Noninvasive prenatal screening (NIPS/cfDNA)

Noninvasive prenatal screening (NIPS), also called cell-free DNA (cfDNA) screening, analyzes fragments of placental DNA circulating in the maternal bloodstream to assess fetal risk for common chromosomal aneuploidies. It is a screening test (not diagnostic) with very high sensitivity and specificity for trisomies 21, 18, and 13, but positive results require confirmation by invasive testing.

• Placental apoptosis releases short (about 150 bp) DNA fragments into maternal circulation. The fetal fraction is roughly 10–13% of total maternal cfDNA at 10 weeks' gestation, rising with gestational age.
• Massively parallel sequencing (or targeted SNP analysis) quantifies chromosomes; an excess of reads mapping to a given chromosome suggests fetal aneuploidy.
• Two main platforms: whole-genome counting (e.g., Illumina Verifi) and SNP-based (e.g., Natera Panorama; can detect triploidy and vanishing twin).

For singleton pregnancies: trisomy 21 detection about 99% sensitivity and 99.9% specificity; trisomy 18 about 97% sensitivity; trisomy 13 about 91% sensitivity. Sex chromosome aneuploidies about 90% sensitivity (lower for 45,X).

• PPV (positive predictive value) varies with population risk: 90% for T21 in high-risk, but often 40–80% in average-risk populations.
• High sensitivity + high specificity, but low PPV in low-prevalence populations, illustrating Bayes' theorem. A "positive" result in average-risk screening needs confirmation before irreversible decisions.

Can detect (with variable PPV):

• Common autosomal trisomies (13, 18, 21)
• Sex chromosome aneuploidies (45,X; 47,XXY; 47,XXX; 47,XYY)
• Some microdeletions (22q11.2, 1p36, Cri-du-chat): PPV is very low; not recommended routinely
• Triploidy (SNP-based platforms only)

Cannot detect:

• Single-gene disorders (most)
• Balanced rearrangements
• Neural tube defects (requires MSAFP or ultrasound)
• Most structural malformations

• Low fetal fraction (<4%): uninformative result. More common with higher maternal BMI, earlier gestational age, and aneuploid pregnancies (trisomy 18 in particular).
• Confined placental mosaicism (CPM): placenta has aneuploidy the fetus does not; a common cause of false-positive NIPS. Seen in 1–2% of pregnancies.
• Vanishing twin: the demised twin's placenta continues to contribute cfDNA, potentially producing a discrepant result for weeks.
• Maternal mosaicism / malignancy: rare but significant; unexpected multi-chromosome aneuploidy signals may unmask occult maternal cancer.
• Multiple gestations: performance is reduced; current ACMG guidance permits NIPS in twins with caveats.

• ACMG (2023): NIPS is the most sensitive screening test for common fetal aneuploidies and can be offered to all pregnant people regardless of risk.
• ACOG and SMFM (2020): NIPS may be offered to all; positive results require diagnostic testing (CVS or amniocentesis).
• Microdeletion panel testing: current evidence does not support routine use; consider only after counseling about low PPV.