk pregnancies seems to be a safe alternative to inpatient or frequent outpatient care, which sets the stage for a new way of thinking of hospital care. The implementation process included staff training workshops and development of patient enrollment practice with clarification of expectations and responsibilities, which can be crucial to the results., (© 2021 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Objective: To investigate prenatal changes in cardiac biometric and flow parameters in fetuses with bicuspid aortic valve (BAV) diagnosed neonatally compared with controls with normal cardiac anatomy., Methods: This analysis was conducted as part of the Copenhagen Baby Heart Study, a multicenter cohort study of 25 556 neonates that underwent second-trimester anomaly scan at 18 + 0 to 22 + 6 weeks' gestation and neonatal echocardiography within 4 weeks after birth, in Copenhagen University Hospital Herlev, Hvidovre Hospital and Rigshospitalet in greater Copenhagen, between April 2016 and October 2018. From February 2017 (Rigshospitalet) and September 2017 (Herlev and Hvidovre hospitals), the protocol for second-trimester screening of the heart was extended to include evaluation of the four-chamber view, with assessment of flow across the atrioventricular valves, sagittal view of the aortic arch and midumbilical artery and ductus venosus pulsatility indices. All images were evaluated by two investigators, and cardiac biometric and flow parameters were measured and compared between cases with BAV and controls. All cases with neonatal BAV were assessed by a specialist. Maternal characteristics and first- and second-trimester biomarkers were also compared between the two groups., Results: Fifty-five infants with BAV and 8316 controls with normal cardiac anatomy were identified during the study period and assessed using the extended prenatal cardiac imaging protocol. There were three times as many mothers who smoked before pregnancy in the group with BAV as in the control group (9.1% vs 2.7%; P = 0.003). All other baseline characteristics were similar between the two groups. Fetuses with BAV, compared with controls, had a significantly larger diameter of the aorta at the level of the aortic valve (3.1 mm vs 3.0 mm (mean difference, 0.12 mm (95% CI, 0.03-0.21 mm))) and the pulmonary artery at the level of the pulmonary valve (4.1 mm vs 3.9 mm (mean difference, 0.15 mm (95% CI, 0.03-0.28 mm))). Following conversion of the diameter measurements of the aorta and pulmonary artery to Z-scores and Bonferroni correction, the differences between the two groups were no longer statistically significant. Pregnancy-associated plasma protein-A (PAPP-A) multiples of the median (MoM) was significantly lower in the BAV group than in the control group (0.85 vs 1.03; P = 0.04)., Conclusions: Our findings suggest that fetuses with BAV may have a larger aortic diameter at the level of the aortic valve, measured in the left-ventricular-outflow-tract view, and a larger pulmonary artery diameter at the level of the pulmonary valve, measured in the three-vessel view, at 20 weeks' gestation. Moreover, we found an association of maternal smoking and low PAPP-A MoM with BAV. © 2021 International Society of Ultrasound in Obstetrics and Gynecology., (© 2021 International Society of Ultrasound in Obstetrics and Gynecology.)

Introduction: Following the wide distribution of non-invasive prenatal genetic screening (NIPS), numerous studies have reported a decline in total invasive tests in the recent years, up to 50-70% in some countries. However, in Denmark and Israel we have not experienced these declines. The objective of our study was to evaluate the trends in NIPS and chromosomal microarray analysis (CMA) use in Denmark and Israel. Methods: This retrospective study was performed by data acquisition from the Danish Cytogenetics Central Registry throughout the years 2000-2019, and Israeli Public Health Services, Ministry of Health computerized database (from 2011). Results: Of the 1,243,956 live births registered in Denmark over the years 2000-2019, a relatively steady level of invasive testing around 6% was noted since 2004, as opposed to 13.0% in Israel based on 1,594,962 live births between 2011 and 2019. The average uptake of NIPS was 1.1 ± 0.5% in Denmark vs. 4.3% in Israel (2013-2019). Relatively steady rates of invasive testing were noted in both countries, compared to a slight decline in NIPS in the recent years. Discussion: The recent decrease in the rates of invasive testing in the NIPS era was not observed in Denmark or in Israel. These results imply that Danish and Israeli women and/or health providers might favor the high resolution and yield of CMA testing over the non-invasiveness of NIPS. We explore and discuss this phenomenon, based on five central factors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sagi-Dain, Singer, Petersen, Lou and Vogel.)

Objective: Studies restricted to live births may underestimate severe teratogenic effects. We address the limitation by including data from both prenatal and postnatal diagnoses of cardiac malformations., Design: Register-based study., Setting: Denmark., Population: 364 012 singleton pregnancies from 2007 to 2014., Methods: We used data from five nationwide registries. Exposure to antidepressants was measured using redeemed prescriptions., Main Outcome Measures: Pregnancies with cardiac malformations that end in miscarriage, termination, stillbirth, postnatal death or cardiac surgery <1 year of birth were classified as severe cardiac malformations (SCM). Propensity scores with adjusted prevalence ratios (PRs) were calculated., Results: SCM were reported in 972 of 364 012 pregnancies overall and in 16 of 4105 exposed. For venlafaxine, the PR for SCM was 2.13 (95% confidence interval [CI] 0.89-5.13), 1.73 (95% CI 1.08-2.77) for other cardiac malformations, and there was a cluster of hypoplastic left heart syndromes (HLHS) (crude PR 17.4 [95% CI 6.41-47.2]), none of which ended in a live birth. For HLHS, the absolute risk increase was 4.4/1000 and the number needed to harm was 225. For selective serotonin reuptake inhibitors, the PRs were 1.09 (95% CI 0.52-2.30) and 1.38 (95% CI 1.00-1.92) for SCM and other cardiac malformations, respectively., Conclusions: Pregnancy exposure to venlafaxine is associated with an increased risk of severe cardiac malformations but with a low absolute risk. Potential mechanisms include direct effects or confounding by indication. Venlafaxine exposure is a marker for risk pregnancies for which fetal echocardiography may be considered., Tweetable Abstract: Exposure to venlafaxine is associated with an increased risk of cardiac malformations but with a low absolute risk., (© 2021 John Wiley & Sons Ltd.)

Objectives: The objective of this study was to evaluate the fetal cardiac function in human pregnancies exposed to sertraline (a selective serotonin reuptake inhibitor) compared to unexposed pregnancies., Method: We included 44 women in gestational week 25 + 0 days to week 26 + 6 days. Fifteen women used sertraline (50-150 mg per day), and 29 women used no daily medication. We assessed fetal cardiac function by Myocardial Performance Index (MPI), E/A ratios and by tricuspid and mitral annular plane systolic excursion (TAPSE and MAPSE) measured by 2D M-mode and by 4D eSTIC M-mode., Results: There were no differences between the sertraline exposed and the unexposed. The mean difference of MPI was 0.03 (95% CI -0.08-0.03), of tricuspid and mitral E/A ratios 0.00 (95% CI -0.03-0.05) and 0.03 (95% CI -0.07-0.01), respectively. The mean difference of TAPSE, by 2D and eSTIC, was 0.07 mm (95% CI -0.56-0.41) and 0.10 mm (95% CI -0.55-0.34). Mean difference of MAPSE, by 2D and eSTIC was 0.16 mm (95% CI -0.22-0.53) and 0.24 mm (95% CI -0.16-0.65), respectively. Serum levels of sertraline in exposed participants ranged from 33-266, median 92 nmol/L., Conclusions: We found no significant differences in fetal cardiac function, assessed by TAPSE, MAPSE, MPI and E/A ratios, in pregnancies exposed to sertraline compared to the unexposed.

Objective: To examine the impact of first-trimester crown-rump length (CRL) measurement error on the interpretation of estimated fetal weight (EFW) and classification of fetuses as small-, large- or appropriate-for-gestational age on subsequent growth scans., Methods: We examined the effects of errors of ± 2, ± 3 and ± 4 mm in the measurement of fetal CRL on percentiles of EFW at 20, 32 and 36 weeks' gestation and classification as small-, large- or appropriate-for-gestational age. Published data on CRL measurement error were used to determine variation present in practice., Results: A measurement error of -2 mm in first-trimester CRL shifts an EFW on the 10 th percentile at the 20-week scan to around the 20 th percentile, and the effect of a CRL measurement error of + 2 mm would shift an EFW on the 10 th percentile to around the 5 th percentile. At 32 weeks, a first-trimester CRL measurement error would shift an EFW on the 10 th percentile to the 7 th (+ 2 mm) or 14 th (-2 mm) percentile; at 36 weeks, the EFW would shift from the 10 th percentile to the 8 th (+ 2 mm) or 12 th (-2 mm) percentile. Published data suggest that measurement errors of 2 mm or more are common in practice., Conclusion: Because of the widespread and potentially severe consequences of CRL measurement errors as small as 2 mm on clinical assessment, patient management and research results, there is a need to increase awareness of the impact of CRL measurement error and to reduce measurement error variation through standardization and quality control. © 2021 International Society of Ultrasound in Obstetrics and Gynecology., (© 2021 International Society of Ultrasound in Obstetrics and Gynecology.)

Introduction: In Denmark, non-invasive prenatal testing (NIPT) has been used since 2013. We aimed to evaluate the early clinical use of NIPT in Danish public and private healthcare settings before NIPT became an integrated part of the national guidelines on prenatal screening and diagnosis in 2017., Material and Methods: NIPT data were collected between March 2013 and June 2017 from national public registries and private providers. Results from follow-up samples (chorionic villi, amniotic fluid, postnatal blood or fetal tissue) were included from The Danish Cytogenetics Central Registry and indications and outcome from The Danish Fetal Medicine Database., Results: A total of 3936 NIPT results were included in the study from public hospitals (n = 3463, 88.0%) and private clinics (n = 473, 12.0%). The total number of prenatal tests was 19 713 during the study period: 20% were NIPT analyses (n = 3936) and 80% invasive procedures (n = 15 777). Twenty-five percent of NIPTs in the private clinics were performed before gestational week 11 +0 , whereas NIPT in public settings was used only after combined first trimester screening (P < .001). Regardless of indication, the national public sensitivity was 96.9% (95% CI 82.0%-99.8%) for trisomy 21, 100% (95% CI 46.3%-100%) for trisomy 18, 100% (95% CI 5.5%-100%) for trisomy 13, and 87.0% (95% CI 74.5%-92.4%) for any fetal chromosomal aberration. Forty-seven true-positive NIPT results included cases of common aneuplodies (trisomy 21, n = 31; trisomy 18, n = 5; and trisomy 13, n = 1), sex chromosomal aberrations (n = 7) and atypical chromosomal aberrations (n = 3). One false-negative NIPT result occurred (trisomy 21). Of 47 cases, 21 (45%) cases with a true-positive NIPT result resulted in live births by choice; 11 of these children had Down and 4 had Edwards syndrome., Conclusions: The total number of NIPT analyses was low compared with the number of invasive procedures in the implementation period. In contrast to the generally high termination rate after a positive result following invasive testing in Denmark, a high proportion of true-positive NIPT results from the public setting resulted in live births. NIPT may be an important risk-free alternative to invasive testing for a minority of women in the public setting who wish to use prenatal genetic testing for information only and not for reproductive decision-making., (© 2021 Nordic Federation of Societies of Obstetrics and Gynecology (NFOG). Published by John Wiley & Sons Ltd.)

Objective: To evaluate the association between prenatally detected isolated ventricular septum defects (VSDs) and chromosomal aberrations in a nationwide study in Denmark., Method: Nationwide, register-based study with prospectively collected data including all singleton pregnancies from 2014-2018. From the Danish Fetal Medicine Database, we retrieved data on maternal characteristics, first-trimester biomarkers, pre- and postnatal diagnoses, genetic test results, and pregnancy outcomes. VSDs were considered isolated in the absence of other malformations or soft markers, and with a low first-trimester risk assessment for trisomies 21, 18 and 13. All cases of an isolated VSD with a chromosomal anomaly were audited. The genetic tests included karyotyping and chromosomal microarray., Results: We retrieved data on 292 108 singleton pregnancies; 323 registered with a prenatally detected VSD and 697 with a VSD detected postnatally (incidence of 0.35%). Only 1/153 (0.7%, 95% CI 0.02;3.6%) of the isolated prenatally detected VSDs had an abnormal genetic test result (del (8)(q23.1)). Moreover, they had a lower free β-hCG MoM (0.9 MoM vs 0.99 MoM, P = 0.02), and were more likely born small for gestational age (SGA), defined as birthweight 2 or more SD below the mean, compared with the control population (5.2% vs 2.5%, P = 0.03)., Conclusion: We found a prevalence of chromosomal aberrations of 0.7% in fetuses with a prenatally detected isolated VSD. Moreover, we found an association between isolated VSDs and a larger proportion being born SGA., (© 2020 John Wiley & Sons Ltd.)