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

Gruhn, Jennifer R.; Petersen, Johannes F.; Wrønding, Tine; Amato, Letizia; Chan, Andrew C.; Wei, Yongjun; Bro-Jørgensen, Maiken Hemme; Werge, L.; Petersen, Mette Marie Babiel Schmidt; Brinkmann, Clara; Petersen, Julie Birch; Dunø, Morten; Bache, Iben; Nielsen, Henriette Svarre; Hartwig, Tanja Schlaikjær; Freiesleben, Nina la Cour; Jørgensen, Finn Stener; Ambye, Louise; Bliddal, Sofie; Søndergaard, Therese Juhlin; Ostrowski, Sisse Rye; Sørensen, Erik Elgaard; Larsen, Margit Anita Hørup; Herregård, Markus J.; Hoffmann, Eva R.; Gruhn, Jenny; Chan, Andy Chi Ho; Kolte, Astrid Marie; Westergaard, David; þorsteinsdóttir, Unnur; Stefánsson, Kāri; Magnússon, Ólafur þ.; Steinthorsdottir, Valgerdur; Schmidt, Lone; Kristiansen, Karsten; Kamstrup, Pia R.; Nyegaard, Mette; Krog, Maria Christine; Løkkegaard, Ellen; Bredkjær, Helle Ejdrup; Wilken‐Jensen, Charlotte

doi:10.1016/s0140-6736(22)02610-1

Cited by 18 publications

(21 citation statements)

References 33 publications

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“…Additionally, cfDNA-based techniques should not be ruled out for aneuploidy assessment at GA of <10 weeks based on insufficient cfDNA. Although studies suggest a high proportion of low FF cases at <8 weeks' gestation, 38,44 we found no differences in FF between GA values, suggesting that the earliest miscarriages may not necessarily increase the likelihood of non-informative results. As in other prospective/ more recent studies, 30,32 cfDNA testing provides informative results before 8 gestational weeks, suggesting no clinically valuable cut-off excluding low FF cases.…”

Section: Discussioncontrasting

confidence: 78%

“…Despite this setback, we observed promising niPOC performance, with sensitivity and specificity values of 0.79 (95% CI 0.67-0.89) and 1.00 (95% CI 0.86-1.00) and a concordance rate of 85.1%; this compares favourably with cytogenetic analysis of POCs and argues against studies questioning the utility of cfDNA testing for POC studies. 30,32,38,44 Although cfDNA testing cannot currently replace cytogenetic testing, this approach could improve the diagnostic yields of current approaches. Studies have reported the cost-effectiveness of cfDNA testing to guide RPL work-up.…”

Section: Discussionmentioning

confidence: 99%

“…good prognoses for future pregnancies with euploid pregnancy loss. 44 InvasivePOC analysis may represent the method of choice in RPL, given its higher diagnostic yield in informative cases (Figure 3). In this scenario, given a euploid result, patients should be referred for an ASRM work-up, but given an aneuploid result, the patient should receive appropriate genetic counselling.…”

Section: Discussionmentioning

confidence: 99%

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Non‐invasive cell‐free DNA‐based approach for the diagnosis of clinical miscarriage: A retrospective study

Balaguer,

Rodrigo,

Mateu‐Brull

et al. 2023

BJOG

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ObjectiveTo evaluate cell‐free DNA (cfDNA) testing as a non‐invasive approach to detecting aneuploidies in clinical miscarriages.DesignA retrospective cohort study of women with pregnancy loss.SettingHospitals and genetic analysis laboratories.Population or samplePregnancy losses in the period 2021–2022.MethodsResults derived from non‐invasive cfDNA testing (Veriseq NIPT Solution V2) of maternal blood and invasive analysis of products of conception (POC) (Ion ReproSeq) compared in 120 women who suffered a miscarriage.Main outcome measuresConcordance rate results, cfDNA testing performance, non‐informative rate (NIR) and fetal fraction (FF).ResultsWe found no significant differences in the NIR between invasive (iPOC) and non‐invasive (niPOC) analysis of POC (10.0% [12/120] versus 16.7% [20/120]). Of 120 samples, 90 provided an informative result in iPOC and niPOC groups (75%). cfDNA analysis correctly identified 74/87 (85.1%) samples (excluding triploidies). Sensitivity and specificity were 79.4% and 100%, respectively; all discordant cases were female. A binomial logistic model suggested fetal sex as the only variable influencing the concordance rate (P = 0.035). A Y‐chromosome‐based FF estimate allowed the optimal reclassification of cfDNA of non‐informative male fetuses and a more accurate evaluation of cfDNA testing performance. The difference between the two FF estimates (native algorithm and Y‐chromosome‐based) suggests that female non‐concordant cases may represent non‐informative cases.ConclusionsCell‐free DNA‐based testing provides a non‐invasive approach to determining the genetic cause of clinical miscarriage.

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Section: Discussioncontrasting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Non‐invasive cell‐free DNA‐based approach for the diagnosis of clinical miscarriage: A retrospective study

Balaguer,

Rodrigo,

Mateu‐Brull

et al. 2023

BJOG

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“…Globally, this symptom imposes a significant burden to women, their families, and healthcare systems. Even though chromosomal aberrations are the underlying cause of most sporadic miscarriages, the etiology of the individual case is often not identified 3,4 . In the clinical setting, it is difficult to predict the outcome of vaginal bleeding with a viable embryo/fetus in utero, and repeated follow‐ups are often necessary.…”

Section: Introductionmentioning

confidence: 99%

“…Even though chromosomal aberrations are the underlying cause of most sporadic miscarriages, the etiology of the individual case is often not identified. 3,4 In the clinical setting, it is difficult to predict the outcome of vaginal bleeding with a viable embryo/fetus in utero, and repeated follow-ups are often necessary. Attempts have been made to determine the risk of pregnancy loss based on clinical, biochemical, and sonographic features, but strong prognostic factors predicting who will ultimately miscarry or have a favorable pregnancy outcome are lacking.…”

Section: Introductionmentioning

confidence: 99%

Immune cell profiling of vaginal blood from patients with early pregnancy bleeding

Guterstam

Acharya

Schott

et al. 2023

American J Rep Immunol

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Problem Vaginal bleeding during early pregnancy is estimated to occur in 20% of all pregnancies and it is often difficult to predict who will ultimately miscarry. The role of immune cells in early pregnancy loss is poorly understood. Method of Study In this prospective cohort study, 28 pregnant women presenting with first‐trimester vaginal bleeding donated vaginal blood, peripheral venous blood, and saliva during their initial emergency room visit, and at a follow‐up. The composition, frequency, and phenotype of immune cells in the vaginal blood were determined using flow cytometry. The proteome of serum and saliva was analyzed with OLINK proximity extension assay and correlated to vaginal immune cell phenotype and outcome of pregnancy. The course and outcome of pregnancies were followed and recorded. Results Vaginal blood contained all main immune cell lineages including B cells, NK cells, T cells, and monocytes/macrophages. Notably, vaginal blood immune cells expressed tissue residency markers including CD49a. Women who subsequently miscarried had a higher frequency of vaginal blood CD49a+ NK cells compared to those who did not miscarry, and this correlated with serum levels of granzyme A and H, as well as CSF1, CAIX, and TWEAK. Women in the miscarriage group also had a higher frequency of peripheral blood T cells expressing CD49a. Conclusions Our study provides novel insight into human reproductive immunology in relation to miscarriage. Tissue‐resident NK cells in vaginal blood alone or in combination with serological biomarkers hold potential as prognostic factors in the prediction of pregnancy outcome in women with early pregnancy bleedings.

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Test performance and clinical utility of expanded non‐invasive prenatal test: Experience on 71,883 unselected routine cases from one single center

Faieta,

Falcone,

Duca

et al. 2024

Prenatal Diagnosis

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ObjectiveThe balance between benefits and risks of discordant outcomes makes the Genome‐Wide Non‐Invasive Prenatal Test (GW‐NIPT) controversial. This study aims to evaluate performance and clinical utility in a wide cohort of unselected clinical cases from a single center when a standardized protocol is applied and integrated with a secondary algorithm for data interpretation.MethodIn 2 years, over 70,000 pregnant patients underwent GW‐NIPT for fetal common trisomies, sex chromosome aneuploidies, rare autosomal aneuploidies, segmental abnormalities (CNVs ≥ 7 Mb) and microdeletions (CNVs < 7 Mb). All samples were uniformly processed with Veriseq NIPT Solution v2 and analyzed using all data metrics along with a home‐made algorithm for sequencing data analysis. Results were retrospectively reviewed for clinical outcomes.ResultsAmong 71,883 eligible cases including twin pregnancies, 1011 (1.4%) received a positive result and 781 were confirmed by invasive prenatal diagnosis. Clinical sensitivity ranged from 99.65% for common trisomy (T21, T18, T13) to 83.33% for microdeletions, while specificity remained high (99.98%) for each class of fetal abnormalities detected.ConclusionsIntegrating a standardized protocol with an internal algorithm allowed discordant results to be reduced, yielding high accuracy. Observed reliability in detecting genome‐wide chromosomal conditions reinforced the expanded NIPT utility in clinical practice.

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

Cited by 18 publications

References 33 publications

Non‐invasive cell‐free DNA‐based approach for the diagnosis of clinical miscarriage: A retrospective study

Non‐invasive cell‐free DNA‐based approach for the diagnosis of clinical miscarriage: A retrospective study

Immune cell profiling of vaginal blood from patients with early pregnancy bleeding

Test performance and clinical utility of expanded non‐invasive prenatal test: Experience on 71,883 unselected routine cases from one single center

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