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Background: Short telomeres in peripheral blood leukocytes are associated with older age and age-related diseases. We tested the hypotheses that short telomeres are associated with both increased cancer mortality and all-cause mortality. Methods: Individuals (n = 64 637) were recruited from 1991 onwards from two Danish prospective cohort studies: the Copenhagen City Heart Study and the Copenhagen General Population Study. All had telomere length measured by quantitative polymerase chain reaction and the genotypes rs1317082 (TERC), rs7726159 (TERT), and rs2487999 (OBFC1) determined. The sum of telomere-shortening alleles from these three genotypes was calculated. We conducted Cox regression analyses and instrumental variable analyses using the allele sum as an instrument. All statistical tests were two-sided. Results: Among 7607 individuals who died during follow-up (0-22 years, median = 7 years), 2420 had cancer and 2633 had cardiovascular disease as causes of death. Decreasing telomere length deciles were associated with increasing allcause mortality (Ptrend = 2*10-15). The multivariable-adjusted hazard ratio of all-cause mortality was 1.40 (95% confidence interval [CI] = 1.25 to 1.57) for individuals in the shortest vs the longest decile. Results were similar for cancer mortality and cardiovascular mortality. Telomere length decreased 69 base pairs (95% CI = 61 to 76) per allele for the allele sum, and the per-allele hazard ratio for cancer mortality was 0.95 (95% CI = 0.91 to 0.99). Allele sum was not associated with cardiovascular, other, or all-cause mortality. Conclusion: Short telomeres in peripheral blood leukocytes were associated with high mortality in association analyses. In contrast, genetically determined short telomeres were associated with low cancer mortality but not with all-cause mortality. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this cross‐sectional questionnaire study was to investigate motivation to participate in a possible new screening for preeclampsia in the first trimester of pregnancy among Danish pregnant women through a questionnaire based on Theory of Planned Behavior developed for this specific purpose. The new screening combines maternal characteristics with mean arterial pressure, uterine artery pulsatility index and biochemical markers to predict the risk of preeclampsia, whereas the current Danish screening uses maternal characteristics alone. Material and methods: Participation was offered to a proportion of women attending a first or a second trimester screening scan at two University Hospitals in Copenhagen. The questionnaire was set up in REDCap® and answers were entered directly into the database, which was accessed via a QR‐code. Results: We invited 772 pregnant women to participate in the questionnaire survey between November 2021 and April 2022 at Copenhagen University Hospital Rigshospitalet (study site one) (n = 238) and Copenhagen University Hospital Hvidovre (study site two) (n = 534). The response rate was 71.8% (171/238) at study site one and 33.9% (181/534) at study site two. A total of 352 women were included in the study (total participation rate 45.6%). Most women had a positive attitude towards preeclampsia screening in pregnancy, and 99.4% said they would participate in a risk assessment for preeclampsia if given the opportunity. A total of 97.4% answered "yes" to whether a first trimester preeclampsia screening should be offered to all pregnant women in Denmark. Positive motivation to participate in preeclampsia screening was correlated with having a network with a positive attitude towards preeclampsia screening. Conclusions: The results of this study indicate that Danish pregnant women have a positive attitude towards participation in a first trimester screening for preeclampsia. This observation might be useful in relation to possible future implementation in Denmark. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

BACKGROUND: Cardiac troponin (cTn) is key in diagnosing myocardial infarction (MI). After MI, the clinically observed half-life of cTn has been reported to be 7 to 20 hours, but this estimate reflects the combined elimination and simultaneous release of cTn from cardiomyocytes. More precise timing of myocardial injuries necessitates separation of these 2 components. We used a novel method for determination of isolated cTn elimination kinetics in humans. METHODS: Patients with MI were included within 24 hours after revascularization and underwent plasmapheresis to obtain plasma with a high cTn concentration. After at least 3 weeks, patients returned for an autologous plasma retransfusion followed by blood sampling for 8 hours. cTn was measured with 5 different high-sensitivity cTn assays. RESULTS: Of 25 included patients, 20 participants (mean age, 64.5 years; SD, 8.2 years; 4 women [20%]) received a retransfusion after a median of 5.8 weeks (interquartile range, 5.0-6.9 weeks) after MI. After retransfusion of a median of 620 mL (range, 180-679 mL) autologous plasma, the concentration of cTn in participants' blood increased 4 to 445 times above the upper reference level of the 5 high-sensitivity cTn assays. The median elimination half-life ranged from 134.1 minutes (95% CI, 117.8-168.0) for the Elecsys high-sensitivity cTnT assay to 239.7 minutes (95% CI, 153.7-295.1) for the Vitros high-sensitivity cTnI assay. The median clearance of cTnI ranged from 40.3 mL/min (95% CI, 32.0-44.9) to 52.7 mL/min (95% CI, 42.2-57.8). The clearance of cTnT was 77.0 mL/min (95% CI, 45.2-95.0). CONCLUSIONS: This novel method showed that the elimination half-life of cTnI and cTnT was 5 to 16 hours shorter than previously reported. This indicates a considerably longer duration of cardiomyocyte cTn release after MI than previously thought. Improved knowledge of timing of myocardial injury may call for changes in the management of MI and other disorders with myocardial injury. [ABSTRACT FROM AUTHOR]

Introduction: Obstetrics research has predominantly focused on the management and identification of factors associated with labor dystocia. Despite these efforts, clinicians currently lack the necessary tools to effectively predict a woman's risk of experiencing labor dystocia. Therefore, the objective of this study was to create a predictive model for labor dystocia. Material and methods: The study population included nulliparous women with a single baby in the cephalic presentation in spontaneous labor at term. With a cohort-based registry design utilizing data from the Copenhagen Pregnancy Cohort and the Danish Medical Birth Registry, we included women who had given birth from 2014 to 2020 at Copenhagen University Hospital–Rigshospitalet, Denmark. Logistic regression analysis, augmented by a super learner algorithm, was employed to construct the prediction model with candidate predictors pre-selected based on clinical reasoning and existing evidence. These predictors included maternal age, pre-pregnancy body mass index, height, gestational age, physical activity, self-reported medical condition, WHO-5 score, and fertility treatment. Model performance was evaluated using the area under the receiver operating characteristics curve (AUC) for discriminative capacity and Brier score for model calibration. Results: A total of 12,445 women involving 5,525 events of labor dystocia (44%) were included. All candidate predictors were retained in the final model, which demonstrated discriminative ability with an AUC of 62.3% (95% CI:60.7–64.0) and Brier score of 0.24. Conclusions: Our model represents an initial advancement in the prediction of labor dystocia utilizing readily available information obtainable upon admission in active labor. As a next step further model development and external testing across other populations is warranted. With time a well-performing model may be a step towards facilitating risk stratification and the development of a user-friendly online tool for clinicians. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Multivitamin use may lower risk of preeclampsia: a meta-analysis. Chen et al. included pregnancy-induced hypertension (without proteinuria) and severe pregnancy-induced hypertension, the latter defined as the presence of systolic blood pressure >=160 mm Hg or diastolic blood pressure >=110 mm Hg.3 There seem to be significant differences between preeclampsia and pregnancy-induced hypertension with respect to their epidemiologic, pathologic, pathogenetic and hemodynamic characteristics.4 Hence, we strictly followed our PROSPERO protocol, therefore excluding the study by Chen et al., as the main outcome of their study was pregnancy-induced hypertension and not preeclampsia. [Extracted from the article]

Finally, because the Elecsys version 1 preanalytical protocol recommended sample storage in -80 °C, we also compared the concentration measurements of A 42 after a single freeze-thaw cycle, using both Sarstedt V1 (25 samples) and Sarstedt V2 (21 samples). Keywords: Alzheimer's dementia; amyloid; biomarkers; Elecsys EN Alzheimer's dementia amyloid biomarkers Elecsys e182 e185 4 07/18/23 20230801 NES 230801 To the Editor, Amyloid-beta 1-42 (A 42) is one of the diagnostic cerebrospinal fluid biomarkers for Alzheimer's dementia [[1]], together with Tau proteins. For Elecsys version 2, we applied the recommended (by Roche) cutoff of 1,030 ng/L. However, in the case of INNOTEST, an upwards drift in the has been observed for results of A 42 within the last 10 years, with data suggesting that the optimal cutoff for INNOTEST A 42 is not constant, but rather period-dependent [[4]], [[5]], [[6]]. [Extracted from the article]

Aim: We examined the heart failure biomarker mid‐regional pro‐atrial natriuretic peptide during the first trimester of pregnancy in relation to early‐onset preeclampsia <34 weeks. Materials and Methods: This case–control study included 34 women with singleton pregnancies with a preeclampsia diagnosis and delivery before 34 weeks of gestation who had attended the routine first‐trimester ultrasound scan at 11–13+6 weeks of gestation between August 2010 and October 2015 at the Copenhagen University Hospital Rigshospitalet, Denmark, and 91 uncomplicated singleton pregnancies matched by time of the routine first‐trimester blood sampling at 8–13+6 weeks. Descriptive statistical analyses were performed for maternal characteristics and obstetric and medical history for the case versus the control group. Concentrations of mid‐regional pro‐atrial natriuretic peptide, placental growth factor, soluble fms‐like tyrosine kinase‐1, and pregnancy‐associated plasma protein A between early‐onset preeclampsia cases and the control group were compared using Students t‐test and the Mann–Whitney U test. Biochemical marker concentrations were converted into multiples of the expected median values after adjustment for gestational age. Results: Mid‐regional pro‐atrial natriuretic peptide levels were not significantly different between early‐onset preeclampsia cases and the control group in the first trimester of pregnancy. As expected, both placental growth factor and pregnancy‐associated plasma protein A levels were significantly lower in early‐onset preeclampsia, whereas soluble fms‐like tyrosine kinase‐1 levels were not statistically significantly different. Conclusion: The maternal first‐trimester concentration of mid‐regional pro‐atrial natriuretic peptide, a peptide with multiple biological functions including a relation to cardiovascular disease, was not significantly different in women with early‐onset preeclampsia. [ABSTRACT FROM AUTHOR]

The serum adiponectin/leptin ratio (A/L ratio) is a surrogate marker of insulin sensitivity. Pre-eclampsia (PE) is associated with maternal metabolic syndrome and occasionally impaired fetal growth. We assessed whether the A/L ratio in first-trimester maternal serum was associated with PE and/or birth weight. Adiponectin and leptin were quantitated in first-trimester blood samples (gestational week 10+3–13+6) from 126 women who later developed PE with proteinuria (98 mild PE; 21 severe PE; 7 HELLP syndrome), and 297 controls, recruited from the Copenhagen First-Trimester Screening Study. The A/L ratio was reduced in PE pregnancies, median 0.17 (IQR: 0.12–0.27) compared with controls, median 0.32 (IQR: 0.19–0.62) (p < 0.001). A multiple logistic regression showed that PE was negatively associated with log A/L ratio independent of maternal BMI (odds ratio = 0.315, 95% CI = 0.191 to 0.519). Adiponectin (AUC = 0.632) and PAPP-A (AUC = 0.605) were negatively associated with PE, and leptin (AUC = 0.712) was positively associated with PE. However, the A/L ratio was a better predictor of PE (AUC = 0.737), albeit not clinically relevant as a single marker. No significant association was found between A/L ratio and clinical severity of pre-eclampsia or preterm birth. PE was associated with a significantly lower relative birth weight (p < 0.001). A significant negative correlation was found between relative birth weight and A/L ratio in controls (β = −0.165, p < 0.05) but not in PE pregnancies), independent of maternal BMI. After correction for maternal BMI, leptin was significantly associated with relative birth weight (β = 2.98, p < 0.05), while adiponectin was not significantly associated. Our findings suggest that an impairment of the A/L ratio (as seen in metabolic syndrome) in the first trimester is characteristic of PE, while aberrant fetal growth in PE is not dependent on insulin sensitivity, but rather on leptin-associated pathways. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the association and predictive value between intertwin discordance in first trimester biometries crown-rump length (CRL) and nuchal translucency (NT), and the first trimester biochemical markers PAPP-A and free β-hCG in relation to birth weight discordance (BWD) ≥25% in monochorionic diamniotic (MCDA) twin pregnancies. First trimester screening information and pregnancy outcome data on MCDA twin pregnancies with delivery from July 2008 to July 2017 were retrieved from the Danish Fetal Medicine Database. CRL discordance was divided into: <10% (reference group) and ≥10%. NT discordance was divided into: <20% (reference group) and ≥20%. The twin pregnancies were classified according to BWD into the following groups: <10% (reference group), 10–24.9%, and ≥25% including cases undergoing umbilical cord occlusion due to selective fetal growth restriction (sFGR). The twin pregnancies with the most severe BWD (BWD ≥25%) were subdivided into three groups including cases with only one growth-restricted (<10th centile) infant defined as sFGR, and cases where both twins were <10th centile. Median multiples of the median (MoM) values of PAPP-A and free ß-hCG were compared with the group with BWD <10% using the Wilcoxon two-sample test. The ability of CRL discordance and NT discordance to predict BWD ≥25% was examined by the area under the receiver operator characteristic (ROC) curve. A total of 762 MCDA pregnancies were included. The proportion of pregnancies with CRL discordance ≥10% and NT discordance ≥20% was significantly higher in the group with severe BWD discordance (27.0% vs. 4.7% (p < 0.001) and 40.9% vs. 23.9% (p = 0.001), respectively). When examining the three subgroups of severe BWD, we found a significantly higher percentage of pregnancies with CRL discordance ≥10% in the group where umbilical cord occlusion was performed (52.6% vs. 4.7% in the group with BWD <10% (p < 0.001)) and in the group of BWD ≥25% with sFGR (21.7% vs. 4.7% (p < 0.001)). Additionally, a significantly higher percentage of pregnancies with NT discordance ≥20% was found in the group where umbilical cord occlusion was performed (52.6% vs. 23.9% (p = 0.005)) and in the group with both twins <10th centile (66.7% vs. 23.9% (p = 0.003)). No statistically significant differences were found when comparing levels of PAPP-A and free β-hCG MoMs with the group with BWD <10%. In ROC curves, CRL discordance yielded an AUC for prediction of BWD ≥25% of 0.70 (95% CI 0.63–0.76), and for NT discordance AUC was 0.59 (95% CI 0.52–0.66)). OR for any BWD ≥ 25% was 6.7 (95% CI 3.8–12.0) for pregnancies with a CRL discordance ≥10% compared to pregnancies with a CRL discordance <10%. This study shows that a discordance in CRL and NT in MCDA twins are both significantly associated with development of BWD. The most important predictor remains CRL discordance ≥10%, thereby suggesting the unequal growth pattern in many cases with BWD is evident already in the first trimester of the pregnancy. No association was found between first trimester biochemical markers and severe BWD. [ABSTRACT FROM AUTHOR]

Objective: Congenital heart disease (CHD) is the most common type of congenital birth defect, but little is known about possible modifiable behavioral risk factors. The study aimed to assess whether intake of periconceptional or postconceptional multivitamin was associated with a decreased risk of CHD in the offspring.Study Design: The study population comprised 15,567 women from the Copenhagen Pregnancy Cohort with complete data on multivitamin intake before and during pregnancy, who gave birth to live-born singletons from October 2012 to October 2016. Main outcome measure was CHD defined according to the International Classification of Diseases (ICD), 10th revision. Cases of CHD were classified into five subgroups based on the clinical phenotype: 1) Conotruncal defects, 2) Left ventricular outflow tract obstruction, 3) Right ventricular outflow tract obstruction, 4) Septal defects, and 5) Other CHD. Multivariate logistic regression analyses were performed with adjustment for maternal age, chronic disease, assisted reproductive technology, smoking status, and alcohol consumption.Results: Of the 15,567 included women, 31.9 % reported a daily multivitamin intake in the periconceptional period, 53.7 % in the postconceptional period, and 14.4 % women did not report a daily multivitamin intake. The prevalence of CHD in the population was 0.7 % (n = 112). Periconceptional and postconceptional multivitamin intake was not associated with risk of overall CHD in offspring: Adjusted OR was 0.64 (95 % CI 0.36-1.13) and 0.77 (95 % CI 0.47-1.30), respectively.Conclusion: The current large cohort study did not show a preventive effect of multivitamin intake in the periconceptional or postconceptional period on the risk of CHD in the offspring. [ABSTRACT FROM AUTHOR]

To investigate the association between neonatal complications and neurophysiological development in twins at 18 and 48–60 months of age. This was a secondary analysis of 841 Danish mono- and dichorionic diamniotic twins from a randomized controlled trial (PREDICT study), which included an assessment of the twin's neurophysiological development using the Ages and Stages Questionnaire (ASQ) that had been filled out by the parents at 18 and 48 or 60 months. The correlation within twin pairs was accounted for by the method of generalized estimating equation. Models were adjusted for maternal educational score and gestational age at delivery. ASQ data were available for 823 children at 18 months and 425 children at 48 or 60 months. Low maternal educational score and preterm delivery <34 weeks were associated with a lower ASQ score at 48–60 months (−15.4 points (95%CI −26.4; −4.5) and −13.2 points (95%CI −23.8; −2.5), respectively). Neonatal sepsis and a compound of intraventricular hemorrhage, retinopathy of prematurity and necrotizing enterocolitis (IVH/ROP/NEC) were associated with lower ASQ score at 18 months (−15.3 points (95%CI −28.1; −2.5) and −30.8 points (95%CI −59.5; −2.1), respectively). Children with IVH/ROP/NEC had a lower ASQ score at 48–60 months (−34.2 points (95%CI −67.9; −0.6)). The associations were not specific to only one ASQ domain. Several neonatal complications are associated with poorer neurophysiological development in twins during childhood, even after adjustment for gestational age at delivery. [ABSTRACT FROM AUTHOR]

It is well known that inflammatory markers play an important role in the development and maintenance of healthy pregnancies. However, the literature regarding inflammation in relation to lifestyle and adverse pregnancy outcomes in twin pregnancies is remarkably uncovered. Therefore, this study aimed at evaluating the concentration of inflammatory markers in dried capillary blood spot samples from 523 women with twin pregnancies, included at a median gestational age of 21+1 weeks. The relationship between inflammatory markers and maternal lifestyle (current smoking status and pre-pregnancy body mass index) in addition to adverse pregnancy outcomes (preeclampsia, gestational diabetes mellitus, and small for gestational age) was analyzed. The study showed that active smoking at inclusion was associated with an elevated concentration of interleukin-8. Furthermore, maternal obesity was associated with an elevated concentration of C-reactive protein and monocyte chemoattractant protein-1. Analysis of the data showed no statistically significant variations in the concentration of the assessed inflammatory markers for neither preeclampsia, gestational diabetes mellitus, nor small for gestational age. The current study promotes future research on the pathophysiology of twin pregnancies in relation to adverse pregnancy outcomes, as the literature within the area remains scarce. • This study examined inflammatory markers in twin pregnant women. • Active smoking during pregnancy was associated with elevated concentrations of IL-8. • Maternal obesity was associated with elevated concentrations of CRP and MCP-1. • Inflammatory markers were not associated with preeclampsia or GDM. • There was no clear association between inflammatory markers and SGA. [ABSTRACT FROM AUTHOR]

Background: Placental protein-13 (PP13) is involved in placental invasion and has been suggested as a maternal serum marker of preeclampsia (PE) development. However, the discriminatory ability of PP13 in first trimester has not been completely clarified. Methods: PP13 was measured in first trimester (week 10+3-13+6) maternal serum from 120 PE pregnancies and 267 control pregnancies and was correlated with clinical parameters. The population screening performance of PP13 in combination with the PE markers pregnancy associated plasma protein A (PAPP-A) and free leptin index (fLI) was assessed by Monte Carlo simulation. Results: In severe PE (including HELLP) cases (n = 26) the median PP13 concentration was 35.8 pg/mL (range: 17.8-85.5 pg/mL) and in PE pregnancies (n = 10) with birth prior to week 34, the median PP13 concentration was 30.6 pg/mL (13.1-50.1 pg/mL), compared to controls with a median of 54.8 pg/mL (range: 15.4-142.6 pg/mL) (p < 0.04). The population screening detection rate (DR) for a falsepositive rate of 10% for severe PE and HELLP was 26% for PP13, 28% for PP13 + PAPP-A, 33% for PP13 + fLI, and 40% for PP13 + PAPP-A + fLI. Conclusions: PP13 is a marker of severe PE and HELLP syndrome. The screening performance of PP13 can be markedly improved by combining it with fLI and PAPP-A. [ABSTRACT FROM AUTHOR]

Importance: Understanding the risk profile of obstetric complications in pregnancies with fetal major congenital heart defects (MCHDs) is crucial for obstetric counseling and care., Objective: To investigate the risk of placenta-related adverse obstetric outcomes in pregnancies complicated by fetal MCHDs., Design, Setting, and Participants: This cohort study retrieved data from June 1, 2008, to June 1, 2018, from the Danish Fetal Medicine Database, which includes comprehensive data on more than 95% of all pregnancies in Denmark since the database was instituted in 2008. All singleton pregnancies that resulted in a live-born child after 24 weeks' gestation without chromosomal aberrations were included. A systematic search of the literature was performed in PubMed, Embase, and the Cochrane Library from inception to June 1, 2024, to compile existing knowledge and data on adverse obstetric outcomes among MCHD subtypes., Exposure: Fetal MCHDs including 1 of 11 subtypes., Main Outcomes and Measures: The primary outcome was a composite adverse obstetric outcome defined as preeclampsia, preterm birth, fetal growth restriction, or placental abruption. Secondary outcomes consisted of each adverse obstetric event. Adjusted odds ratios (AORs) were computed using generalized estimating equations adjusted for maternal body mass index, age, smoking, and year of delivery. Meta-analyses were conducted using random-effects models to pool effect sizes for each MCHD subtype and adverse obstetric outcome., Results: A total of 534 170 pregnancies were included in the Danish cohort, including 745 with isolated fetal MCHDs (median [IQR] maternal age, 29.0 [26.0-33.0] years) and 533 425 without MCHDs (median [IQR] maternal age, 30.0 [26.0-33.0] years). Pregnancies with fetal MCHDs exhibited a higher rate of adverse obstetric outcomes at 22.8% compared with 9.0% in pregnancies without fetal MCHDs (AOR, 2.96; 95% CI, 2.49-3.53). Preeclampsia (AOR, 1.83; 95% CI, 1.33-2.51), preterm birth at less than 37 weeks (AOR, 3.84; 95% CI, 3.15-4.71), and fetal growth restriction (AOR, 3.25; 95% CI, 2.42-4.38) occurred significantly more frequently in pregnancies with MCHDs. Except for fetal transposition of the great arteries (AOR, 1.19; 95% CI, 0.66-2.15), all MCHD subtypes carried a greater risk of adverse obstetric outcomes. The meta-analysis included 10 additional studies that supported these results., Conclusions and Relevance: These findings suggest that nearly 1 in 4 women expecting a child with an MCHD, except transposition of the great arteries, may be at high risk of adverse obstetric outcomes.

Introduction: We aimed to investigate the prevalence of SARS-CoV-2 infection and SARS-CoV-2 antibodies in parturient women and their newborns during the first Danish COVID-19 wave and to identify associations with maternal background characteristics, self-reported symptoms, and pregnancy outcomes., Methods: In a single-centre, prospective cohort study from Denmark, we invited 1,883 women with singleton pregnancies giving live birth from 25 May 2020 to 2 November 2020. Hereof, 953 (50.6%) women were included. Nasopharyngeal swabs, maternal and umbilical cord blood samples, and questionnaires were collected. Medical records were available for participants and non-participants., Results: SARS-CoV-2 antibodies were found in 1.3% of the women. All newborns of seropositive women had SARS-CoV-2 antibodies in cord blood. No association was found between SARS-CoV-2 antibodies and pregnancy outcomes. Self-reported loss of smell correlated with seropositivity (p less-than 0.001). No women were hospitalised due to COVID-19 during pregnancy or had a positive nasopharyngeal swab intrapartum., Conclusions: The prevalence of COVID-19 in pregnancy was low during the first wave. Maternal SARS-CoV-2 antibodies were associated with antibodies in cord blood, loss of smell and positive SARS-CoV-2 swab during pregnancy, but not with any adverse pregnancy outcomes., Funding: Ferring Pharmaceuticals funded part of the study., Trial Registration: The study was approved by the Regional Committee on Health Research Ethics (H-20028002) and the Danish Data Protection Agency (P-2020-264)., (Published under Open Access CC-BY-NC-BD 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/.)

Pre-eclampsia affects 3-4% of pregnancies and is associated with maternal and infant mortality and morbidity. High-risk pregnancies in Denmark are recommended prophylactic low-dose acetylsalicylic acid (LDA). If new screening algorithms are implemented, LDA will be recommended to around 10% of pregnant women. The use of LDA may slightly increase the risk of minor bleeding disturbances. Otherwise, there is a lot of promising data regarding the safety of LDA use during pregnancy, as argued in this review., (Published under Open Access CC-BY-NC-BD 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/.)

Objective: To determine whether mitochondrial haplogroups function as disease-modifiers or as susceptibility factors in preeclampsia using a traditional haplogroup association model., Methods: This retrospective study haplotyped 235 control and 78 preeclamptic pregnancies from Denmark using either real-time PCR or Sanger sequencing depending on the rarity of the haplogroup., Results: No significant association between haplogroups and the risk of preeclampsia was found, nor was any role for haplogroups in disease severity uncovered., Conclusion: Mitochondrial haplogroups are not associated with preeclampsia or the severity of preeclampsia in the Danish population. However, this study cannot exclude a role for less common mtDNA variation. Models that can examine these should be applied in preeclamptic patients., 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.)

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.

Objective: To examine changes in concentration, time-to-peak and the ensuing half-life of cardiac biomarkers in patients with myocardial infarction., Methods: Blood sampling was performed every third hour within 24 h after percutaneous coronary intervention (PCI) on a cohort of patients with ST elevation myocardial infarction. Cardiac troponin (cTn) was measured by the Dimension Vista, Vitros, Atellica, and Alinity high-sensitivity (hs) cTnI assays, and the Elecsys hs-cTnT assay. Further, creatine kinase (CK), myoglobin, creatine kinase MB (CKMB) and other biomarkers were analyzed., Results: A total of 36 patients completed blood sampling (median age 60 years, IQR 56.4-66.5 years; seven women, 19.4%). Hs-cTnI measured by the Vitros assay was the first hs-cTn to peak at 9.1 h (95%-CI 6.2-10.1) after PCI and 11.7 h (95%-CI 10.4-14.8) after symptoms onset. There were no notable differences between hs-cTn assays in regard to time-to-peak. Also, Vitros hs-cTnI reached the highest median ratio of concentration to upper reference level of nearly 2,000. The median half-life from peak concentration ranged from 7.6 h for myoglobin (CI 6.8-8.6) to 17.8 h for CK (CI 6.8-8.6). For hs-cTn assays the median T½ ranged from 12.4 h for the Vista hs-cTnI assay (95%-CI 11.0-14.1 h) to 17.3 h for the Elecsys hs-cTnT (95%-CI 14.9-20.8 h)., Conclusions: This study updates knowledge on the kinetics of cardiac biomarkers in current clinical use. There was no notable difference in trajectories, time-to-peak or half-life between hs-cTn assays., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [HB received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Amgen, Sanofi, BMS, MSD. HB owns stock or stock options in Novo Nordic. PRK reported a grant from Gangsted Fonden outside the present work. PRK reported consulting fees from Novartis and Silence Therapeutics. PRK reported Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Physicians’ Academy for Cardiovascular Education, Novartis and PCSK9 Forum. RFS reported grants or contracts outside the present work from Lundbeck Foundation, Innovation Fund Denmark, The Danish Heart Foundation, Sygeforsikringen Denmark Research Fund, Leducq Foundation. RFS reported payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Novo Nordic. RFS reported being a steering committee member of the Copenhagen General Population Study, Steering committee member of the Copenhagen Baby Heart Study, and Deputy Head, Department of Clinical Medicine, University of Copenhagen. JK reports a grant or contract from Novo Nordic outside the present work. LH reported personal payment or honoraria for lectures from Boeringer Ingelheim and payment or honoraria to her institution for lectures from Bayer. LH reported receiving support for travel from Abbott to her Institution. MVB reported receiving honoraria for a lecture from Bristol-Myers.]., (© 2023 The Authors.)

Aims: Paracetamol is commonly consumed by pregnant women, even though recent data have questioned its safety. Having chronic medical diseases (CMDs) may influence the prevalence of use during pregnancy. We aimed to assess the prevalence and patterns of use 3 months prior to pregnancy and in the first trimester among women with and without CMDs and the potential influence of CMDs on frequent use in the first trimester., Methods: We used patient-reported data from the Copenhagen Pregnancy Cohort from 1 October 2013 to 23 May 2019 with information on CMDs and paracetamol use. Prevalence and patterns of use were assessed descriptively and by multivariable logistic regression models., Results: We included 24 019 pregnancies. Use of paracetamol prior to and in early pregnancy was significantly higher among women with CMDs compared to women without (40.7% vs. 35.8% and 9.1% vs. 5.1%, respectively). Women with CMDs were 2.7 times more likely to have a frequent intake compared to women without [aOR 2.69 (95% CI 2.05-3.32)]. Migraine, rheumatoid arthritis and mental disease were associated with a higher use of paracetamol [aOR 4.39 (3.20-6.02), aOR 4.32 (2.41-7.72) and aOR 2.74 (1.67-4.49), respectively]., Conclusions: Women with CMDs had a higher paracetamol use before and during pregnancy than women without CMDs. Women with migraine, rheumatoid arthritis and mental disease showed the highest risk of frequent use. This study highlights the importance of discussing pain relief in pregnancy and evaluating the influence of maternal CMDs when assessing adverse effects of paracetamol use during pregnancy., (© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Objective: To identify maternal factors associated with labor dystocia in low-risk nulliparous women., Methods: MEDLINE, Embase, ClinicalTrials.gov, Cochrane, and CINAHL were searched for intervention studies and observational studies published from January 2000 to January 2022. Low-risk was defined as nulliparous women with a singleton, cephalic birth in spontaneous labor at term. Labor dystocia was defined by national or international criteria or treatment. Countries were restricted to OECD members. Two authors independently screened 11,374 titles and abstracts, extracted data, and assessed risk of bias using the Newcastle-Ottawa Scale. Results were presented narratively and by meta-analysis when compatible., Results: Seven cohort studies were included. Overall, the certainty of the evidence was moderate. Three studies found that higher maternal age was associated with an increased frequency of labor dystocia (relative risk 1.68; 95% CI 1.43-1.98). Further three studies found that higher maternal BMI was associated with increased frequency of labor dystocia (relative risk 1.20; 95% CI 1.01-1.43). Maternal short stature, fear of childbirth, and high caffeine intake were also associated with an increased frequency of labor dystocia, while maternal physical activity was associated with a decreased frequency., Conclusion: Maternal factors associated with an increased frequency of labor dystocia were mainly maternal age, physical characteristics, and fear of childbirth. Maternal physical activity was associated with a decreased frequency. Intervention studies targeting these maternal factors would need to be initiated before or early in pregnancy to test the causality of the identified factors and labor dystocia., 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 Author(s). Published by Elsevier B.V. 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.)

Objectives: Our objective was to investigate if an increased nuchal translucency (NT) was associated with higher mortality in chromosomally normal children with congenital heart defects (CHD)., Methods: In a nationwide cohort using population-based registers, we identified 5,633 liveborn children in Denmark with a pre- or postnatal diagnosis of CHD from 2008 to 2018 (incidence of CHD 0.7%). Children with chromosomal abnormalities and non-singletons were excluded. The final cohort compromised 4,469 children. An increased NT was defined as NT > 95th-centile. Children with a NT > 95th-centile vs. NT < 95th-centile including subgroups of simple- and complex CHD were compared. Mortality was defined as death from natural causes, and mortalities were compared among groups. Survival analysis with Cox-regression was used to compare rates of mortality. Analyses were adjusted for mediators (possibly explanatory factors between increased NT and higher mortality): preeclampsia, preterm birth and small for gestational age. And for confounding effects of extracardiac anomalies and cardiac intervention, due to their close association to both the exposure and the outcome (i.e., confounders)., Results: Of the 4,469 children with CHD, 754 (17%) had complex CHD and 3,715 (83%) simple CHD. In the combined group of CHDs the mortality rate was not increased when comparing those with a NT > 95th-centile to those with a NT < 95th-centile [Hazard ratio (HR) 1.6, 95%CI 0.8;3.4, p  = 0.2]. In simple CHD there was a significantly higher mortality rate with a HR of 3.2 (95%CI: 1.1;9.2, p  = 0.03) when having a NT > 95th centile. Complex CHD had no differences in mortality rate between a NT > 95th-centile and NT < 95th-centile (HR 1.1, 95%CI: 0.4;3.2, p  = 0.8). All analysis adjusted for severity of CHD, cardiac operation and extracardiac anomalies. Due to limited numbers the association to mortality for a NT > 99th centile (>3.5 mm) could not be assessed. Adjustment for mediating (preeclampsia, preterm birth, small for gestational age) and confounding variables (extracardiac anomalies, cardiac intervention) did not alter the associations significantly, except for extracardiac anomalies in simple CHD., Conclusion: An increased NT > 95th-centile is correlated with higher mortality in children with simple CHD, but the underlying cause is unknown and undetected abnormal genetics might explain the correlation rather than the increased NT itself, hence further research is warranted., 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., (© 2023 Kristensen, Omann, Gaynor, Rode, Ekelund and Hjortdal.)

Objective: First, to evaluate the risks of stillbirth and neonatal death by gestational age in twin pregnancies with different levels of growth discordance and in relation to small for gestational age (SGA), and on this basis to establish optimal gestational ages for delivery. Second, to compare these optimal gestational ages with previously established optimal delivery timing for twin pregnancies not complicated by fetal growth restriction, which, in a previous individual patient meta-analysis, was calculated at 37 0/7 weeks of gestation for dichorionic pregnancies and 36 0/7 weeks for monochorionic pregnancies., Data Sources: A search of MEDLINE, EMBASE, ClinicalTrials.gov, and Ovid between 2015 and 2018 was performed of cohort studies reporting risks of stillbirth and neonatal death in twin pregnancies from 32 to 41 weeks of gestation. Studies from a previous meta-analysis using a similar search strategy (from inception to 2015) were combined. Women with monoamniotic twin pregnancies were excluded., Methods of Study Selection: Overall, of 57 eligible studies, 20 cohort studies that contributed original data reporting on 7,474 dichorionic and 2,281 monochorionic twin pairs., Tabulation, Integration, and Results: We performed an individual participant data meta-analysis to calculate the risk of perinatal death (risk difference between prospective stillbirth and neonatal death) per gestational week. Analyses were stratified by chorionicity, levels of growth discordance, and presence of SGA in one or both twins. For both dichorionic and monochorionic twins, the absolute risks of stillbirth and neonatal death were higher when one or both twins were SGA and increased with greater levels of growth discordance. Regardless of level of growth discordance and birth weight, perinatal risk balanced between 36 0/7-6/7 and 37 0/7-6/7 weeks of gestation in both dichorionic and monochorionic twin pregnancies, with likely higher risk of stillbirth than neonatal death from 37 0/7-6/7 weeks onward., Conclusion: Growth discordance or SGA is associated with higher absolute risks of stillbirth and neonatal death. However, balancing these two risks, we did not find evidence that the optimal timing of delivery is changed by the presence of growth disorders alone., Systematic Review Registration: PROSPERO, CRD42018090866., Competing Interests: Financial Disclosure Elena Carreras is a member of the European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability ERN-ITHACA (EU Framework Partnership Agreement ID: 3HP-HP-FPA ERN-01-2016/739516). One included research project was supported, in part, by the Division of Population Health, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, and, in part, with federal funds for the NICHD Fetal Growth Studies – Dichorionic Twins under Contract Numbers: HHSN275200800013C; HHSN275200800002I; HHSN27500006; HHSN275200800003IC; HHSN275200800014C; HHSN275200800012C; HHSN275200800028C; and HHSN275201000009C. Katherine L. Grantz has contributed to this work as part of her official duties as an employee of the United States federal government. Wessel Ganzevoort reports government funding (ZonMW 843002825) and free-of-charge test kits from Roche Diagnostics. Sanne J. Gordijn disclosed that money was paid to their institution from ZonMW, Roche (in-kind kits unrestricted and shipping and handling of material), and SCEM (conference payment to research fund). They also received funding from Dublin Maternity Hospital (payment for travels for Charter Day lecture). In addition, they report holding government funding (ZonMW 852002034) and free-of-charge test kits from Roche Diagnostics. R. Katie Morris disclosed money was paid to her through a consultancy to a company that designs neonatal vital signs monitors (SUREPULSE), and money was paid to her institution from the NIHR. Ben W. Mol is supported by a NHMRC Investigator grant (GNT1176437), and reports consultancy for ObsEva and research funding from Ferring and Merck. The PREDICT study received funding from The Danish Medical Research Council, The Fetal Medicine Foundation, The Copenhagen University Hospital's Research Fund, The Aase and Ejnar Danielsens Fund, The Augustinus Fund, The Ivan Nielsen Fund, The Doctor Sofus Carl Emil Friis, and wife Olga Doris Friis' Fund, The Simon Fougner Hartmanns Family Fund, The Danish Medical Society in Copenhagen, and The A.P. Moeller Foundation. The other authors did not report any potential conflicts of interest., (Copyright © 2022 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

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.)