By Diane Allingham-Hawkins, PhD, FCCMG, FACMG, Senior Director, Genetic Test Evaluation Program and Technical Editing
A recent study published as a letter to the editor in the journal Ultrasound in Obstetrics and Gynecology has called into question the quality of commercially available noninvasive prenatal tests (NIPT). NIPT is an advanced screening test designed to detect the most common fetal chromosome abnormalities, including trisomy 21 (Down syndrome), trisomy 18 (Edwards syndrome), trisomy 13 (Patau syndrome) and abnormalities of the sex chromosomes (X and Y). All of the commercially available tests rely on the presence of cell-free fetal DNA (cffDNA) in the blood stream of a pregnant woman. The exact methodology and algorithms for data analysis, however, differ between different NIPT tests. None of the commercially available tests have been cleared by the Food and Drug Administration (FDA) and all are marketed as laboratory-developed tests (LDTs). LDT is an inclusive term used to describe in vitro diagnostic tests that are manufactured by and performed in the same laboratory. Originally planned as a category for simple, single-analyte tests that are easily replicated in other labs, LDTs now include certain genetic and molecular tests that require complex interpretation and often lead patients to make important decisions about their health care.
In an attempt to assess the reliability of NIPT results, the authors sent 2 blood samples from nonpregnant women to each of 5 American labs offering NIPT. The gestational age was recorded as 12 weeks on the requisition forms sent with the specimens and the labs were not informed that the women were not actually pregnant. Alarmingly, 3 of the labs returned results consistent with a normal female fetus for both patients. The remaining 2 labs cited test failures due to insufficient cffDNA. Two of the labs that issued incorrect results did not measure the amount of cffDNA in the specimen while the third indicated that cffDNA accounted for 3.9% to 4.3% of the cell-free DNA in the maternal sample. It is important to note that cffDNA clears from the maternal circulation within hours of delivery so there should be no cffDNA in the circulation of nonpregnant women.
This study, although admittedly small and very preliminary, shines a light on an apparent gap in the quality control measures used by most labs performing NIPT: failure to ensure adequate amounts of cffDNA in a specimen before testing. As the authors point out, this should be an integral part of the quality control standards for any lab performing NIPT. Clearly, larger studies are needed to confirm the results of this study. As it stands, however, these findings should make any referring healthcare provider pause whenever a normal female result is obtained through NIPT.
Hayes believes that the current regulatory environment surrounding LDTs is insufficient to ensure the accuracy and safety of these tests. The FDA has recently moved to increase regulatory oversight of LDTs by issuing a draft guidance on the issue. The NIPT study clearly demonstrates that such regulation is desperately needed and we encourage the FDA to move forward with implementation of their regulatory framework as quickly as possible.