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False-positive NIPT results may be due to presence of maternal malignancies
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Occult maternal malignancies may provide a biological explanation for some discordant non-invasive prenatal test results.
Many professional societies recommend noninvasive prenatal testing (NIPT) for pregnant women at high risk for having a fetus with autosomal aneuploidy, according to study background. Women with a positive result are recommended for confirmatory diagnostic testing.
Diana W. Bianchi, MD, executive director of Mother Infant Research Institute at Tufts Medical Center, vice chair for research and academic affairs in the department of pediatrics, and attending geneticist and neonatologist at Tufts University School of Medicine, and colleagues evaluated massively parallel DNA sequencing data to identify patterns of copy-number variations that could allow for prospective identification of maternal malignancies in pregnant women with abnormal NIPT results involving aneuploidies of certain chromosomes, or those diagnosed with cancer after NIPT.
Diana W. Bianchi
“Understanding the relationship between aneuploidy detection on NIPT and occult maternal malignancies may explain results that are discordant with the fetal karyotype and improve maternal care,” Bianchi and colleagues wrote.
The investigators identified 125,426 pregnant women who underwent DNA sequencing in the Illumina clinical laboratory in Redwood City, Calif., between February 2012 and September 2014. Of these, 3,757 (3%) tested positive for one or more aneuploidies that involved chromosomes 13, 18, 21, X or Y. From this subset, researchers identified 10 cases of maternal cancer and obtained DNA sequencing data from eight of those 10.
The subset included three cases of B-cell lymphoma, and one case each of T-cell leukemia, Hodgkin’s lymphoma, colorectal carcinoma, anal carcinoma, neuroendocrine carcinoma, leiomyosarcoma and an unspecified adenocarcinoma.
Researchers detected seven of the maternal cancers among the 39 cases in which more than one aneuploidy was detected (18%; 95% CI, 7.5-33.5).
In the eight cases for which DNA sequencing data was available, researchers observed unique patterns of nonspecific copy-number gains and losses in multiple chromosomes, spanning from 4% to 44% (median, 29%) of the genome.
The data support the need for a diagnostic procedure to determine the true fetal karyotype if NIPT results identify abnormalities in chromosomes, Bianchi and colleagues concluded.
“When there is discordance between the fetal karyotype and the NIPT result, occult maternal malignancy, although very uncommon, may be an explanation for the findings,” the researchers wrote. “Based on the results of the study, we estimate there is between a [20% and 44%] risk of maternal cancer if multiple aneuploidies are detected. However, until further studies are done to assess the clinical implications of discordant NIPT and fetal karyotype results, it is not clear what, if any, follow-up clinical evaluation is appropriate.”
This study strengthens the argument that false-positive NIPT results could be due to the presence of maternal malignancies, Roberto Romero, MD, DMedSci, head of the program for perinatal research and obstetrics at Eunice Kennedy Shriver National Institute of Child Health and Human Development, and Maurice J. Mahoney, MD, JD, professor of genetics, obstetrics, gynecology, reproductive sciences and pediatrics at Yale University School of Medicine, wrote in an accompanying editorial.
The calculated 20% to 44% risk for maternal cancer when multiple aneuploidies are detected is the “best estimate based on available data” and serves as “an important advance” from prior case reports and small case series, they wrote.
“The data emphasize the need for performing a diagnostic procedure to determine the fetal karyotype in all situations in which there is an abnormal NIPT result,” Romero and Mahoney wrote. “Given that it is likely that NIPT will increase in the coming years, an active dialogue among stakeholders (obstetricians, patients, laboratories, ethicists, policy makers, etc) needs to take place to provide informed advice to potentially affected pregnant women and to guide the care of such patients.” – by Anthony SanFilippo
Disclosure: The study was funded by Illumina. The researchers report research funding and honoraria from, employment with, and advisory or speakers bureau roles with Illumina. They also report speakers bureau roles with Myriad Genetics; research funding from Ariosa Diagnostics, Myriad Genetics, Novartis and Sequenom; and consultant roles with Pfizer and Sequenom. Romero reports no relevant financial disclosures. Mahoney reports serving as a principal investigator for a study of NIPT under contract with Yale University.
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