Finn Stener Jørgensen

Introduction: We describe timing, diagnostic yield, secondary findings of prenatal whole genome sequencing (pWGS) in ongoing pregnancies during the first 5 years of implementation within a publicly funded healthcare system. Moreover, we discuss our collective clinical experiences implementing pWGS in prenatal care. Material and Methods: We conducted a historical cohort study, including all singleton pregnancies undergoing pWGS after a normal chromosomal microarray between 2019 and 2023. Data on sample type, gestational age at test ordering, turnaround time, diagnostic yield, and secondary findings were extracted from all four Danish clinical genetics laboratories. Results: A total of 207 cases were analyzed, including 85 chorionic villus samples and 122 amniotic fluid samples; trio sequencing was performed in 204/207 (98.6%). Median gestational age at ordering was 20 weeks (IQR 17–21). Median turnaround time for ongoing pregnancies was 11 working days (IQR 8–17). Pathogenic or likely pathogenic variants explaining the phenotype were identified in 33/207 pregnancies (15.9%, 95% CI 11.6–21.5). Yield was highest in hydrops (25.0%, 95% CI 12.0–44.9) and multiple anomalies (24.3%, 95% CI 13.4–40.1), and lowest in isolated increased nuchal translucency (7.1%, 95% CI 2.0–22.6). Secondary findings were reported in 18/207 cases (8.7%, 95% CI 5.6–13.3). Conclusions: pWGS was delivered within clinically relevant turnaround times. Applied after normal chromosomal microarray, the yield represents incremental diagnostic value in a chromosomal microarray‐negative population. In clinical practice, both normal and abnormal pWGS results form a central component of counseling in ongoing pregnancies with unresolved fetal risk. However, the impact of such results on parental decision‐making or pregnancy outcomes was not assessed in this study.

Women with essential thrombocythemia (ET) and polycythemia vera (PV) are at increased risk of pregnancy complications. During pregnancy, hematologic parameters tend to approach normal values, and previous studies have reported that a greater decline in platelet counts in ET is associated with reduced risk of complications. In this study, we examined longitudinal trajectories of platelet count, hemoglobin, hematocrit, and leukocyte count during pregnancy, characterized pregnancy outcomes, and investigated the association between platelet trajectories and preeclampsia. We established a longitudinal cohort of pregnant women with ET and PV in the Capital Region and Region Zealand between 2010 and 2024, using data from regional laboratory information systems and Danish health registries. In total, 41 ET and 5 PV pregnancies in 35 women were included. The mean age at MPN diagnosis was 30.1 years in women with ET and 34.1 years in women with PV. In ET pregnancies, platelet counts, hemoglobin, hematocrit and leukocyte count changed by − 44%, − 5%, − 12% and + 55%, respectively, from baseline to delivery, and in PV pregnancies − 36%, − 26%, − 25% and + 47%, respectively. Overall, 29% of ET pregnancies had a maternal complication, with preeclampsia being the most common (12%). ET women who developed preeclampsia had significantly higher platelet counts before pregnancy and experienced a greater decline in platelet counts during pregnancy than women without preeclampsia. Thus, hematologic trajectories during pregnancy may help identify women at increased risk of preeclampsia.

How fast does cell-free fetal DNA (cffDNA) decline after early pregnancy loss and which factors affect the decline? After pregnancy loss cffDNA declines gradually with detectable levels persisting up to 3 days post-tissue passage correlating with β-hCG decline. Postpartum clearance of cffDNA occurs within hours, but little is known about its decline following early pregnancy loss. Initial results from the Copenhagen Pregnancy Loss (COPL) study showed slower clearance in relation to pregnancy loss with detectable levels found up to 24 h after tissue passage. This prospective cohort study included 1463 women from the COPL cohort, enrolled between 12 November 2020 and 19 December 2022. Participants were divided into three groups based on sampling time: the standard group (samples collected before tissue passage), the delayed sample group (samples collected after tissue passage at maximum 24 h), and the repeated sample group (samples collected at multiple time points after medical and surgical treatment). Eligible women were 18 years old with a confirmed intrauterine pregnancy loss before 22 gestational weeks. Exclusion criteria included ectopic, molar, or unknown-location pregnancies and inability to consent. For the repeated sample group, additional exclusions were vaginal bleeding at diagnosis, anembryonic pregnancies, and opting for expectant management. Blood samples were analyzed for β-hCG and cffDNA, with fetal fraction measured using the sequencing-based fetal fraction (SeqFF) method. In the repeated sampling group, analyses were performed on Days 2 and 3 for surgically treated and Days 7 and 14 for medically treated. After pregnancy tissue passage, both cffDNA and β-hCG levels declined consistently over time with a corresponding increase in no-call rates. The decline in SeqFF following pregnancy loss occurred more gradually than the immediate clearance previously reported after delivery, remaining measurable for up to 3 days after pregnancy loss, though 30% of samples became inconclusive at this timepoint. The fetal fraction of cffDNA was highest when tissue remained in utero and declined significantly beyond 12-h post-passage (median 4.7% 12 h). The no call rate was 9.1% when the tissue was still in situ but increased to 27.1% in the 12- to 24-h post-passage group. Higher β-hCG levels correlated with increased odds of a conclusive cffDNA test (OR 1.30, 95% CI: 1.20–1.43, P < 0.001). β-hCG is accounting for 20% of the variability in fetal fraction measurements. Variability in the decline of cffDNA between groups reflects the differences in the timing of sampling and treatment approaches. The small size of the repeated sample group may limit the generalizability of the findings. Reliance on the SeqFF method introduces variability, as it may not perform consistently. Adjustment for key confounders including BMI, gestational age, type of pregnancy loss, and timing of sampling was performed, but residual confounding cannot be ruled out. As a non-invasive method, cffDNA testing offers critical genetic insights for couples facing time-sensitive reproductive decisions or those with recurrent pregnancy loss. The correlation between β-hCG and fetal fraction suggests β-hCG screening could optimize sequencing decisions. These findings support refining cffDNA diagnostics to enhance pregnancy loss evaluation and reproductive care. The study was funded by the Ole Kirks Foundation, the BioInnovation Institute Foundation (BII21SG1020554, NNF20SA0066125, and NNF15OC0016662), the Novo Nordisk Foundation (NNF22OC0077221 and NNF23OC0087269), and the A.P. Møller Foundation. The authors have declared their COI. N/A.

All pregnant women in Denmark are offered a first-trimester ultrasound screening examination between 11 and 14 weeks of gestation. Additionally, women are offered a risk assessment for foetal chromosomal abnormalities. The main results in this review are that more than 90% of pregnant women attend the first-trimester screening, and of those, 5% receive a high-risk screening result for trisomy 21. The first-trimester screening detects more than 90% of trisomy 21 cases and a large proportion of severe structural malformations. The Danish Fetal Medicine Database (DFMD) was established in 2008-2010. DFMD is a national clinical research and quality database.

Passive maternal-fetal transfer of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies has been demonstrated, whilst the degree of transfer depending on the trimester of infection is lacking. Due to neonates’ immature immune systems, this knowledge could be of interest when investigating the degree of early-life protection against SARS-CoV-2. For perinatal infections such as Rubella and Toxoplasmosis, the timing of infection related to gestational age is crucial for the severity of maternal-fetal outcomes; hence, the trimester of SARS-CoV-2 infection could potentially be crucial. So far, there is no stratification on all three trimesters of SARS-CoV-2 infection in relation to maternal antibody levels in SARS-CoV-2 positive women, and the degree of transfer of SARS-CoV-2 antibodies to the newborn nor on obstetric and neonatal outcomes, which we examined in this study. Eleven departments in Denmark invited women who tested SARS-CoV-2 positive during pregnancy to participate with a blood sample and a cord blood sample at delivery. 459 SARS-CoV-2 positive women and 2567 SARS-CoV-2 negative women were included. A percentage of 87.5%, 95.3%, and 60.3% of newborns of women who tested positive in their first, second, and third trimester, respectively, had a significantly higher immunoglobin G (IgG) antibody level than their mother at delivery, indicating that the fetus is able to concentrate antibody levels or maintain the level of IgG antibodies transferred. None of the examined maternal-fetal outcomes were increased in women infected with SARS-CoV-2.

Introduction: The Danish national haemoglobinopathy screening programme offers screening to at‐risk pregnant women. Despite efforts to increase awareness of the screening programme, most women in the target population remain unscreened. In contrast, > 90% of pregnant women in Denmark attend a screening for chromosomal abnormalities by combined first‐trimester screening (cFTS).Methods: This study aimed to improve adherence to the Danish national haemoglobinopathy screening programme by offering screening to at‐risk unscreened pregnant women in relation to their cFTS.Results: During a 27‐week intervention period, 3254 women attended cFTS at Copenhagen University Hospital—Amager Hvidovre Hospital. Of these, 938 women (28.8%) were identified as at risk of carrying haemoglobinopathy variants based on their ethnic origins. Of the 938 women at risk, 539 (57.5%) were unscreened prior to their cFTS and were targeted for the intervention. These women were contacted with an offer of haemoglobinopathy screening. Subsequently, 253/539 (46.9%) of the at‐risk unscreened women were tested for haemoglobinopathies, of these 4/253 (1.6%) carried haemoglobinopathy variants necessitating partner screening. No partners carried haemoglobinopathy variants necessitating testing of the fetus.Conclusion: The study increased the proportion of at‐risk pregnant women tested for haemoglobinopathies from 42.5% to 69.5% and made haemoglobinopathy screening more readily available to women attending cFTS.

Summary: 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.

Conjoined twins are estimated to occur in 1:50 000 pregnancies. Eighteen cases of pregnancies achieved by ART have been published of which three were achieved after single embryo transfer, allowing discussion of embryo characteristics. We report, to the best of our knowledge, the first case of parapagus conjoined twins after ART. Furthermore, this is the first report of conjoined twins with detailed morphokinetics of the earliest embryogenesis from zygote to expanded and hatched blastocyst stage. The case zygote had three refractile bodies, which were all allocated to one blastomere at first cleavage following an asynchronous pronuclei fading. Within 2 h, this blastomere cleaved to four and fragmented. The remaining blastomere cleaved symmetrically and regularly and a blastocyst (score: 4AB) was vitrified 120 h after IVF. Pregnancy was achieved following a frozen-thawed single blastocyst transfer. The etiopathogenetic mechanism of the origin of conjoined twins is unknown and several hypotheses exist. The morphokinetics in the present case and morphology of other reported cases will be discussed in this context.

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.