Clinical Report: What's Next for Prenatal Screening?

Overview

A review in Science Advances examines biological features of cell-free fetal DNA (cffDNA) that limit noninvasive prenatal testing (NIPT), including its low proportion in maternal blood, difficulty distinguishing it from maternal DNA, and imperfect representation of the fetal genotype. The authors argue that defining cffDNA’s cellular origin and physical forms could support improved enrichment and interpretation, but that the biology must be better understood before NIPT can reliably move from screening toward comprehensive genetic diagnosis.

Background

NIPT screens for fetal genetic abnormalities using DNA in maternal blood and can be performed from around 10 weeks’ gestation. A high-risk result is not diagnostic and requires confirmation, typically through chorionic villus sampling or amniocentesis. The article reports that 47 percent of high-risk results in the cited context are false alarms, which can lead to stress and an invasive procedure. A further interpretive challenge is that much of the DNA commonly called fetal DNA originates in the placenta, whose genome can differ from the fetal genome in cases of mosaicism.

Data Highlights

Key Findings

• The review identifies three barriers to NIPT: cffDNA is a small fraction of circulating DNA, fetal DNA is difficult to distinguish from maternal DNA, and cffDNA may not represent the fetal genotype accurately.
• Much of the DNA termed “fetal” originates in the placenta; mosaicism can produce differences between placental and fetal genomes. The authors suggest “cell-free placental DNA” may sometimes be a more accurate term.
• The review challenges the view that cffDNA consists predominantly of short, linear fragments produced through apoptosis. Reported forms include circular DNA, ultrashort fragments, longer fragments, and fragments exceeding 23,000 base pairs.
• The mechanism by which placental DNA enters circulation remains unresolved. The authors note that direct evidence for apoptotic extracellular vesicles as the release mechanism is lacking; other possible carriers described include extracellular vesicles, nonvesicular particles, DNA-protein-lipid complexes, and unbound DNA.
• Potential enrichment approaches discussed include exploiting fragment size, density, molecular associations, or placental surface markers, with immunoaffinity enrichment and microfluidics identified as approaches for further investigation.
• The review identifies determining cffDNA’s cellular origin and the extent of its association with extracellular particles as research priorities; it states that better biological definition is needed before NIPT can progress reliably from screening to comprehensive genetic diagnosis.

Clinical Implications

The article emphasizes that a high-risk NIPT result remains a screening result requiring diagnostic confirmation, and that placental origin and mosaicism can complicate interpretation. The authors describe fetal-DNA enrichment as a potential route to improved sensitivity and specificity, while stating that the underlying biology must first be better defined.

Conclusion

The review presents cffDNA biology—including its origin, structure, and mode of circulation—as central to improving prenatal screening. Better characterization may support more selective DNA enrichment, but the authors caution that reliable expansion from screening to comprehensive diagnosis depends on resolving these biological questions.

Related Resources & Content

1. Reappraising the topology of cell-free fetal DNA in maternal blood toward improved prenatal genetic diagnostics, PubMed, year not provided
2. Society for Maternal-Fetal Medicine, Consult Series #74: Cell-free DNA screening for aneuploidies: Updated guidance, 2025
3. the pathologist — The Next Generation of Newborn Screening
4. the pathologist — Rethinking Race in Prenatal Risk Calculations
5. the pathologist — Beyond the Heel Prick
6. ASCO Publications — Population-based cancer predisposition testing as a component of newborn screening: A cost-effectiveness analysis.
7. Reappraising the topology of cell-free fetal DNA in maternal blood toward improved prenatal genetic diagnostics
8. Society for Maternal-Fetal Medicine Consult Series #74: Cell-free DNA screening for aneuploidies: Updated guidance
9. Society for Maternal‐Fetal Medicine Consult Series #74: Cell‐free DNA screening for aneuploidies: Updated guidance
10. Impact of a detailed ultrasound in pregnancies with high-risk cell-free DNA for common autosomal aneuploidies: a systematic review and meta-analysis - PubMed
11. Reappraising the topology of cell-free fetal DNA in maternal blood toward improved prenatal genetic diagnostics.