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journal of medicine
established in 1812 october 9 , 2003 vol. 349 no. 15
abstract
background
Screening for aneuploid pregnancies is routinely performed after 15 weeks of gesta- From Drexel University College of Medicine,
Philadelphia (R.W., L.J.); the George Wash-
tion and has a sensitivity of approximately 65 percent, with a false positive rate of 5 per-
ington University Biostatistics Center, Wash-
cent. First-trimester markers of aneuploidy have been developed, but their use in combi- ington, D.C. (E.T., J.Z.); Baylor College of
nation has not been adequately evaluated in clinical practice. Medicine, Houston (J.L.S.); the Department
of Obstetrics and Gynecology, Northwest-
methods ern University Medical School, Chicago
(E.P., R. Sabbagha); the Fetal Diagnostic
We conducted a multicenter study of screening for trisomies 21 and 18 among patients Center, Evanston Hospital of Northwest-
with pregnancies between 74 and 97 days of gestation, based on maternal age, mater- ern University Medical School, Evanston,
nal levels of free b human chorionic gonadotropin and pregnancy-associated plasma Ill. (R. Silver, S.M.); UCLA Center for the
Health Sciences, Los Angeles (K.F.); the
protein A, and ultrasonographic measurement of fetal nuchal translucency. A screening Department of Obstetrics and Gynecolo-
result was considered to be positive for trisomy 21 if the calculated risk was at least 1 in gy, Cedars–Sinai Medical Center, Los Ange-
270 pregnancies and positive for trisomy 18 if the risk was at least 1 in 150. les (L.P., R. Snijders, N.G.); Yale University,
New Haven, Conn. (M.M.); the Department
of Obstetrics and Gynecology, Wayne State
results University, Detroit (A.J.); Magee Women’s
Screening was completed in 8514 patients with singleton pregnancies. This approach Hospital, Pittsburgh (A.H., L.H.); BC Wom-
to screening identified 85.2 percent of the 61 cases of Down’s syndrome (95 percent en’s Hospital, Vancouver, B.C., Canada (D.W.,
A.G.); McMaster University Medical Centre,
confidence interval, 73.8 to 93.0), with a false positive rate of 9.4 percent (95 percent Hamilton, Ont., Canada (P.M.); Prenatal Di-
confidence interval, 8.8 to 10.1). At a false positive rate of 5 percent, the detection rate agnosis of Northern California Medical
was 78.7 percent (95 percent confidence interval, 66.3 to 88.1). Screening identified Group, Sacramento (D.H.); and NTD Lab-
oratories, Huntington Station, N.Y. (D.K.,
90.9 percent of the 11 cases of trisomy 18 (95 percent confidence interval, 58.7 to 99.8), T.H.). Address reprint requests to Dr. Wap-
with a 2 percent false positive rate. Among women 35 years of age or older, screening ner at the Department of Obstetrics and Gy-
identified 89.8 percent of fetuses with trisomy 21, with a false positive rate of 15.2 necology, Drexel University College of Medi-
cine, 245 N. 15th St., MS 495, Philadelphia,
percent, and 100 percent of fetuses with trisomy 18. PA 19102.
102 (1.2%) With previous pregnancy with 196 (2.3%) Had unknown cytogenetic
trisomy 18 or 21 analyzed separately and phenotypic status (lost to follow-up)
11 Cases of trisomy 18
www.nejm.org
new england journal
813 (52) Had a positive first-trimester 7392 (9) Had a negative first-trimester
medicine
722 (12) Had 21 (5) Had 55 (35) Terminated 15 (0) Had an 7259 (4) Had 33 (0) Had an
66 (0) Had spon- 34 (5) Terminated
live-born infants spontaneous losses the pregnancy unknown delivery live-born infants unknown delivery
taneous losses the pregnancy
587 (11) Were 15 (3) Were 44 (30) Were outcome* 3376 (1) Were outcome*
38 (0) Were ≥35 yr old 17 (4) Were ≥35 yr old
≥35 yr old ≥35 yr old ≥35 yr old 10 (0) Were ≥35 yr old ≥35 yr old 25 (0) Were ≥35 yr old
Downloaded from nejm.org on February 6, 2011. For personal use only. No other uses without permission.
Figure 1. Number and Disposition of Patients Who Were Screened for the Study.
Numbers in parentheses are the numbers of patients who had a fetus with trisomy 21. Asterisks indicate cytogenetically normal pregnancies with unknown delivery outcome.
first-trimester screening for trisomies 21 and 18
(10.1–11.4)
4.7 (4.1–5.4)
Trisomy 21 or 18 (N=72)
screening for trisomy 18 resulted in the detection
48.0
26.1
11.8
10.7
of two additional cases of trisomy 18 and 1 addition-
al case of trisomy 21, with an associated increase of
1.4 percent in the false positive rate. Coincidentally,
80.0 (51.9–95.7)
Detection Rate
(79.3–95.1)
were positive for both trisomies 21 and 18 on screen-
77.8
87.5
81.9
88.9
† The results exclude one patient with a positive screening test for trisomy 21. The inclusion of this patient would have resulted in a detection rate of 100 percent.
ing, and one was positive for trisomy 21 alone. Three
of the four patients with triploid pregnancies had
a positive screening result: one was at risk for hav-
Rate with Cutoff
Detection Rate False Positive
1.3 (1.0–1.7)
2.6 (2.2–3.2)
ing a fetus with trisomy 21, and two were at risk for
(1.7–2.3)
of 1:150
2.9
2.0
Trisomy 18 (N=11)
89.8 (77.8–96.6) 15.2 (14.1–16.3) 77.6 (63.4–88.2)§ 67.4 (52.5–80.1)§ 100 (63.1–100)
66.7 (9.4–99.2)
(58.7–99.8)†
with Cutoff
27.3
81.8
81.8
90.9
47.5
63.9
(66.3–88.1)
¶ Among these patients, 49 had a fetus with trisomy 21 and 8 had a fetus with trisomy 18.
32.8
67.2
68.8
78.7
Trisomy 21 (N=61)
11.9
9.4
* Maternal age was the patient’s age at the estimated date of delivery.
tation.
Table 3 presents the first-trimester screening
results for the nine patients with false negative tests
66.7 (34.9–90.1)
80.3
85.2
82.0
85.2
8216
8216
8216
8216
4096
4120
chemical measurements,
(57.1 percent).
translucency
Screening Test
discussion
We have demonstrated at multiple clinical sites in
North America that screening for Down’s syndrome
Sensitivity
reported with the addition of inhibin A levels to sec-
ond-trimester triple-marker screening (on the ba-
sis of a 5 percent false positive rate).2 0.4
Among women who were 35 years of age or
older, many of whom may have elected to undergo
screening to avoid an invasive procedure, all preg-
0.2
nancies involving trisomy 18 and 89.8 percent of
those involving trisomy 21 were identified by screen-
ing, with a false positive rate of 15.2 percent. Thus,
if screening results were used preferentially over ma- 0.0
0.0 0.1 0.2 0.3
ternal age, 85 percent of women 35 years of age or False Positive Rate
older could avoid an invasive procedure. At the same
cutoff value of 1:270, the use of second-trimester Figure 2. Receiver-Operating-Characteristic Curves for the Prediction of
triple-marker screening in women who are 35 years Trisomy 21 with Use of the Combined Approach to Screening, Screening
of age or older would identify a similar proportion Based on Maternal Age and Nuchal Translucency, and Screening Based
on Maternal Age and Serum Measurements.
of fetuses (89 percent) with trisomy 21 but with a
false positive rate of 34 percent.14
Comparisons of the clinical performance of first-
and second-trimester screening must take into con-
sideration differences in the rates of spontaneously
Table 3. Serum Biochemical and First-Trimester Nuchal-Translucency Values
aborted pregnancies involving trisomy 21 at vari- and Calculated Risk for the Nine Patients with a Fetus with Trisomy 21
ous gestational ages. We used the calculations sug- and a Negative Result on First-Trimester Screening.
gested by Dunstan and Nix15 and published infor-
mation regarding the rates of spontaneous first- and Pregnancy- Free b Human
Maternal Associated Chorionic Nuchal Risk of
second-trimester losses of pregnancies involving tri- Age Plasma Protein A Gonadotropin Translucency Trisomy 21*
somy 2116 to account for these differences. Since 69
percent of fetuses with trisomy 21 identified in the yr multiples of the median
first trimester and 76 percent of those identified in 37 0.96 2.39 0.79 1:295
the second trimester will be viable, second-trimes- 42 1.26 0.96 0.96 1:321
ter screening would have to detect 75 percent of fe-
41 1.13 0.90 1.04 1:501
tuses with Down’s syndrome to be considered sim-
ilar to our first-trimester detection rate of 79 percent. 40 0.69 1.01 0.98 1:515
First-trimester screening would lose some ad- 35 0.64 0.61 1.52 1:1392
vantage if it preferentially identified nonviable preg- 33 0.83 1.12 1.18 1:1830
nancies involving trisomy 21. Using the above esti-
34 0.30 0.23 1.47 1:2037†
mates of the gestational-age–dependent viability
of pregnancies involving trisomy 21 and assuming 31 0.44 1.16 0.89 1:2283
the worst-case scenario — that all terminated preg- 33 0.73 0.80 1.14 1:3521
nancies that were negative for trisomy 21 on screen-
ing would have resulted in a live birth — we estimat- * The risk was based on maternal age, serum biochemical values, and nuchal-
ed that at least 80 percent of the fetuses identified translucency measurements combined.
† Although the results of screening were negative for trisomy 21, they were pos-
as having Down’s syndrome would have been born itive for trisomy 18.
alive. (see the Supplementary Appendix, available
with the full text of this article at http://www.nejm. went second-trimester screening and six were found
org). Thus, the good performance of first-trimester to be positive. Use of a 1 percent false positive rate
screening is not simply based on the identification for the second-trimester screening would have iden-
of pregnancies that would have been spontaneous- tified four of these seven patients. Although sequen-
ly aborted anyway. tial first- and second-trimester screening may have
Concern has been expressed that standardiza- some role, further detailed evaluation is required.
tion of nuchal-translucency measurements may not This includes an understanding of the interaction of
be feasible in clinical practice.17 However, we used first- and second-trimester analytes and the balance
more than 40 sonographers at 12 centers and had among improved rates of detection, an increased
excellent screening results. In our experience, a false positive rate, the delay in informing patients of
learning period was required, with measurements their risk, and the costs of this approach.
becoming more consistent over time. This required The 61 pregnancies involving trisomy 21 iden-
stringent training, formalized evaluation of sonog- tified in our population exceeds the 49 predicted
raphers’ competence, and continuing external qual- on the basis of maternal-age distribution. Women
ity control. who were referred because of a finding of increased
A review of our false negative results for triso- nuchal translucency were not included in this study;
my 21 reveals that the majority of the risk estimates thus, ascertainment bias is unlikely. This observa-
were well below the 1:270 cutoff, with only one of tion, although difficult to explain, gives us confi-
the nine between 1:271 and 1:300. Seven had val- dence that our ascertainment of affected pregnan-
ues of less than 1:500. This finding suggests that cies was maximized.
minor modifications of the methods will not sub- In conclusion, our cohort study shows that first-
stantially improve screening performance. Several trimester screening that combines maternal age, lev-
other complementary approaches to first-trimes- els of pregnancy-associated plasma protein A and
ter screening have been suggested, including the free b human chorionic gonadotropin, and nuchal-
use of new ultrasonographic markers (for example, translucency thickness is accurate and efficient in
nasal-bone hypoplasia and ductus venosus Dop- clinical practice. Its performance is good as com-
pler flow),18,19 sequential use of second-trimester pared with second-trimester screening, even after
biochemical analytes,20 and analysis of fetal DNA adjustment for potentially nonviable pregnancies.
or fetal cells in the maternal circulation.21-23 The Most important, first-trimester screening with these
roles of these variables in screening will require for- markers offers patients greater privacy, earlier re-
mal evaluation. sults, and safer reproductive alternatives than sec-
The usefulness of second-trimester screening ond-trimester screening.
in a patient who had negative results during the Supported by grants (R01 HD31991 and R01 HD32109) from the
National Institute of Child Health and Human Development and by
first trimester is unclear. Of our nine patients with the Fetal Medicine Foundation, which offered support in the train-
false negative results for trisomy 21, seven under- ing and certification of sonographers.
ap p e n d i x
In addition to the authors, the members of the First Trimester Maternal Serum Biochemistry and Ultrasound Fetal Nuchal Translucency
Screening (BUN) Study are as follows: Drexel University College of Medicine — M. DiVito, M. McGee, E. Waters, and P. Morgan; Baylor
College of Medicine — J. Dungan, K. Leonard, N. Agan, and G. Brewster; Northwestern University Medical School — N.A. Ginsberg and
K. DeMarco; Evanston Hospital of Northwestern University Medical School — K. Blum, E. Leeth, M. Kambick, L. Geibel, and P. Chilis; Ce-
dars–Sinai Medical Center — D.E. Carlson and C.A. Walla; Magee Women’s Hospital: E. Smith, K. Ventura, and J. Hecker; UCLA Center for
the Health Sciences — S. Beverly; Wayne State University — M.C. Treadwell, E. Krivchenia, P. Devers, and R. Richter; Yale University —
R. Bahado-Singh, S. Turk, and M. Feather; McMaster University Medical Centre — M.L. Beecroft and S. Kinnear; BC Women’s Hospital —
S. Soanes and A. Sleep; Prenatal Diagnosis of Northern California Medical Group — K. Kahl and M. Palmer; George Washington University
Biostatistics Center — P. Van and B. Fisher; and the National Institute of Child Health and Human Development — F. de la Cruz.
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