Quadruple test in DCDA twins can it be done
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Here is the full, evidence-based answer:
Quadruple Test in DCDA Twins - Can It Be Done?
Yes, it can be done, but with important caveats. The quadruple test (AFP, hCG, uE3, inhibin-A) is technically feasible in DCDA (dichorionic-diamniotic) twins, but its performance is significantly inferior to singletons and results are interpreted as a "pseudorisk" rather than a true risk.
Why Standard Interpretation Fails in Twins
In any twin pregnancy, all four serum analytes are roughly doubled compared to singletons. The median MoMs in an unaffected twin pregnancy are approximately:
| Analyte | Twin Median MoM |
|---|---|
| AFP | ~2.0 |
| uE3 | ~1.7 |
| hCG | ~1.9 |
| Inhibin-A | ~2.0 |
Because both fetuses contribute to the maternal blood pool, singleton reference ranges and risk cut-offs cannot be directly applied. If you apply singleton algorithms without correction, virtually every twin pregnancy would be screen-positive.
- Tietz Textbook of Laboratory Medicine, 7th Ed., p. 2427
How It Is Performed in DCDA Twins (Pseudorisk Calculation)
Since DCDA twins are presumed dizygotic (approximately 90% of dichorionic twins are dizygous), each twin is presumed to have an independent chromosome complement. The approach is:
- Divide each measured analyte MoM by the corresponding twin median (not the singleton median) to generate a "twin-adjusted MoM."
- Apply singleton risk algorithms using these twin-adjusted MoMs to generate a risk estimate.
- For DCDA twins, each fetus gets a fetus-specific risk (if NT measurements are available per fetus); these fetus-specific risks are then added together to give an overall pregnancy risk.
- The result is called a pseudorisk - it is compared to the same singleton cut-off (e.g., 1:270 or 1:250) to call screen-positive or screen-negative.
The pseudorisk correctly ranks pregnancies from highest to lowest risk and maintains a screen-positive rate comparable to singletons - but the absolute numeric risk stated may not be accurate.
- Creasy & Resnik's Maternal-Fetal Medicine, p. 685
- Tietz Textbook of Laboratory Medicine, 7th Ed., p. 2427
Why DCDA Is the Most Problematic Scenario for Serum Screening
The key problem specific to DCDA twins is analyte dilution:
- In DCDA twins, the two fetuses are most likely dizygotic and therefore discordant for chromosomal abnormalities (only one twin affected in ~two-thirds of twin Down syndrome cases).
- The abnormal biochemical signal from the affected fetus gets diluted and masked by the normal analyte contribution from the unaffected co-twin.
- This is less of a problem in monochorionic twins where both fetuses share the same karyotype and both would contribute abnormal analytes, which is why detection rates are theoretically slightly better in MC twins.
Estimated detection rates for trisomy 21 in twins using second-trimester serum screening (modelled data, 5% FPR):
| Markers Used | Predicted Detection Rate |
|---|---|
| AFP + hCG + maternal age | ~41% |
| AFP + hCG + uE3 + maternal age (triple) | ~44% |
| AFP + hCG + uE3 + inhibin-A + maternal age (quad) | ~47% |
Compare this to ~81% detection for the quadruple test in singleton pregnancies - a substantial drop.
- Creasy & Resnik's Maternal-Fetal Medicine, p. 685 (citing Cuckle's modelled data)
Additional Limitations to Be Aware Of
- Unknown affected-twin marker distribution: The exact distribution of the four analytes in Down syndrome-affected twin pregnancies is not well defined due to the low number of cases - this is why only a pseudorisk (not a true risk) can be generated.
- Prevalence uncertainty: The true prevalence of Down syndrome in twin pregnancies is not the same as singletons and is not well established, further complicating risk calculation.
- No neural tube defect (NTD) screening advantage: In DCDA twins, AFP is ~2.0 MoM at baseline. For open spina bifida (OSB), the expected AFP is only ~4.5 MoM (1.0 from normal + 3.5 from affected fetus), compared to ~3.5 MoM in a singleton. The distributions overlap more, reducing NTD screening performance as well.
What Is Preferred Over the Quad Test in DCDA Twins
Given these limitations, current practice increasingly favors:
- First-trimester combined screening (NT + PAPP-A + free beta-hCG): In DCDA twins, each fetus gets a fetus-specific NT and risk estimate. A meta-analysis showed sensitivity of 86.2% and specificity of 95.2% for dichorionic twins. This is significantly better than second-trimester serum screening alone.
- Cell-free DNA (cfDNA/NIPT): The Merck Manual and recent review (Benn & Rebarber, Prenat Diagn 2021, PMID 34170028) confirm cfDNA screening performance is comparable for singleton and twin pregnancies, making it the preferred modality.
- Sequential screening: Combining first-trimester NT-based screening with second-trimester markers (including quad markers) as part of an integrated or sequential protocol can improve detection rates further.
Bottom Line
| Feature | DCDA Twin Quad Test |
|---|---|
| Can it be done? | Yes - technically feasible |
| How is risk calculated? | Pseudorisk using twin-specific medians |
| Detection rate for T21 | ~47% (vs ~81% in singletons) |
| Risk value reported | Pseudorisk - not a true risk |
| Preferred alternative | cfDNA or first-trimester combined screen |
The quad test in DCDA twins is not recommended as a standalone screening tool but can be used as part of integrated/sequential screening if better options (first-trimester NT + biochemistry, cfDNA) are unavailable. Screen-positive women must be counselled that their actual risk is uncertain and that the absolute risk figure provided is an approximation only.
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