New choices in prenatal screening for Down syndrome

Serum markers or ultrasound alone not enough in first trimester

Two serum markers together, without nuchal translucency, or nuchal translucency alone, without the serum markers, do not constitute a sufficient first-trimester screening test, since they each detect about 60% to 65% of Down syndrome cases with a 5% false-positive rate. This is clearly inferior to the best we can do during the second trimester (about 80% detection rate for a 5% false-positive rate). Only when nuchal translucency and serum markers are used together is first-trimester screening a viable option.

Timing is important in integrated screening

For the integrated screening option, instead of requiring that screening be offered in the late first or early second trimester, each marker is measured when it is most informative. The optimal time for nuchal translucency and PAPP-A measurement is at 10 to 11 weeks, while the optimal time for the measurement of hCG (or its free β subunit), inhibin A, alpha fetoprotein (AFP), and unconjugated estriol (uE₃) is at 15 to 20 weeks.

Therefore, the integrated test is accomplished in 2 steps. At about 11 weeks, a woman undergoes nuchal translucency ultrasound imaging and has a blood sample drawn for PAPP-A measurement. At about 15 weeks (the earlier in the second-trimester window the better), she has a second sample drawn for measurement of the quad markers. A risk report then is generated, using all 6 markers to calculate the woman’s new risk. Such a test has to be superior to any test that uses fewer markers or the same markers at less than the optimal time.

The integrated test can also be carried out without nuchal translucency, by measuring PAPP-A during the first trimester and the quad serum markers during the second trimester, for an estimated detection rate of 85% with a 5% false-positive rate.

Integrated option has 1% screen-positive rate

Integrated screening reduces the screen-positive rate by as much as fourfold—to 1% or less. That is, only 1 in 100 women undergoing screening will be called screen-positive, and, in that 1%, approximately 85% of all Down syndrome pregnancies will be found.^1,2,7

First-trimester serum markers

The most informative serum marker during the first trimester is PAPP-A, a large glycoprotein complex made by the placenta. In pregnancies affected by Down syndrome, PAPP-A levels tend to be low: about 0.4 MoM on average, or about 2.5 times lower than in unaffected pregnancies.

The second most commonly used serum marker is the free βsubunit of hCG, which is, on average, 1.8 MoM in pregnancies affected by Down syndrome, or almost twice as high as in normal pregnancies.^4,8 Studies indicate that hCG and inhibin A are also effective serum markers during the late first trimester, providing screening performance equivalent to that of the free β-hCG when combined with nuchal translucency and PAPP-A.⁴

Nuchal translucency: A powerful marker

Both the fully integrated and first-trimester screening approaches necessitate ultrasound measurement of nuchal translucency, which is always measured along with fetal crown-rump length. The nuchal translucency value—initially measured in tenths of millimeters—then is normalized for gestational age based on crown-rump length, and reported in multiples of the median, the same unit used to normalize serum screening markers.

FIGURE 1 shows how nuchal translucency values (in millimeters) measured in a general population increase with gestation. The most commonly accepted period of gestation to measure nuchal translucency is between 10 and 13 completed weeks.

Why nuchal translucency is more informative

Nuchal translucency values tend to be increased in Down syndrome pregnancies, as are certain serum markers such as hCG or its free β subunit and inhibin A. However, nuchal translucency is more informative than these markers because there is less overlap between Down syndrome and unaffected case values. This is not because nuchal translucency values tend to be higher in affected pregnancies. In fact, all 3 markers are, on average, about twice as high in cases of Down syndrome as in controls. However, because the distribution of nuchal translucency values in unaffected fetuses is much narrower (or tighter) than is true for hCG (or its free β subunit) or inhibin A, very few unaffected fetuses have increased nuchal translucency values. Therefore, when nuchal translucency is elevated, it is more likely to be associated with an affected pregnancy than is either of the other 2 markers.

FIGURE 2 shows the overlapping distributions in cases and controls for both hCG and nuchal translucency. In unaffected pregnancies, the distribution of values centers around 1 MoM, while in Down syndrome pregnancies, the values center around 2 MoM. About 8% of hCG values in unaffected pregnancies exceed 2 MoM, but only about 1.5% of nuchal translucency values do. Thus, for a detection rate of 50%, the false-positive rate using nuchal translucency is 1.5%, much smaller than the false-positive rate of 8% using hCG.