NIPT in DCDA twins
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NIPT in DCDA (Dichorionic-Diamniotic) Twins
Why DCDA Twins Are a Distinct Challenge
DCDA twins are most commonly dizygotic (DZ), with each fetus having its own placenta and its own potentially different genome. A small minority (~30%) are monozygotic. This creates unique problems for cell-free DNA (cfDNA) screening not seen in singletons or MCMA/MCDA twins:
- Each dizygotic fetus contributes its own cfDNA into maternal circulation
- An aneuploid fetus's individual contribution may fall below the detection threshold even when the total fetal fraction appears adequate
- Zygosity is not always known sonographically in DCDA twins, adding interpretive complexity
Fetal Fraction: The Core Technical Problem
In singleton pregnancies, a total fetal fraction ≥4% is generally required for a reportable result. In DCDA twins:
- The average individual fetal fraction in DZ twins (~6.4%) is ~68% of that seen in singletons (~9.5%)
- Because two fetuses share the total fetal fraction, the individual contribution of each fetus is roughly half the total
- If one fetus is aneuploid but its individual fetal fraction is <4%, it may be missed even when total fetal fraction looks satisfactory - this is the key failure mode unique to DCDA/DZ twins
- SNP-based platforms can measure individual fetal fractions per fetus and thus give a truer picture of whether each twin is individually screened adequately
No-call rates differ by zygosity:
- Singletons: ~1.7% no-call rate
- Monozygotic twin pairs: ~0.8% (lower because both fetuses contribute the same DNA - effectively doubles fetal fraction)
- Dizygotic twin pairs: ~5.6% no-call rate (highest, because individual fractions are lower)
Detection Performance for Common Aneuploidies
Data from a 2021 meta-analysis by Khalil et al. (12 prospective studies, 74 T21 cases, 22 T18 cases, 5 T13 cases in twin pregnancies) showed:
| Aneuploidy | Pooled Detection Rate | False Positive Rate |
|---|---|---|
| Trisomy 21 | 95% (95% CI 90-99%) | 0.09% |
| Trisomy 18 | 82% (95% CI 66-93%) | 0.08% |
| Trisomy 13 | 80% (4/5 cases detected) | 0.13% |
The T21 performance is similar to singletons. T18 and T13 performance may be somewhat lower, but sample sizes are too small to draw firm conclusions.
- Creasy & Resnik's Maternal-Fetal Medicine, pp. 687-688
- Harrison's Principles of Internal Medicine 22E, p. 864
Zygosity and Concordance/Discordance of Results
This is a major interpretive issue unique to DCDA twins:
- Monozygotic (MZ) DCDA twins: Both fetuses are genetically identical, so a positive result applies to both. MCDA twins are always MZ; DCDA twins may or may not be MZ.
- Dizygotic (DZ) DCDA twins: Only one fetus may be aneuploid ("discordant aneuploidy"). Conventional cfDNA platforms originally could not distinguish which twin is affected.
SNP-based NIPT platforms can:
- Determine zygosity from cfDNA
- Measure individual fetal fractions for each twin
- In DZ pairs, help identify whether one or both fetuses are affected
This is clinically important because if only one twin is aneuploid and invasive testing (amniocentesis) is planned, the correct fetus must be sampled. It also influences counseling about selective termination.
Vanishing Twin
If one twin demises early in pregnancy (vanishing twin), cfDNA from the demised fetus persists in maternal circulation for weeks to months. This can cause:
- False positive results (if the demised twin was aneuploid)
- Increased no-call rates
- Difficulty interpreting any NIPT result
This is listed as a specific cause of "no-call" or unreliable results in most NIPT programs.
Sex Chromosome Aneuploidy in DCDA Twins
Even in singletons, sex chromosome aneuploidy NIPT has lower sensitivity and PPV due to sex chromosome mosaicism in the fetus, placenta, and mother. In DCDA twins, if the twins are of discordant sex (one male, one female), interpretation becomes particularly difficult - the presence of both X and Y DNA is expected and does not indicate pathology.
Screening for Neural Tube Defects (NTDs)
cfDNA does not screen for open NTDs. Maternal serum AFP (MSAFP) is used, but in twins the mean MSAFP is 2.0-2.5 MoM (vs 1.0 MoM in singletons) due to double production. Standard singleton cutoffs (2.5 MoM) cannot be used. NTD screening using MSAFP in twins uses twin-specific MoM cutoffs.
Guidelines and Recommendations
- ACOG/SMFM (2020 Practice Bulletin): cfDNA screening can be performed in twin gestations, with the caveat that the total number of reported affected pregnancies remains small, limiting precise detection rate estimates for T18 and T13
- International guidelines: Several academic bodies now recommend cfDNA as an option in twin pregnancies
- Counseling should specifically address: higher no-call rate in DZ twins, individual fetal fraction limitations, zygosity uncertainty, and the inability to assign which twin is affected on most platforms
- Confirmed abnormal NIPT in a twin pregnancy requires invasive testing (amniocentesis or CVS) of the correct fetus before any clinical action
Summary Table
| Feature | DCDA (DZ) vs Singleton |
|---|---|
| Total fetal fraction | Higher (two placentas) but individual fraction per fetus is lower |
| No-call rate | Higher (~5.6% DZ vs ~1.7% singleton) |
| T21 detection | Similar (~95%) |
| T18/T13 detection | Possibly lower; limited data |
| Zygosity | Must be considered; SNP platforms can determine |
| Discordant aneuploidy | Possible; most platforms cannot specify which twin |
| Vanishing twin | Causes false positives/no-calls |
| Sex chromosome NIPT | Unreliable if discordant fetal sex |
Sources:
- Creasy & Resnik's Maternal-Fetal Medicine: Principles and Practice, pp. 687-688
- Harrison's Principles of Internal Medicine 22E (2025), p. 864
- Khalil et al. meta-analysis, 2021 (12 prospective studies)
- Boo HY & Han YJ, "Cell-free DNA screening in twin pregnancies," Obstet Gynecol Sci 2024 [PMID: 38268143]
- D'Antonio F & Khalil A, "Screening and diagnosis of chromosomal abnormalities in twin pregnancy," Best Pract Res Clin Obstet Gynaecol 2022 [PMID: 36335006]
- ACOG/SMFM Practice Bulletin 2020
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