In the first trimester, nuchal translucency (NT) measurements combined with maternal serum levels of free β-human chorionic gonadotrophin and pregnancy-associated plasma protein A and maternal age can be effective in screening for trisomy 21. This article summarizes the results of first-trimester screening performed at a single clinical center over a 10-year period to assess the efficacy for detecting trisomies 13, 18, and 21 and to analyze the results of conventional chromosome analysis of at-risk pregnancies.
Patients had the NT ultrasound at 12 weeks’ gestation, with blood drawn 1 to 2 weeks before the ultrasound. Risk results were provided for Down syndrome and a combined risk of trisomy 18/13. Patients with a positive result could choose to have chorionic villus sampling (CVS) before 14 weeks’ gestation, a second-trimester serum screen to obtain a combined risk analysis before deciding on amniocentesis, or amniocentesis at 15 to 16 weeks’ gestation. For patients who chose CVS or amniocentesis, fluorescence in situ hybridization analysis for chromosomes 13, 18, 21, X, and Y as well as a conventional chromosome analysis was done. Statistical comparisons of values of multiples of the median were performed using the Wilcoxon rank sum test.
Over the 10-year period, 23,329 fetuses were screened. The median NT measurement was 1.55 mm; 258 (1.1%) and 136 (0.6%) of pregnancies measured 3.0 mm or greater and 3.5 mm or greater, respectively. Of the 1479 patients with positive screens, 656 (44.4%) underwent CVS or amniocentesis, from which 47 cases of Down syndrome, 16 of trisomy 18, and 6 of trisomy 13 were found. Of the 23,329 screen results, 1320 (5.7%) were positive for Down syndrome only. Fifty-two of these pregnancies (3.9%) had an abnormal karyotype; 34 (65.4%) were confirmed as Down syndrome, and 18 (34.0%) had different chromosome abnormalities. Four and 3 pregnancies, respectively, had a 47,XYY or 45,X karyotype. The other 11 chromosome abnormalities were either structural or numerical abnormalities other than Down syndrome. Eighty-seven pregnancies (0.4%) were screen positive for trisomies 13/18 only; 12 (13.8%) had an abnormal karyotype, of which 7 (58.3%) were trisomy 13 or 18, and 5 (41.7%) were a different aberration. Of 72 pregnancies (0.3%) screen positive for both Down syndrome and trisomies 13/18, 33 (45.8%) had an abnormal karyotype; 27 (81.8%) were confirmed as Down syndrome, trisomy 13, or trisomy 18. Six (18.2%) had a 45,X karyotype. Of the 97 screen-positive pregnancies with an abnormal karyotype, 52, 12, and 33 were positive for Down syndrome, trisomy 13 or 18, or both, respectively. The detection rate was 94% for Down syndrome and 100% for trisomies 13/18. Only 68 (70.1%) of screen-positive pregnancies with an abnormal karyotype had the aneuploidy indicated by the first-trimester screen. Seventeen of 28 were nonmosaic numerical abnormalities (trisomy 16; 47,XYY; 45,X; triploidy, and polyploidy). Five (17.9%) were mosaic for aneuploidy or polyploidy. Three pregnancies among 21,850 screen-negative results were false negatives; 3 infants were diagnosed with Down syndrome after having a screen-negative result. No false-negative results were reported for trisomy 13/18. Of the total cohort, 136 pregnancies (0.6%) had an NT measurement of 3.5 mm or greater; 42 (30.9%) had an abnormal karyotype. For NT of 3.0 mm or greater, 47 (18.2%) of 258 had an abnormal karyotype. All 15 pregnancies with NT of 8.0 mm or greater had an abnormal karyotype, including all 9 cases of 45,X.
These results confirm that first-trimester screening can be effective in assessing risk for Down syndrome and trisomies 13/18, with detection rates of 94% and 100%, respectively. The prevalence of chromosomal defects was directly related to NT thickness. The range of results can make counseling difficult, with each patient requiring an individualized interpretation of possible clinical consequences and the need for further diagnostic testing. Patients should be counseled about the possible presence of a fetal chromosome abnormality other than trisomies 13, 18, or 21 and that further genetic testing and evaluation may be necessary.
Northwestern Reproductive Genetics, Inc (C.M.L.A., M.F., E.P.), Chicago, IL; Perkin Elmer (D.K.), NTD Laboratories, Melville, NY; and Comprehensive Genetics, Inc (M.E.), New York, NY