The Danish national haemoglobinopathy screening programme: Report from 16 years of screening in a low-prevalence, non-endemic region.

The Danish national haemoglobinopathy screening programme seeks to determine parental haemoglobinopathy carrier state antenatally. In this retrospective register-based study, we evaluated the 16-year trajectory of this programme, utilising the Danish Red Blood Cell Centre's laboratory database, covering approximately 77% of the Danish population. During the study period, we observed a substantial increase in annual diagnostic examinations performed, from 389 in 2007 to 3030 in 2022. Women constituted 88% of these cases, aligning with the emphasis of the screening programme. Of these, 54% of women of reproductive age (15-40 years) and 10% of women >40 years were specified as pregnant. During our study period, 61 children were born with a severe haemoglobinopathy, out of which 23 children were born from mothers not residing in Denmark during their first trimester thus not included in the screening programme. Prenatal invasive testing was performed for 60 fetuses, identifying 12 with homozygous or compound heterozygous haemoglobinopathy. The Danish haemoglobinopathy screening programme has provided screening, information and reproductive choices for numerous families. During the study period, screening for haemoglobinopathies has been steadily increasing and is expected to continue to increase. Awareness of and adherence to the screening programme is subject of further investigation and optimisation.

Cell-free fetal DNA for genetic evaluation in Copenhagen Pregnancy Loss Study (COPL): a prospective cohort study.

BACKGROUND: One in four pregnancies end in a pregnancy loss. Although the effect on couples is well documented, evidence-based treatments and prediction models are absent. Fetal aneuploidy is associated with a higher chance of a next successful pregnancy compared with euploid pregnancy loss in which underlying maternal conditions might be causal. Ploidy diagnostics are therefore advantageous but challenging as they require collection of the pregnancy tissue. Cell-free fetal DNA (cffDNA) from maternal blood has the potential for evaluation of fetal ploidy status, but no large-scale validation of the method has been done. METHODS: In this prospective cohort study, women with a pregnancy loss were recruited as a part of the Copenhagen Pregnancy Loss (COPL) study from three gynaecological clinics at public hospitals in Denmark. Women were eligible for inclusion if older than 18 years with a pregnancy loss before gestational age 22 weeks (ie, 154 days) and with an intrauterine pregnancy confirmed by ultrasound (including anembryonic sac), and women with pregnancies of unknown location or molar pregnancies were excluded. Maternal blood was collected while pregnancy tissue was still in situ or within 24 h after pregnancy tissue had passed and was analysed by genome-wide sequencing of cffDNA. Direct sequencing of the pregnancy tissue was done as reference. FINDINGS: We included 1000 consecutive women, at the time of a pregnancy loss diagnosis, between Nov 12, 2020, and May 1, 2022. Results from the first 333 women with a pregnancy loss (recruited between Nov 12, 2020, and Aug 14, 2021) were used to evaluate the validity of cffDNA-based testing. Results from the other 667 women were included to evaluate cffDNA performance and result distribution in a larger cohort of 1000 women in total. Gestational age of fetus ranged from 35-149 days (mean of 70·5 days [SD 16·5], or 10 weeks plus 1 day). The cffDNA-based test had a sensitivity for aneuploidy detection of 85% (95% CI 79-90) and a specificity of 93% (95% CI 88-96) compared with direct sequencing of the pregnancy tissue. Among 1000 cffDNA-based test results, 446 (45%) were euploid, 405 (41%) aneuploid, 37 (4%) had multiple aneuploidies, and 112 (11%) were inconclusive. 105 (32%) of 333 women either did not manage to collect the pregnancy tissue or collected a sample classified as unknown tissue giving a high risk of being maternal. INTERPRETATION: This validation of cffDNA-based testing in pregnancy loss shows the potential and feasibility of the method to distinguish euploid and aneuploid pregnancy loss for improved clinical management and benefit of future reproductive medicine and women's health research. FUNDING: Ole Kirks Foundation, BioInnovation Institute Foundation, and the Novo Nordisk Foundation.

Impact of maternal age and body mass index on the structure and function of the heart in newborns: a Copenhagen Baby Heart Study.

BACKGROUND: Maternal obesity and advanced age have been associated with an increased risk of structural congenital heart defects in the offspring. Whether these factors may also cause abnormalities in infant cardiac dimension and function is unknown. This study investigates whether maternal body mass index (BMI) and maternal age are associated with changes in left ventricular (LV) dimensions and function in the newborn. METHODS: Infants enrolled in the Copenhagen Baby Heart Study (CBHS), who were born at term, and contributed with a transthoracic echocardiography (TTE) within 60 days of birth were included. The exposure variables were prepregnancy maternal BMI (kg/m2) < 18.5; 18.5-24.9 (reference); 25-29.9; 30-34.9 and ≥ 35 and maternal age (years) < 25; 25-29; 30-34 (reference); 35-39 and ≥ 40. Outcomes were LV parameters ascertained by 2D-echocardiography. Associations between each maternal factor and infant LV parameters were analysed with either a linear model adjusted for the child's weight and length at birth, gestational age, sex, age at TTE, and maternal smoking, or a linear mixed model, further adjusted for random effects of analyst and month of analysis. Analyses investigating impact of maternal BMI were adjusted for maternal age, and vice versa. RESULTS: The study cohort included 24,294 infants. Compared with infants in the BMI reference group, infants born to women with a BMI ≥ 25 kg/m2 generally had smaller measures of LV internal diameters in end-diastole, reaching statistical significance for BMI 30-34.9 kg/m2 [-0.11 ± 0.04 mm, p = 0.01]. All groups of infants born to women with a BMI ≥ 25 kg/m2 had significantly smaller LV internal diameters in end-systole: BMI 25-29.9 kg/m2 [-0.04 ± 0.02 mm, p = 0.04], BMI 30-34.9 kg/m2 [-0.12 ± 0.03 mm, p = 0.001] and BMI ≥ 35 kg/m2 [-0.11 ± 0.05 mm, p = 0.03]. Compared with infants in the age reference group, infants born to women ≥ 40 years had significantly smaller LV internal diameters in end-diastole [-0.15 ± 0.04 mm, p = 0.001] and end-systole [-0.09 ± 0.04 mm, p = 0.009]. CONCLUSIONS: Systematic population-based echocardiography of infants showed that a maternal prepregnancy BMI ≥ 25 kg/m2 and maternal age ≥ 40 years were associated with smaller systolic and diastolic LV diameters. The long-term effects are unknown. CLINICAL TRIAL REGISTRATION: April 2016, Copenhagen Baby Heart, NCT02753348 .

Risks and pregnancy outcome after fetal reduction in dichorionic twin pregnancies: a Danish national retrospective cohort study.

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.

Motivation towards first trimester screening for preeclampsia among pregnant women in Denmark: A cross-sectional questionnaire study.

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.

Second-trimester cardiovascular biometry in growth-restricted fetuses; a multicenter cohort study.

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.

Maternal first trimester iron status and its association with obstetric and perinatal outcomes.

PURPOSE: To assess the following in singleton pregnant women: (1) associations between first trimester iron deficiency and obstetric and perinatal outcomes, (2) overall first trimester iron status and (3) post-treatment iron status after intensified iron supplementation. METHODS: A prospective cohort study was conducted with linkage of first trimester hemoglobin and plasma ferritin with obstetric and perinatal data from a hospital database. Blood sample data were obtained from a Danish University Hospital. The cohort was divided into groups according to ferritin and hemoglobin: (1) iron-deficient anemic (ferritin < 30 ng/mL and Hb < 110 g/L), (2) iron-deficient non-anemic (ferritin < 30 ng/mL and Hb ≥ 110 g/L), and (3) iron-replete non-anemic (ferritin 30-200 ng/mL and Hb ≥ 110 g/L). Obstetric and perinatal outcomes in each iron-deficient group were compared to the iron-replete non-anemic group using multivariable logistic regression. The effect of 4 weeks intensified iron supplementation on hemoglobin and ferritin was assessed by groupwise comparisons. RESULTS: The cohort comprised 5763 singleton pregnant women, of which 14.2% had non-anemic iron deficiency, and 1.2% had iron-deficiency anemia. Compared to iron-replete non-anemic women, iron-deficient anemic women had a higher risk of gestational diabetes (aOR 3.8, 95% CI 1.4-9.0), and iron-deficient non-anemic women had a higher risk of stillbirth (aOR 4.0, 95% CI 1.0-14.3). In group 1 and 2, 81.5% and 67.7% remained iron-deficient after intensified iron supplementation. CONCLUSION: Iron-deficiency anemia was associated with gestational diabetes, and non-anemic iron deficiency with stillbirth, although risk estimates were imprecise due to few events. Iron deficiency was present in 15.4% and often persisted despite 4 weeks intensified iron supplementation.

Prenatally detected isolated ventricular septum defects and the association with chromosomal aberrations-A nationwide register-based study from Denmark.

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 ß-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.

Prevalence of Bicuspid Aortic Valve and Associated Aortopathy in Newborns in Copenhagen, Denmark.

Importance: The prevalence and characteristics of bicuspid aortic valve (BAV) are mainly reported from selected cohorts. BAV is associated with aortopathy, but it is unclear if it represents a fetal developmental defect or is secondary to abnormal valve dynamics. Objective: To determine the prevalence of BAV and BAV subtypes and to describe the associated aortopathy in a large, population-based cohort of newborns. Design, Setting, and Participants: The Copenhagen Baby Heart Study was a cross-sectional, population-based study open to all newborns born in Copenhagen between April 1, 2016, and October 31, 2018. Newborns with BAV were matched 1:2 to newborns with a tricuspid aortic valve (non-BAV group) on sex, singleton/twin pregnancy, gestational age, weight, and age at time of examination. Exposures: Transthoracic echocardiography within 60 days after birth. Main Outcomes and Measures: Primary outcome was BAV prevalence and types, ie, number of raphes and spatial orientation of raphes or cusps (no raphes), according to the classification system of Sievers and Schmidtke (classified as type 0, 1, or 2, with numbers indicating the number of raphes). Secondary outcome was valve function and BAV-associated aortopathy, defined as aortic diameter z score of 3 or greater or coarctation. Results: In total, 25 556 newborns (51.7% male; mean age, 12 [SD, 8] days) underwent echocardiography. BAV was diagnosed in 196 newborns (prevalence, 0.77% [95% CI, 0.67%-0.88%]), with male-female ratio 2.1:1. BAV was classified as type 0 in 17 newborns (8.7% [95% CI, 5.5%-13.5%]), type 1 in 178 (90.8% [95% CI, 86.0%-94.1%]) (147 [75.0% {95% CI, 68.5%-80.5%}] right-left coronary raphe, 27 [13.8% {95% CI, 9.6%-19.3%}] right coronary-noncoronary raphe, 4 [2.0% {95% CI, 0.8%-5.1%}] left coronary-noncoronary raphe), and type 2 in 1 (0.5% [95% CI, 0.1%-2.8%]). Aortic regurgitation was more prevalent in newborns with BAV (n = 29 [14.7%]) than in those without BAV (1.3%) (absolute % difference, 13.4% [95% CI, 7.8%-18.9%]; P < .001). Newborns with BAV had higher flow velocities across the valve (0.67 [95% CI, 0.65-0.69] m/s vs 0.61 [95% CI, 0.60-0.62] m/s; mean difference, 0.06 m/s [95% CI, 0-0.1]) and larger aortic root and tubular ascending aortic diameters than those without BAV (10.7 [95% CI, 10.7-10.9] mm vs 10.3 [95% CI, 10.2-10.4] mm; mean difference, 0.43 mm [95% CI, 0.2-0.6 mm] and 9.8 [95% CI, 9.6-10.0] mm vs 9.4 [95% CI, 9.3-9.5] mm; mean difference, 0.46 mm [95% CI, 0.30-0.70], respectively) (P < .001 for all). Aortopathy was seen in 65 newborns (33.2%) with BAV (62 with aortic z score ≥3; 3 with coarctation). Conclusions and Relevance: Among newborns in Copenhagen, the prevalence of BAV was 0.77%. Aortopathy was common in newborns with BAV, suggesting that it also represents a fetal malformation.

Copenhagen Baby Heart Study: a population study of newborns with prenatal inclusion.

Congenital heart diseases (CHDs) are reported in 0.8% of newborns. Numerous factors influence cardiovascular development and CHD prevalence, and possibly also development of cardiovascular disease later in life. However, known factors explain the probable etiology in only a fraction of patients. Past large-scale population-based studies have made invaluable contributions to the understanding of cardiac disease, but none recruited participants prenatally and focused on the neonatal period. The Copenhagen Baby Heart Study (CBHS) is a population-based study of the prevalence, spectrum, and prognosis of structural and functional cardiac abnormalities. The CBHS will also establish normal values for neonatal cardiac parameters and biomarkers, and study prenatal and early childhood factors potentially affecting later cardiovascular disease risk. The CBHS is an ongoing multicenter, prospective study recruiting from second trimester pregnancy (gestational weeks 18-20) (expected n = 25,000). Information on parents, pregnancy, and delivery are collected. After birth, umbilical cord blood is collected for biochemical analysis, DNA purification, and biobank storage. An echocardiographic examination, electrocardiography, and post-ductal pulse oximetry are performed shortly after birth. Infants diagnosed with significant CHD are referred to a specialist or admitted to hospital, depending on CHD severity. CBHS participants will be followed prospectively as part of specific research projects or regular clinical follow-up for CHD. CBHS design and methodology are described. The CBHS aims to identify new mechanisms underlying cardiovascular disease development and new targets for prevention, early detection, and management of CHD and other cardiac diseases presenting at birth or developing later in life.

High risk-What's next? A survey study on decisional conflict, regret, and satisfaction among high-risk pregnant women making choices about further prenatal testing for fetal aneuploidy.

OBJECTIVES: To investigate decision making among pregnant women when choosing between noninvasive prenatal testing, invasive testing, or no further testing. METHODS: Women with a high-risk result from the first trimester screening were invited to fill in two online questionnaires at gestational age 12 to 14 (Q1) and 24 weeks (Q2). The scales used were Decisional Conflict and Regret Scales, Satisfaction with genetic Counselling Scale, and Health-Relevant Personality Inventory. RESULTS: Three hundred thirty-nine women agreed to participate, and the response rates were 76% on Q1 and 88% on Q2. A percentage of 75.4% chose an invasive test, 23.8% chose noninvasive prenatal testing (NIPT), 0.4% chose no further testing, and 0.4% had both NIPT and invasive testing. Among all participants, 13.3% had a high level of decisional conflict. We found that choosing NIPT was associated with a high decisional conflict (p = 0.013), receiving genetic counselling the same day was associated with a high decisional conflict (p = 0.039), and a high satisfaction with the genetic counselling was associated with low decisional conflict (p < 0.001). Furthermore, the personality subtrait "alexithymia" was associated with low decisional conflict (p = 0.043). There was a significant association between high decisional conflict and later decisional regret (p = 0.008). CONCLUSION: We present evidence that satisfaction with and timing of counselling are important factors to limit decisional conflict. Interestingly, women choosing NIPT had more decisional conflict than women choosing invasive testing.

Discordant non-invasive prenatal testing (NIPT) - a systematic review.

With a high sensitivity and specificity, non-invasive prenatal testing (NIPT) is an incomparable screening test for fetal aneuploidy. However, the method is rather newly introduced, and experiences with discordant results are few. We did a systematic review of literature reporting details of false positive and false negative NIPT results. Discordant sex chromosome results were not included. We identified 22 studies reporting case details. In total, 206 discordant cases were included, of which 88% were false positive and 12% false negative. Details on maternal age, gestational age, platform/company, Z-score, fetal fraction, results and explanation were specified. The main reasons for discordant results were confined placental mosaicism, maternal copy number variation, vanished twin, maternal cancer and true fetal mosaicism. A very high percentage of cases (67%) were reported with no obvious biological or technical explanation for the discordant result. The included cases represent only a minor part of the true number of false positive or false negative NIPT cases identified in fetal medicine clinics around the world. To ensure knowledge exchange and transparency of NIPT between laboratories, we suggest a systematic recording of discordant NIPT results, as well as a quality assurance by external quality control and accreditation. © 2017 John Wiley & Sons, Ltd.

Investigation on the ability of first trimester glycodelin and angiopoietin-2 to predict small-for-gestational age pregnancies at delivery.

BACKGROUND: The aim was to investigate whether first trimester glycodelin and angiopoietin-2 can predict small-for-gestational age (SGA) at delivery, individually or in combination. METHODS: In this case-control study we measured glycodelin and angiopoietin-2 on serum from 170 singleton pregnant women delivering SGA neonates and 985 singleton pregnant women delivering normal-weighted neonates. All values were converted to multiples of the medians (MoM). RESULTS: Pregnant women delivering SGA neonates had lower first trimester glycodelin and angiopoietin-2 MoM values [median (interquartile range)] compared with pregnant women delivering normal-weighted neonates for glycodelin: 0.86 (0.58-1.24) vs. 1.03 (0.74-1.45), p<0.001, and for angiopoietin-2: 0.89 (0.69-1.19) vs. 1.01 (0.78-1.31), p<0.001. The prediction performances of the biomarkers showed that the areas under the curve (AUC) were 0.59 (glycodelin), 0.58 (angiopoietin-2), and 0.60 (glycodelin and angiopoietin-2). CONCLUSIONS: We demonstrated that first trimester glycodelin and angiopoietin-2 were associated with SGA, but they were, individually and in combination, poor predictors of SGA at delivery. The AUCs were low which indicate low detection rates and high false positive rates.

First trimester PAPP-A2, PAPP-A and hCGß in small-for-gestational-age pregnancies.

BACKGROUND: Pregnancy-associated plasma protein-A2 (PAPP-A2) is a recently discovered protease that cleaves a subset of insulin-like growth factor binding proteins (IGFBP). The molecular function suggests its involvement in the IGF system that is vital for fetal growth and development. Our objectives were to establish first trimester median curves of PAPP-A2, PAPP-A and hCGß for singleton normal pregnancies and to investigate whether an altered level of one or more of the biomarkers is associated with small-for-gestational-age (SGA) neonates before and after stratification according to maternal hypertension and/or proteinuria. METHODS: This was a case-control study based on 985 pregnant women delivering normal-weighted neonates and 170 pregnant women delivering SGA neonates. PAPP-A2 was measured by ELISA. PAPP-A and hCGß were measured by an automatic analyzer. Median curves from 8+1 to 14+0 were established and all concentration values were converted to multiples of the median (MoM) values. RESULTS: Before stratification the SGA cases had unaffected PAPP-A2 MoM and hCGß MoM levels but lower PAPP-A MoM compared with normal controls. After stratification the SGA normotensive subgroup had lower PAPP-A2 MoM and PAPP-A MoM levels than the normal normotensive subgroup. Severe preeclamptic women delivering SGA neonates had higher PAPP-A2 MoM compared to the normotensive women delivering SGA neonates. CONCLUSIONS: Pregnant women delivering SGA neonates did not have altered levels of PAPP-A2 or hCGß but had lower PAPP-A level in the first trimester compared with pregnant women delivering normal-weighted neonates. Pregnancies complicated with severe preeclampsia and SGA may be associated with high PAPP-A2 level.

The maternal age-related first trimester risks for trisomy 21, 18 and 13 based on Danish first trimester data from 2005 to 2014.

OBJECTIVES: Most currently used age-related risks of T21, T18 and T13 are based on estimates of the live-birth prevalence, and describe an exponential increase of risk by increased maternal age. We investigated the first trimester prevalence of T21, T18 and T13 in a large population of Danish women. METHODS: From the Danish Cytogenetic Central Registry we got the information of all pre- and postnatally diagnosed fetuses with T21, T18 or T13 between 2005 and 2014 in Denmark. Information on the total number of births and maternal age at birth were gathered from StatBank Denmark. RESULTS: The total number of included women was 605 853. The total number of T21 cases was 1564, T18 cases was 401 and T13 cases was 157. The overall first trimester prevalence per 10 000 pregnancies was 25.8 for T21, 6.6 for T18 and 2.6 for T13. Boltzmann sigmoidal model (Y = Bottom + (top-bottom / (1 - exp (V50 - X) / slope)) was found to best describe the age-related risk of T21, T18 and T13. CONCLUSION: We found that the age-related risks are better described by sigmoidal functions, contrary to the widely assumed exponential functions. Our results indicate a lower age-related a priori risk of T21, T18 and T13 compared to widely used risk models. © 2016 John Wiley & Sons, Ltd.

Women with minor menstrual irregularities have increased risk of preeclampsia and low birthweight in spontaneous pregnancies.

INTRODUCTION: Very few studies describe the obstetric and neonatal outcome of spontaneous pregnancies in women with irregular menstrual cycles. However, menstrual cycle irregularities are common and may be associated with increased risk, and women who develop pregnancy complications more frequently recollect irregular menstrual cycles before the time of conception in case-control studies. MATERIAL AND METHODS: This retrospective cohort study compares obstetric and neonatal outcomes in spontaneous singleton pregnancies in 3440 primiparous Danish women stratified according to menstrual cycle regularity. All pregnancies delivered after 22 weeks of gestation and had a nuchal translucency examination at Copenhagen University Hospital Hvidovre between 1 January 2009 and 31 December 2010. Menstrual cycle irregularity was defined as more than 7 days' deviation between self-reported and ultrasound examination-based gestational age. Outcome measures were gestational diabetes, hypertension, preeclampsia, preterm premature rupture of membranes, preterm birth, prolonged pregnancy, birthweight, umbilical artery pH <7.1, APGAR <7 after 5 min, admission to neonatal intensive care unit and stillbirth. Women with more than 7 days' deviation between self-reported and ultrasound examination-based gestational age were compared with women with a deviation of 7 days or less. RESULTS: Irregular menstrual cycle before conception increases the risk of preeclampsia (7.9% vs. 5.2%, p < 0.05) and low birthweight (6.0% vs. 3.6%, p < 0.05) in spontaneous pregnancies, but reduces the risk of prolonged pregnancy (1.4% vs. 4.7%, p < 0.001). CONCLUSION: Irregular menstrual cycle before conception is associated with increased risk of adverse obstetric and neonatal outcome.

Prenatal detection of congenital heart disease in a low risk population undergoing first and second trimester screening.

OBJECTIVES: The prenatal detection rate of congenital heart disease (CHD) is low compared with other fetal malformations. Our aim was to evaluate the prenatal detection of CHD in Eastern Denmark. METHODS: Fetuses and infants diagnosed with CHD in the period 01.01.2008-31.12.2010 were assessed regarding prenatal detection rate and accuracy, as well as correlation with nuchal translucency (NT) thickness. RESULTS: Out of 86 121 infants, 831 were born with CHD (0.96%). The prenatal detection rate of 'all CHD' was 21.3%, of 'Major CHD' 47.4%. Full agreement between prenatal and postnatal/autopsy findings was found in 96% of prenatally detected diagnoses. An NT thickness >95(th) percentile was found in 15.0% fetuses with 'Major CHD'. Of 'Major CHDs' detected prenatally, 77% were picked up at the time of the malformation scan at weeks 18-21. CONCLUSIONS: Nearly half of 'Major CHDs' were detected prenatally. The prenatal cardiac diagnoses showed a high degree of accuracy. Increased NT thickness as a screening tool for CHD performed moderately but is an important high risk group for specialist examination. A minority of the prenatally detected CHDs was identified because of extra scans performed in high risk pregnancies. © 2014 John Wiley & Sons, Ltd.

Are there characteristics of the false-negative cases from the first trimester combined screening programme for Down syndrome?

PURPOSE OF REVIEW: To review if there are any characteristics of false-negative cases from the first trimester combined screening programme for Down syndrome and by that to stimulate new approaches for improvements of the screening performance. RECENT FINDINGS: We are aware of only two studies based on screening results of false-negative cases. Screening results from false-negative cases show that maternal age is lower, nuchal translucency smaller, pregnancy-associated plasma protein-A level higher, ß-human chorionic gonadotropin level lower and crown-rump length bigger than among true positive cases. Around 50% of false-negative cases had a final risk between 1 : 300 and 1 : 1000. There might also be a difference in maternal smoking status, conception method, ethnicity and weight discrepancy between false-negative and true positive cases. New biomarkers and secondary sonographic markers may also characterize false-negative cases, but investigations on these subjects have not been done so far. Finally, we think that the organization of a screening programme in all its details is a very important factor when it comes to optimizing screening performance. SUMMARY: Screening parameters of false-negative cases tend toward the values of unaffected pregnancies with lower maternal age, smaller nuchal translucency, higher pregnancy-associated plasma protein-A level, lower ß-human chorionic gonadotropin level and bigger crown-rump length than among true positive cases.

Autocorrelation and cross-correlation between hCGß and PAPP-A in repeated sampling during first trimester of pregnancy.

BACKGROUND: Theoretically, repeated sampling of free ß-human chorionic gonadotropin (hCGß) and pregnancy associated plasma protein-A (PAPP-A) in the first trimester of pregnancy might improve performance of risk assessment of trisomy 21 (T21). To assess the performance of a screening test involving repeated measures of biochemical markers, correlations between markers must be estimated. The aims of this study were to calculate the autocorrelation and cross-correlation between hCGß and PAPP-A in the first trimester of pregnancy and to investigate the possible impact of gestational age at the first sample and time between sampling on the correlation. METHODS: A prospective study was conducted including 3891 unaffected singleton pregnancies. Two measurements of hCGß and PAPP-A were obtained during the first trimester in each pregnancy. Correlations between the four parameters, hCGß first, hCGß second, PAPP-A first and PAPP-A second, were estimated and presented in terms of Pearson's r coefficients. Furthermore, the correlation between paired samples as a function of time between samples was investigated. RESULTS: The study demonstrated high correlation between first and second samples of hCGß and PAPP-A with a correlation coefficient of 0.80 and 0.79, respectively. By contrast, the correlations between hCGß and PAPP-A were low. In addition, the study demonstrated that the correlation between paired samples of hCGß and PAPP-A decreases with earlier gestational age at the first sample and with increasing time between samples. CONCLUSIONS: We have developed a parameter set in terms of correlations between biochemical markers, which can be incorporated into a T21 screening algorithm based on repeated measures within the first trimester.