PMID- 32386059 OWN - NLM STAT- MEDLINE DCOM- 20210427 LR - 20210526 IS - 1460-2350 (Electronic) IS - 0268-1161 (Print) IS - 0268-1161 (Linking) VI - 35 IP - 5 DP - 2020 May 1 TI - Maternal plasma genome-wide cell-free DNA can detect fetal aneuploidy in early and recurrent pregnancy loss and can be used to direct further workup. PG - 1222-1229 LID - 10.1093/humrep/deaa073 [doi] AB - STUDY QUESTION: Can maternal plasma cell-free DNA (cfDNA) detect chromosomal anomalies in early pregnancy loss (EPL) and recurrent pregnancy loss (RPL)? SUMMARY ANSWER: Genome-wide cfDNA testing can serve as an alternative to cytogenetic analysis in products of conception (POCs) in RPLs and can guide further management. WHAT IS KNOWN ALREADY: Random chromosomal anomalies are the single most common cause for EPL and RPL. Cytogenetic analysis in POCs may be used to direct management in RPL because the detection of random chromosomal anomalies can eliminate further unwarranted testing. STUDY DESIGN, SIZE, DURATION: This was a prospective diagnostic test study from March 2018 to January 2019 of 109 patients experiencing pregnancy loss before 14 weeks gestation at a tertiary-care academic medical center. PARTICIPANTS/MATERIALS, SETTING, METHODS: Blood samples were drawn for genome-wide cfDNA testing prior to chorionic villous sampling for cytogenetic analysis of POCs with both short-term cultures (STCs) and long-term cultures (LTCs). Final analysis included 86 patients with non-mosaic cytogenetic results in POCs and available cfDNA results. Aneuploidy detection rates by cfDNA testing and POC cytogenetic analysis were compared. The first 50 samples served as the Training Set to establish pregnancy loss-specific log-likelihood ratio (LLR) thresholds using receiver-operator characteristic (ROC)-like analyses. These were then used for the entire cohort. MAIN RESULTS AND THE ROLE OF CHANCE: Seventy-eight samples (71.5%) had results available from both STC and LTC; 12 samples (11%) had a result from STC only, and 7 samples (6.4%) had a result from LTC only. A chromosomal anomaly was detected in 55/86 (64%). The rates of chromosomal anomalies were 61, 72, 73 and 44% in patients undergoing their first, second, third and >/=4th pregnancy losses, respectively. The median cfDNA fetal fraction was 5%. With standard LLR thresholds used for noninvasive prenatal screening, the sensitivity of cfDNA in detecting aneuploidy was 55% (30/55) and with a specificity of 100% (31/31). Using pregnancy loss-specific LLR thresholds, the sensitivity of cfDNA in detecting aneuploidy was 82% (45/55), with a specificity of 90% (28/31). The positive and negative likelihood ratios were 8.46 and 0.20, respectively. Fetal sex was correctly assigned in all cases. LIMITATIONS, REASONS FOR CAUTION: Cases with a false-positive result by cfDNA analysis would not receive the indicated RPL workup. Specificity could be improved by using a fetal fraction (FF) cutoff of 4%, but this would result in exclusion of more than a quarter of cases. WIDER IMPLICATIONS OF THE FINDINGS: cfDNA-based testing can serve as an alternative to POC cytogenetic analysis and can guide further RPL management: if cfDNA demonstrates aneuploidy, no further action is taken and if no abnormality is detected, the recommended RPL workup is performed. STUDY FUNDING/COMPETING INTEREST(S): Cell-free DNA testing was funded by Illumina, Inc., San Diego, CA. Y.Y. is a member of Illumina's Clinical Expert Panel and has received travel grants. A.B. has received travel grants from Illumina. All authors have no competing interest to declare. CI - (c) The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. FAU - Yaron, Yuval AU - Yaron Y AD - Prenatal Genetic Diagnosis Unit, Genetic Institute, Sourasky Medical Center, Tel Aviv, Israel. AD - Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. FAU - Pauta, Montse AU - Pauta M AD - Department of Maternal-Fetal Medicine, BCNatal, Hospital Clinic, Barcelona, Catalonia, Spain. FAU - Badenas, Celia AU - Badenas C AD - Department of Maternal-Fetal Medicine, BCNatal, Hospital Clinic, Barcelona, Catalonia, Spain. FAU - Soler, Anna AU - Soler A AD - Department of Maternal-Fetal Medicine, BCNatal, Hospital Clinic, Barcelona, Catalonia, Spain. FAU - Borobio, Virginia AU - Borobio V AD - Department of Maternal-Fetal Medicine, BCNatal, Hospital Clinic, Barcelona, Catalonia, Spain. FAU - Illanes, Carmen AU - Illanes C AD - Department of Maternal-Fetal Medicine, BCNatal, Hospital Clinic, Barcelona, Catalonia, Spain. FAU - Paz-Y-Mino, Fernanda AU - Paz-Y-Mino F AD - Department of Maternal-Fetal Medicine, BCNatal, Hospital Clinic, Barcelona, Catalonia, Spain. FAU - Martinez-Portilla, Raigam AU - Martinez-Portilla R AD - Department of Maternal-Fetal Medicine, BCNatal, Hospital Clinic, Barcelona, Catalonia, Spain. FAU - Borrell, Antoni AU - Borrell A AD - Department of Maternal-Fetal Medicine, BCNatal, Hospital Clinic, Barcelona, Catalonia, Spain. AD - BCNatal, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - England TA - Hum Reprod JT - Human reproduction (Oxford, England) JID - 8701199 RN - 0 (Cell-Free Nucleic Acids) SB - IM CIN - Hum Reprod. 2021 Feb 18;36(3):829-830. PMID: 33378533 CIN - Hum Reprod. 2021 Feb 18;36(3):827-829. PMID: 33378535 MH - Aneuploidy MH - *Cell-Free Nucleic Acids MH - *Chromosome Disorders MH - Female MH - Humans MH - Plasma MH - Pregnancy MH - Prospective Studies PMC - PMC7259365 OTO - NOTNLM OT - aneuploidy OT - cell-free DNA OT - chromosome anomalies OT - noninvasive OT - recurrent pregnancy loss EDAT- 2020/05/10 06:00 MHDA- 2021/04/28 06:00 PMCR- 2020/05/09 CRDT- 2020/05/10 06:00 PHST- 2019/11/16 00:00 [received] PHST- 2020/03/15 00:00 [revised] PHST- 2020/05/10 06:00 [pubmed] PHST- 2021/04/28 06:00 [medline] PHST- 2020/05/10 06:00 [entrez] PHST- 2020/05/09 00:00 [pmc-release] AID - 5834872 [pii] AID - deaa073 [pii] AID - 10.1093/humrep/deaa073 [doi] PST - ppublish SO - Hum Reprod. 2020 May 1;35(5):1222-1229. doi: 10.1093/humrep/deaa073.