Background: Prenatal cell-free DNA (cfDNA) screening is a success story of clinical genomics that has translated to and transformed obstetric care. It is a highly sensitive and specific method of screening for the most common fetal aneuploidies, including trisomies 13, 18, and 21. While primarily designed to detect fetal chromosomal abnormalities, the test also analyzes maternal cfDNA, which can complicate interpretation of results. Occasionally, abnormalities in cfDNA that do not align with fetal aneuploidy may indicate benign or malignant maternal disease states, presenting unique diagnostic challenges and opportunities.
Content: This review explores the methods and implications of incidental cancer detection through prenatal cfDNA screening. Early case reports noted instances in which abnormal cfDNA results, initially suggestive of fetal aneuploidies, led to post-pregnancy diagnoses of maternal cancers. Subsequent large retrospective studies have established significant correlations between atypical prenatal cfDNA results and undiagnosed maternal malignancies. Abnormal cfDNA profiles, particularly those indicating multiple aneuploidies, first require fetal diagnostic tests, such as amniocentesis. If the fetal studies are normal, further investigation into a maternal source should proceed. Clinical management of these findings may involve a multidisciplinary approach, incorporating advanced imaging techniques and genetic counseling to ensure timely and accurate maternal diagnoses.
Summary: The integration of genome-wide analysis and innovative bioinformatics tools into prenatal cfDNA screening has enhanced its ability to identify potential cancer cases. Developing standardized guidelines for reporting and managing incidental findings is crucial to optimizing patient outcomes and mitigating psychological impacts on expectant persons and their partners.
Published by Oxford University Press on behalf of Association for Diagnostics & Laboratory Medicine 2025.