Valérie Malan1,2,3, Laurence Bussières4,5, Norbert Winer6,7, Jean-Philippe Jais3,8, Amandine Baptiste5, Marc Le Lorc'h1, Caroline Elie5, Neil O'Gorman3,4, Nicolas Fries9,10, Véronique Houfflin-Debarge7,11, Loic Sentilhes7,12,13, Michel Vekemans1,3, Yves Ville3,4, Laurent J Salomon3,4,7,10. 1. Department of Histology-Embryology and Cytogenetics, Hôpital Necker-Enfants Malades, AP-HP, Paris, France. 2. INSERM U1163, Hôpital Necker-Enfants Malades, Paris, France. 3. Paris Descartes University, Sorbonne Paris Cité, Institut Imagine, Paris, France. 4. Department of Obstetrics and Gynecology, Hôpital Necker-Enfants Malades, AP-HP, Paris, France. 5. Clinical Unit Research/Clinic Investigation Center, Paris Descartes, Hôpital Necker-Enfants Malades, AP-HP, Paris, France. 6. Department of Obstetrics and Gynecology, CHU de Nantes, UMR 1280 PHAN (Physiologie des Adaptations Nutritionnelles), INRA University, Nantes, France. 7. Groupe de Recherche en Obstétrique et Gynécologie (GROG), Paris, France. 8. Department of Biostatistics and Medical Informatics, Hôpital Necker-Enfants Malades, AP-HP, Paris, France. 9. Department of Obstetrics and Gynecology, CHU de Montpellier, Montpellier, France. 10. Collège Français d'Echographie Fœtale (CFEF), Chateaubriand, France. 11. Department of Obstetrics and Gynecology, CHU de Lille, Lille, France. 12. Department of Obstetrics and Gynecology, CHU d'Angers, Angers, France. 13. Department of Obstetrics and Gynecology, CHU de Bordeaux, Bordeaux, France.
Abstract
Importance: Cell-free DNA (cfDNA) tests are increasingly being offered to women in the first trimester of pregnancies at a high risk of trisomy 21 to decrease the number of required invasive fetal karyotyping procedures and their associated miscarriages. The effect of this strategy has not been evaluated. Objective: To compare the rates of miscarriage following invasive procedures only in the case of positive cfDNA test results vs immediate invasive testing procedures (amniocentesis or chorionic villus sampling) in women with pregnancies at high risk of trisomy 21 as identified by first-trimester combined screening. Design, Setting, and Participants: Randomized clinical trial conducted from April 8, 2014, to April 7, 2016, in 57 centers in France among 2111 women with pregnancies with a risk of trisomy 21 between 1 in 5 and 1 in 250 following combined first-trimester screening. Interventions: Patients were randomized to receive either cfDNA testing followed by invasive testing procedures only when cfDNA tests results were positive (n = 1034) or to receive immediate invasive testing procedures (n = 1017). The cfDNA testing was performed using an in-house validated method based on next-generation sequencing. Main Outcomes and Measures: The primary outcome was number of miscarriages before 24 weeks' gestation. Secondary outcomes included cfDNA testing detection rate for trisomy 21. The primary outcome underwent 1-sided testing; secondary outcomes underwent 2-sided testing. Results: Among 2051 women who were randomized and analyzed (mean age, 36.3 [SD, 5.0] years), 1997 (97.4%) completed the trial. The miscarriage rate was not significantly different between groups at 8 (0.8%) vs 8 (0.8%), for a risk difference of -0.03% (1-sided 95% CI, -0.68% to ∞; P = .47). The cfDNA detection rate for trisomy 21 was 100% (95% CI, 87.2%-100%). Conclusions and Relevance: Among women with pregnancies at high risk of trisomy 21, offering cfDNA screening, followed by invasive testing if cfDNA test results were positive, compared with invasive testing procedures alone, did not result in a significant reduction in miscarriage before 24 weeks. The study may have been underpowered to detect clinically important differences in miscarriage rates. Trial Registration: ClinicalTrials.gov Identifier: NCT02127515.
RCT Entities:
Importance: Cell-free DNA (cfDNA) tests are increasingly being offered to women in the first trimester of pregnancies at a high risk of trisomy 21 to decrease the number of required invasive fetal karyotyping procedures and their associated miscarriages. The effect of this strategy has not been evaluated. Objective: To compare the rates of miscarriage following invasive procedures only in the case of positive cfDNA test results vs immediate invasive testing procedures (amniocentesis or chorionic villus sampling) in women with pregnancies at high risk of trisomy 21 as identified by first-trimester combined screening. Design, Setting, and Participants: Randomized clinical trial conducted from April 8, 2014, to April 7, 2016, in 57 centers in France among 2111 women with pregnancies with a risk of trisomy 21 between 1 in 5 and 1 in 250 following combined first-trimester screening. Interventions: Patients were randomized to receive either cfDNA testing followed by invasive testing procedures only when cfDNA tests results were positive (n = 1034) or to receive immediate invasive testing procedures (n = 1017). The cfDNA testing was performed using an in-house validated method based on next-generation sequencing. Main Outcomes and Measures: The primary outcome was number of miscarriages before 24 weeks' gestation. Secondary outcomes included cfDNA testing detection rate for trisomy 21. The primary outcome underwent 1-sided testing; secondary outcomes underwent 2-sided testing. Results: Among 2051 women who were randomized and analyzed (mean age, 36.3 [SD, 5.0] years), 1997 (97.4%) completed the trial. The miscarriage rate was not significantly different between groups at 8 (0.8%) vs 8 (0.8%), for a risk difference of -0.03% (1-sided 95% CI, -0.68% to ∞; P = .47). The cfDNA detection rate for trisomy 21 was 100% (95% CI, 87.2%-100%). Conclusions and Relevance: Among women with pregnancies at high risk of trisomy 21, offering cfDNA screening, followed by invasive testing if cfDNA test results were positive, compared with invasive testing procedures alone, did not result in a significant reduction in miscarriage before 24 weeks. The study may have been underpowered to detect clinically important differences in miscarriage rates. Trial Registration: ClinicalTrials.gov Identifier: NCT02127515.
Authors: Bénédicte Buffin-Meyer; Julie Klein; Loes F M van der Zanden; Elena Levtchenko; Panogiotis Moulos; Nadia Lounis; Françoise Conte-Auriol; An Hindryckx; Elke Wühl; Nicola Persico; Dick Oepkes; Michiel F Schreuder; Marcin Tkaczyk; Gema Ariceta; Magdalena Fossum; Paloma Parvex; Wout Feitz; Henning Olsen; Giovanni Montini; Stéphane Decramer; Joost P Schanstra Journal: Clin Kidney J Date: 2019-09-26
Authors: M M Gil; F S Molina; M Rodríguez-Fernández; J L Delgado; M P Carrillo; J Jani; W Plasencia; V Stratieva; N Maíz; P Carretero; A Lismonde; P Chaveeva; J Burgos; B Santacruz; J Zamora; C De Paco Matallana Journal: Ultrasound Obstet Gynecol Date: 2020-10-17 Impact factor: 7.299