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.

Pregnancy Loss and Cardiovascular Diseases in Women: Recent Findings and Potential Mechanisms.

PURPOSE OF REVIEW: Pregnancy loss (PL) has been acknowledged by the American Heart Association as a risk factor for cardiovascular diseases (CVD) later in life. This review aims to sum up recent findings (< ~ 5 years), concerning the link between PL and CVD. RECENT FINDINGS: The association between PL and risk of CVD increased with increasing number of PLs and is inversely correlated to maternal age, indicating that the association concerns euploid PLs. Likely mechanisms leading to PL and an increased risk of CVD include endothelial dysfunction, a pro-inflammatory state, antiphospholipid syndrome, autoimmunity, and genetic predisposition. PL as an independent risk factor for CVD constitutes an obvious gateway for a more targeted approach to future research, prevention, and treatment. Future research should clarify the following questions to which the answers are still unknown: whether PL is (a) directly causing the increased risk of CVD or (b) sharing pathophysiological mechanisms also leading to CVD.

The natural history of vestibular schwannoma growth-prospective 40-year data from an unselected national cohort.

BACKGROUND: Optimal management of vestibular schwannoma (VS) is still debated and thus international consensus has not been achieved. Treatment options are observation, radiotherapy, and surgery. Knowledge on the natural history of tumor growth is essential for choice of treatment modality. The aim is to present intra-/extrameatal tumor growth and management data from a prospective, unselected national cohort of patients diagnosed with VS during the period 1976-2015. METHODS: Since 1976, all data from patients diagnosed with sporadic VS in Denmark have been referred to our national treatment center, where they have been entered prospectively into the national database. Data on tumor localization, growth, and treatment were retrieved. Growth definition: >2 mm by linear measurement, in accordance with the Tokyo 2001 consensus-meeting recommendations. RESULTS: 3637 cases of VS were diagnosed, in which 1304 patients had surgery and 21 received radiotherapy post diagnosis. 2312 patients were observed with mean follow-up of 7.33 years. Of these, 434(19%; 102 intra-and 332 extrameatal tumors) changed to active treatment during the observation period due to tumor growth. 5 years after diagnosis, 21% of the intrameatal tumors exhibited growth during observation, whereas 37% of extrameatal tumors had grown, increasing to 25% intrameatal and 42% extrameatal after 10 years. Following growth, the intrameatal tumors were mostly observed further and the extrameatal mostly underwent surgery. Tumor growth occurred mainly within the first 5 years post diagnosis. CONCLUSION: This natural history study documents the growth occurrence of both intra-and extrameatal VS during the first 12 years after diagnosis and should be used in patient counseling, management, and treatment decision making.

Epidemiology and Diagnostic Characteristics of Vestibular Schwannomas-Does Gender Matter?

INTRODUCTION: A number of epidemiological studies have reported data on, e.g., tumor size and hearing at diagnosis for patients with a vestibular schwannoma (VS), whereas only a few have touched upon the potential significance of sex. The aim of this report is thus to present gender-specific data on incidence and age, tumor localization, tumor size, and hearing loss at diagnosis. MATERIAL AND METHODS: Since 1976, various data for all patients diagnosed with a sporadic VS in Denmark have been entered prospectively into a national database. Data on sex, incidence, age, tumor localization, tumor size, and hearing (discrimination) were extracted for the period 1976 to 2015. RESULTS: Over the 40 years, 3,637 cases were diagnosed, of which 1,804 were women (50%) and 1,833 men (50%). For both sexes, an increasing incidence of tumors with a steadily decreasing size was found. Age was increasing and hearing at diagnosis was increasingly better.Previously, women had more extrameatal and thus larger tumors. During the most recent decade, more tumors were found in men and hearing at diagnosis was better for women, whereas age and tumor size were comparable. CONCLUSION: The data on gender-specific epidemiology and diagnostic characteristics show varying trends over the 40-year-period spanned. For both sexes, an increasing incidence of tumors with a steadily decreasing size was found. Age is increasing and hearing at diagnosis is increasingly better. More extrameatal and thus larger tumors were previously found in women. Contemporarily, more vestibular schwannomas are found in men and diagnostic hearing is better in women.

Epidemiology Of Vestibular Schwannomas - Prospective 40-Year Data From An Unselected National Cohort.

OBJECTIVE: Reports on the epidemiology of vestibular schwannoma (VS) indicate an increase in diagnosed cases, often based on selected materials over a limited period of time. This report presents prospective 40-year epidemiological data from an unselected national cohort of all patients diagnosed with a VS in Denmark since 1976. STUDY-DESIGN: Data on gender, age, tumor localization and size registered during the period 1976-2015 were retrieved. RESULTS: 3637 new cases of VS were diagnosed during the 40-year period. The annual number of diagnosed VS increased from 14 in 1976 to 193 in 2015. Mean extrameatal tumor size decreased from 26mm in 1976 to 13.4mm in 2015. Large and giant tumors were more frequent during the first decades, whereas predominantly smaller tumors were diagnosed during the recent years. Median age at diagnosis increased gradually from 49.2 years in 1976 to 60 years in 2015. CONCLUSION: Over the past 40 years, the incidence rate of vestibular schwannomas has increased steadily from 3 VS/million/year to 34 VS/million/year, primarily due to easier access to improved diagnostics and the finding of more tumors in older people. Concurrently, the diagnostic tumor size has decreased from 26mm to 7mm, and the age at diagnosis has increased from 49 to 60 years.