Objective
We sought to determine efficacy of minor markers for detection of Down syndrome (DS) in a population prescreened with first-trimester combined screening (FTS).
Study Design
FTS was modified using established likelihood ratios to generate a new composite risk (NCR).
Results
Of 3845 women, 390 had ≥1 marker. There were 10/3845 cases of DS; 3 were among patients with low-risk FTS (n = 3727). In 55 patients, NCR adjusted the risk from low to high without increasing detection rate. NCR did not modify risk to allow for detection of the 3 DS among patients with low-risk FTS even though 2 of these fetuses had 1 minor marker each. There were 7 DS among patients with high-risk FTS (n = 118). Use of NCR increased positive predictive value from 7/118 (5.1%) to 7/53 (13.2%).
Conclusion
Screening for minor markers is useful in patients with high-risk FTS. It is of questionable benefit in patients with low-risk FTS.
The second-trimester genetic sonogram, in various forms, has been used successfully for many years and has been shown to effectively modify age-related and second-trimester serum-based risks and improve Down syndrome (DS) detection. In the last few years, the first-trimester combined screen (FTS), incorporating maternal age, nuchal translucency, and maternal serum markers (free beta human chorionic gonadotropin and pregnancy-associated plasma protein A), has come into widespread use as a screening strategy to detect fetal DS. It is unknown whether the advent of FTS and early invasive testing by chorionic villus sampling (CVS) has changed the screening environment for second-trimester ultrasound by reducing the number of aneuploid fetuses entering the second trimester. In addition, there is a paucity of data regarding whether the minor sonographic markers for DS are still useful in predicting aneuploidy in a population prescreened with FTS.
Despite this lack of data to guide its interpretation, the second-trimester genetic sonogram is still widely performed in clinical practice. Indeed, a recent survey of the members of the Society of Maternal-Fetal Medicine showed that 98.7% of practices screen for DS with a second-trimester ultrasound. In addition, FTS was performed by 97.3% of practices.
The objective of this study was to determine whether the use of second-trimester minor markers for DS improves the efficacy of FTS.
Materials and Methods
This is a retrospective cohort study that received institutional review board approval. We included all singleton pregnancies that underwent FTS followed by a second-trimester detailed genetic sonogram at our university hospital from Jan. 1, 2004, through June 30, 2007. Patients were excluded if second-trimester ultrasound showed a major structural anomaly, or if a chromosomal abnormality other than DS was ascertained. A total of 3845 patients were evaluated.
Nuchal translucency for FTS was performed from 11 weeks 1 day to 13 weeks 6 days of gestation by certified sonographers and/or physicians. Dried blood specimens were collected via finger-stick and evaluated for free beta human chorionic gonadotropin and pregnancy-associated plasma protein A. Second-trimester ultrasound was performed at 18-22 weeks of gestation. Six minor markers were evaluated for DS detection: nuchal skin fold (thickening ≥6 mm), pyelectasis (renal pelvis at least 4 mm), echogenic intracardiac focus, echogenic bowel, short femur (observed/expected ratio of ≤0.91), and short humerus (observed/expected ratio of ≤0.89).
Previously published likelihood ratios (LRs) (Nyberg et al ) were used to modify each patient’s quantitative risk as ascertained by the FTS. An overall LR was calculated as the product of positive LRs for markers that were present with negative LRs for markers that were absent. A completely negative genetic scan was given an overall LR of 0.36. This overall LR was then multiplied with the odds from the FTS to generate a new risk, the new composite risk (NCR). LRs for positive and negative findings were as previously described and as follows: nuchal skin fold (positive LR = 61.0, negative LR = 0.61); pyelectasis (positive LR = 5.2, negative LR = 0.888); echogenic intracardiac focus (positive LR = 6.3, negative LR = 0.756); echogenic bowel (positive LR = 33.8, negative LR = 0.799); short femur (positive LR = 6.1, negative LR = 0.721); and short humerus (positive LR = 15.3, negative LR = 0.792).
A fixed risk cutoff of 1/300 for DS was used for both FTS and the NCR. If second-trimester screening was performed, it was not included in the analysis.
Results
Patient characteristics are shown in Tables 1 and 2 . There were 10 fetuses with DS in this cohort, giving a prevalence of 2.6 per 1000 in the second trimester. Overall, 390 of 3845 women had ≥1 minor sonographic markers (10.1%; 95% confidence interval, 9.2–11.1%). Of these, 344 of 3845 (8.9%) had an isolated marker, and 46 of 3845 (1.2%) had ≥2 markers. Among patients with low first-trimester risk, ≥1 minor markers were seen in 369 of 3724 (9.9%) unaffected and 2 of 3 (67%) DS fetuses. Among patients with high first-trimester risk, 15 of 111 (13.5%) unaffected and 4 of 7 (57.1%) DS fetuses had ≥1 minor marker. The distribution of the patient population with regard to minor markers is shown in Table 3 .
| Characteristic | Value |
|---|---|
| Age at EDC (y), mean ± SD | 32.03 ± 3.08 |
| Age ≥ 35 y | 24% |
| Nuchal translucency, mean ± SD | 1.31 ± 0.28 |
| CRL (mm), mean ± SD | 62.4 ± 6 |
| Gravidity, mean ± SD | 2.4 ± 1.0 |
| Parity, mean ± SD | 0.76 ± 0.69 |
| Ethnicity | Percentage |
|---|---|
| White | 68.50 |
| African American | 4.40 |
| Asian | 9.50 |
| Hispanic | 7.90 |
| Asian Indian | 3.60 |
| Native American | 0.20 |
| Other/unknown | 5.90 |
| Minor marker | n (%) | |
|---|---|---|
| None | 3455 (89.9) | |
| Any | 390 (10.1) | |
| Nuchal fold | 9 (0.2) | |
| Echogenic intracardiac focus | 158 (4.1) | |
| Echogenic bowel | 10 (0.3) | |
| Short femur | 113 (2.9) | |
| Short humerus | 11 (0.3) | |
| Pyelectasis | 43 (1.1) | |
| ≥2 | 46 (1.2) |
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