Maternal Malignancy After Atypical Findings on Single-Nucleotide Polymorphism-Based Prenatal Cell-Free DNA Screening
Authors: Goldring Georgina , Trotter Cindy , Meltzer Jeffrey T. , Souter Vivienne , Pais Lynn , DiNonno Wendy , Xu Wenbo , Weitzel Jeffrey N. , Vora Neeta L. 
Published: October 2023

Technological advances in prenatal testing are allowing for earlier screening to detect fetal aneuploidies, infection, or abnormalities. Noninvasive tests in particular have enabled clinicians to screen early in pregnancy for conditions that severely affect fetal and neonatal outcomes (trisomies 21, 18, and 13, among others). Some of these methods rely on cell-free DNA (cfDNA) circulating in the maternal blood stream; although cfDNA can be released by the placenta, malignancy can be another cause for the release of cfDNA. The detection of such malignancies on noninvasive prenatal tests is rare but occurs. This study was designed to assess the incidence of cfDNA results indicating maternal malignancy and compare these findings to the existing literature.

This was a retrospective cohort study, including data obtained from a commercial laboratory that performed single-nucleotide polymorphism (SNP)–based noninvasive prenatal screening between January 2015 and October 2021. Screenings were considered suggestive of malignancy if retrospective bioinformatics and SNP plots suggested multiple maternal copy number variants for at least 2 chromosomes; the laboratory returned these tests as fetal uninterpretable results.

Of 2,004,428 samples included in the analysis, 38 (0.002%, or 1 in 52,748) were considered suggestive of malignancy. For 30 patients where follow-up was completed, health outcomes were analyzed for mother and child with maternal malignancy observed in 20 of them (66.7%). Six individuals had a preexisting diagnosis of cancer, 2 of which had a personal history of cancer but were thought to be in remission. Malignancies included lymphoma (10 patients), breast cancer (5 patients), and colon cancer (3 patients). Fetal outcomes for 15 of these patients were normal, with a few abnormal outcomes in the others; negative outcomes included fetal abnormality, multiple soft markers on prenatal ultrasound, and fetal growth restriction. Of the 10 patients without reported malignancy, 2 had identified fetal triploidy, 1 had maternal glomerulonephritis, and 1 had uterine leiomyomas. Of the original 30 patients with results suggestive of malignancy, 6 had no issues reported on follow-up.

The findings reported in this study are similar to previous findings of maternal malignancy detected by noninvasive prenatal screenings. The prevalence of maternal malignancy identified in this study was lower than in previous studies, which estimated the prevalence to range from 1/2000 to 1/21,000. The percentage of patients with a confirmed malignancy after suspicious results in this study was 67% and has ranged from 8% to 73% in other studies. Some patients who had an identified malignancy were diagnosed as long as 11 months after the noninvasive prenatal screening; this indicates that longitudinal follow-up may result in higher rates of identified malignancy among those who have screening results suggestive of malignancy. Clinically, these findings highlight the need for information given to expectant mothers about incidental findings pertaining to noninvasive prenatal screenings, as well as the importance of reporting suspicious results of these screenings.

Further research should focus on determining rates of underreporting for maternal malignancy, as well as obtaining more complete follow-up data and potentially developing a standardized procedure or diagnostic workup to determine the true incidence.