"NIPT detects a placental chromosomal abnormality that may predict placental dysfunction."
NIPT: trisomy 16 positive
Amniocentesis: 46,XX
This is not simply "NIPT was wrong."
One important possibility is: euploid fetus + trisomic placenta = CPM for trisomy 16.
Trisomy 16 is particularly important because placental trisomy 16 has a well-established association with FGR and adverse obstetric outcome.
More broadly, a meta-analysis found increased risk of SGA in pregnancies with CPM, with particularly strong associations reported for trisomy 16.
A trisomic trophoblast population may have different effects depending on:
chromosome involved
• percentage of abnormal cells
• whether the abnormality is confined mainly to cytotrophoblast or also mesenchymal core
• distribution of the abnormal cells across the placenta
• meiotic versus mitotic origin.
There is evidence that the amount of trisomic trophoblast correlates with adverse outcome.
In one study of NIPT-detected rare autosomal trisomies, the estimated placental mosaicism ratio was substantially higher in pregnancies with adverse outcomes than in those without them
"The fetal genome is normal, but the placenta may carry an aneuploid clone."
That changes surveillance because CPM itself can be associated with impaired fetal growth.
In a study of FGR pregnancies, cfDNA screening identified suspected CPM in about 12.5% of cases, and more extensive placental involvement was associated with more severe growth restriction.
NIPT signal = contribution from abnormal placental DNA + normal placental DNA + maternal DNA
Therefore: higher abnormal chromosome representation
may indicate
• larger abnormal placental clone
• which may indicate a greater chance of placental dysfunction.
But this relationship is imperfect because the cfDNA signal is affected by:
• fetal fraction
• gestational age
• placental heterogeneity
• trophoblast turnover
• sampling
• sequencing/algorithm characteristics.
After the blastocyst forms:
• trophectoderm → placenta
• inner cell mass → fetus
A chromosomal error occurring around this developmental period can therefore preferentially populate the extraembryonic lineage.
There is also another common mechanism:
trisomic conception
→ trisomy rescue
→ fetus becomes euploid
→ abnormal cells persist in placenta
→ CPM
This becomes especially important with chromosomes such as 15 and 16 because trisomy rescue can also generate UPD
1. NIPT chromosomal signal
Tells you which placental chromosomal abnormality may be present.
2. Diagnostic fetal testing
Amniocentesis/CMA tells you whether the fetus itself is affected.
3. Placental phenotype
• Serial:
• growth
• uterine artery Doppler
• umbilical artery Doppler
• MCA/DV when indicated
• placental morphology
• maternal BP/pre-eclampsia surveillance
NIPT abnormality
→ cytogenetically normal fetus
→ suspected CPM
→ placental surveillance
→ functional assessment of placental reserve
rather than treating the NIPT result only as a fetal genetic screening result.
A 2025 systematic review/meta-analysis of more than 681,000 pregnancies found that about 80% of RAT-positive results were false-positive for fetal trisomy, but these discordant results were associated with increased rates of adverse pregnancy outcomes, particularly involving chromosomes 2, 4, 11, 16 and 22. Trisomy 16 showed the strongest and most consistent association in that analysis.
the "false-positive fetal NIPT" may actually be a true-positive placental finding.
Conceptual point
"NIPT may identify placental chromosomal abnormalities that are associated with placental dysfunction and adverse obstetric outcome."
A clinically useful schematic
NIPT
↓
Placenta-derived cfDNA
↓
Chromosomal imbalance detected
↓
A. Fetal aneuploidy
or
B. CPM
↓
If fetus is euploid → consider CPM
↓
Abnormal trophoblast/placental clone
↓
Impaired placental development/function
↓
Placental insufficiency
↓
FGR ± abnormal UA/MCA/DV ± pre-eclampsia ± oligohydramnios
