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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–

Spontaneous pregnancy loss occurs in approximately 1 in 4 pregnancies; however, diagnostic workup is mostly restricted to women with recurrent pregnancy loss. The lack of workup on first pregnancy loss is likely a result of the high de novo fetal aneuploidy rate; however, this ignores the association of euploid pregnancy loss with an increased risk of future losses. Diagnosis of ploidy is advantageous but requires collection of pregnancy tissue. Cell-free fetal DNA (cffDNA) has revolutionized prenatal screening and has shown evidence in 2 small studies of diagnostic utility in pregnancy loss. The prospective Copenhagen Pregnancy Loss (COPL) study is a large initiative with the overall aim to explore the causes of pregnancy loss. This prospective cohort study of women from the COPL aimed to investigate the clinical utility of cffDNA-based testing in women with pregnancy loss. Adult women with a pregnancy loss before gestational age 22 weeks seen between November 2020 and May 2022 at 1 of the 3 participating COPL sites were invited to participate. Blood samples for cffDNA analysis were obtained before treatment to remove pregnancy tissue or within 24 hours of passage of pregnancy tissue. Pregnancy tissue was collected for direct sequencing and comparison to cffDNA results. Aneuploidy was assessed for all chromosomes, and discordant results were considered false-positive if the cffDNA result was aneuploid and false-negative if the cffDNA result was euploid. A total of 1000 women were recruited and underwent cffDNA blood draws, and 32% of women either did not manage to collect pregnancy tissue or collected a sample classified as unknown tissue. The cffDNA result was inconclusive in 112 (11%) of initial cases due to a low fetal fraction or low sequencing quality and were excluded from sensitivity and specificity analysis. The association between inconclusive results and gestational age was approximately 10% from gestational age 7 weeks on, whereas resul