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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., 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.

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 e

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, 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 emb

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 pr

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

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 < 3rd centile (aOR 2.41, 95% 1.85–3.14) and SGA < 10th 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.

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

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.

Denmark was one of the first countries in the world to introduce a universal and free-of-charge offer of combined first-trimester screening for chromosomal anomalies to all pregnant women. In the present chapter, we describe the development and current status of the program and reflect on future directions in the era of exome sequencing and cell-based noninvasive testing. Now, prenatal screening programs differ vastly all over the world and even between countries that are often considered comparable, such as Denmark and Norway. In this chapter, we will present a few such comparisons but will focus mainly on a thorough description of the Danish context. The aim is to give the reader a point of reference to consider and compare their specific, national context.

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.

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 asce

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.

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 stag