SAN FRANCISCO — Repeating one of the assays used in serum-integrated screening for Down syndrome could halve the false-positive rate, Dr. Fergal D. Malone said at the annual meeting of the Society for Maternal-Fetal Medicine.
Adding another repeat assay could reduce the false-positive rate by a further 25%, said Dr. Malone, professor and chairman of ob.gyn. at the Royal College of Surgeons, Dublin.
Conventional serum-integrated screening entails collecting first- and second-trimester blood samples. The first-trimester sample is assayed for pregnancy-associated plasma protein A (PAPP-A) and assays are performed on the second-trimester sample for several other markers of Down syndrome risk: alpha-fetoprotein, total HCG, unconjugated estriol, and inhibin A. The marker results are combined in a single assessment of risk for trisomy 21.
Serum-integrated screening detects 90% of Down syndrome cases with a 4.9% false-positive rate. If the PAPP-A assay is simply repeated on the second-trimester serum sample, the false-positive rate would drop to 1.9%, according to a modeling study that Dr. Malone and associates conducted using data from the First and Second Trimester Evaluation of Risk trial.
Doing an HCG assay on the first-trimester sample in addition to repeating the PAPP-A assay on the second-trimester sample should further reduce the false-positive rate to 1.4%, he added.
Repeating the PAPP-A assay would improve the Down syndrome detection rate to about 92%. Doing the PAPP-A and the HCG assays on first- and second-trimester samples would increase detection to nearly 100%, he calculated.
A similar benefit is seen when repeating PAPP-A measures in fully integrated screening for Down syndrome, which combines first-trimester imaging of nuchal translucency with serum-integrated screening. Fully integrated screening detects 90% of Down syndrome cases with a 1.3% false-positive rate. Repeating the PAPP-A assay on the second-trimester serum sample would decrease the false-positive rate to 0.5%, Dr. Malone said.
Reducing false positives could reduce the use of invasive tests for Down syndrome and terminations of some pregnancies, and improve the cost-effectiveness of screening.
These preliminary modeling results must be supported by prospective studies before repeat-measures screening is adopted in clinical practice, he cautioned.
The concept of repeat-measures screening expands screening strategies beyond conventional notions of evaluating each marker individually and measuring it at the one time point where it provides the best information. Measuring PAPP-A alone at 10 weeks' gestation, for example, detects 85% of Down syndrome cases with a 17% false-positive rate. Measuring PAPP-A alone only in the second trimester produces a massive 60% false-positive rate.
“Conventional wisdom says that PAPP-A in the first but not the second trimester is the way to proceed,” Dr. Malone noted. “However, things are not that simple.”
Measuring PAPP-A at 10 weeks and again between 14 and 22 weeks has not been recommended because the marker is highly correlated across gestation ages and is a poor marker for detection in the second trimester alone.
“It may surprise you, therefore, to see that PAPP-A in the first and second trimester has been estimated to provide a huge improvement in performance, for an 85% detection rate and only a 2% screen positive rate,” he said.
A low PAPP-A at 10 weeks accurately identifies trisomy 21 but falsely identifies quite a few unaffected infants. PAPP-A levels tend to be higher in Down syndrome cases in the second trimester.
“Having the added knowledge of what the second-trimester PAPP-A value is allows us to almost completely discriminate Down syndrome from normal pregnancies,” Dr. Malone said.