Understanding Fetal DNA’s Origins Could Refine Prenatal Screening

Understanding the origin and structure of cell-free fetal DNA (cffDNA) could help overcome the biological bottlenecks limiting noninvasive prenatal testing (NIPT), according to a new review published in Science Advances. An international team of scientists, led by Adelaide University, reviewed decades of research to better understand where cffDNA comes from, how it is released into the maternal bloodstream, and what structures it may be associated with once circulating in maternal plasma. 

According to the authors, NIPT has markedly changed maternal-fetal medicine by enabling earlier and safer detection of fetal genetic abnormalities, but it remains limited to a screening test due to fundamental biological bottlenecks: the small proportion of cffDNA relative to cell-free maternal DNA in maternal plasma, the challenge of reliably distinguishing fetal from maternal DNA, and discordance between cffDNA and the true fetal genotype. Despite millions of NIPT tests being conducted each year, the exact origin and structural topology of cffDNA remain unclear.

NIPT screens for genetic conditions during pregnancy by analyzing small fragments of placental DNA that circulate in the mother’s bloodstream. Since its introduction in 2011, millions of women worldwide have used NIPT because it offers a safer alternative to invasive procedures such as amniocentesis.

Despite its success and popularity, NIPT still has limitations, according to lead author Kieran Sparkes. “For most parents, a negative NIPT result provides reassurance about the health of their unborn baby. However, if NIPT does indicate a high risk for a chromosomal condition, parents have to wait over a month for confirmation and undergo an invasive diagnostic procedure,” Sparkes said. “High-risk NIPT results are rare, but in 47% of cases, a high-risk result turns out to be a false alarm, creating unnecessary stress as well as an unnecessary surgical operation. If we can better understand how fetal DNA is packaged and transported, we may be able to develop new ways to enrich and isolate it. That could improve test accuracy, reduce false results and potentially allow screening for a much broader range of genetic conditions.”

The researchers found that while cffDNA is generally believed to originate from the placenta, key questions remain unanswered about the exact cell types that release it and whether the DNA travels attached to biological particles such as extracellular vesicles or other molecular structures. According to the authors, solving these questions could help scientists increase the “fetal fraction”—the proportion of fetal DNA available for testing—and could unlock new technological advances that address the bottlenecks currently limiting NIPT, helping realize the full potential of state-of-the-art sequencing approaches.

“Science and technology have advanced rapidly, but our biological understanding of fetal DNA has not kept pace,” said senior author Professor Benjamin Thierry. “By uncovering the fundamental biology of fetal DNA, we can create new tools that make prenatal testing more reliable, more comprehensive and potentially more affordable.”

The researchers believe future advances could also allow prenatal tests to detect a wider range of genetic disorders from a simple blood sample and may even help identify pregnancy complications such as preeclampsia earlier. The team says further research into the origins and structure of fetal DNA is now a critical priority if the full potential of prenatal genetic testing is to be realized.