Aneuploidy screening: Newer noninvasive test gains traction

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Favorable results from the 2 studies reviewed here have prompted ACOG to recommend that cell-free DNA screening be discussed with all pregnant patients.




Discuss cell-free DNA testing when offering fetal aneuploidy screening to pregnant women.1,2

Strength of recommendation

A: Based on multiple large, multi-center cohort studies.

Bianchi DW, Parker RL, Wentworth J, et al; CARE Study Group. DNA sequencing versus standard prenatal aneuploidy screening. N Engl J Med. 2014;370:799-808.1
Norton ME, Jacobsson B, Swamy GK, et al. Cell-free DNA analysis for noninvasive examination of trisomy. N Engl J Med. 2015;372:1589-1597.2

Illustrative case

A 28-year-old gravida 2, para 1001 at 10 weeks gestation presents to your clinic for a routine first-trimester prenatal visit. Her first child has no known chromosomal abnormalities and she has no family history of aneuploidy. She asks you which tests are available to screen her fetus for chromosomal abnormalities.

Pregnant women have traditionally been offered some combination of serum biomarkers and nuchal translucency to assess the risk of fetal aneuploidy. Cell-free DNA testing (cfDNA) is a form of noninvasive prenatal testing that uses maternal serum samples to conduct massively parallel sequencing of cell-free fetal DNA fragments. It has been offered to pregnant women as a screening test to detect fetal chromosomal abnormalities since 2011 after multiple clinical studies found high sensitivities, specificities, and negative predictive values (NPVs) for detecting aneuploidy.3-6 However until 2015, practice guidelines from the American Congress of Obstetricians and Gynecologists (ACOG) recommended that standard aneuploidy screening or diagnostic testing be offered to all pregnant women and cfDNA be reserved for women with pregnancies at high risk for aneuploidy (strength of recommendation: B).7

CARE (Comparison of Aneuploidy Risk Evaluation) and NEXT (Noninvasive Examination of Trisomy) are 2 large studies that compared cfDNA and standard aneuploidy screening methods in pregnant women at low risk for fetal aneuploidy. Based on new data from these and other studies, ACOG and the Society for Maternal-Fetal Medicine (SMFM) released a new consensus statement in June 2015 that addressed the use of cfDNA in the general obstetric population. The 2 groups still recommend conventional first- and second-trimester screening by serum chemical biomarkers and nuchal translucency as the first-line approach for low-risk women who want to pursue aneuploidy screening; however, they also recommend that the risks and benefits of cfDNA should be discussed with all patients.8


CARE was a prospective, blinded, multicenter (21 US sites across 14 states) study that compared the aneuploidy detection rates of cfDNA to those of standard screening. Standard aneuploidy screening included assays of first- or second-trimester serum biomarkers with or without fetal nuchal translucency measurement.

This study enrolled 2042 pregnant patients ages 18 to 49 (mean: 29.6 years) with singleton pregnancies. The population was racially and ethnically diverse (65% white, 22% black, 11% Hispanic, 7% Asian). This study included women with diabetes mellitus, thyroid disorders, and other comorbidities. cfDNA testing was done on 1909 maternal blood samples for trisomy 21 and 1905 for trisomy 18.

cfDNA and standard aneuploidy screening results were compared to pregnancy outcomes. The presence of aneuploidy was determined by physician-documented newborn physical exam (97%) or karyotype analysis (3%). In both live and non-live births, the incidence of trisomy 21 was 5 of 1909 cases (0.3%) and the incidence of trisomy 18 was 2 of 1905 cases (0.1%).

The NPV of cfDNA in this study was 100% (95% confidence interval, 99.8%-100%) for both trisomy 21 and trisomy 18. The positive predictive value (PPV) was higher with cfDNA compared to standard screening (45.5% vs 4.2% for trisomy 21 and 40% vs 8.3% for trisomy 18). This means that approximately 1 in 25 women with a positive standard aneuploidy screen actually has aneuploidy. In contrast, nearly one in 2 women with a positive cfDNA result has aneuploidy.

Similarly, false positive rates with cfDNA were significantly lower than those with standard screening. For trisomy 21, the cfDNA false positive rate was 0.3% compared to 3.6% for standard screening (P<.001); for trisomy 18, the cfDNA false positive rate was 0.2% compared to 0.6% for standard screening (P=.03).

NEXT was a prospective, blinded cohort study that compared cfDNA testing with standard first-trimester screening (with measurements of nuchal translucency and serum biochemical analysis) in a routine prenatal population at 35 centers in 6 countries.

This study enrolled 18,955 women ages 18 to 48 (mean: 31 years) who underwent traditional first-trimester screening and cfDNA testing. Eligible patients included pregnant women with a singleton pregnancy with a gestational age between 10 and 14.3 weeks. Prenatal screening results were compared to newborn outcomes using a documented newborn physical examination and, if performed, results of genetic testing. For women who had a miscarriage or stillbirth or chose to terminate the pregnancy, outcomes were determined by diagnostic genetic testing.


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