Aneuploidy Screening in the News

Yesterday, I heard on NPR that the New England Journal of Medicine published an article about a new prenatal aneuploidy screening test, maternal cell-free plasma DNA (cfDNA), that may replace the standard screening test in place. Lucky for me, I have access to journal articles at the hospital and I wanted to summarize what I read.

DNA Sequencing versus Standard Prenatal Aneuploidy Screening

The use of cfDNA as a screening test for aneuploidy started back in 2011 after clinical validation studies all showed high sensitivity, specificity and negative predictive value for detection of the most common aneuploidies (trisomy 21 and 18). The studies had taken plasma samples retrospectively from patients with known karyotypes or prospectively from high risk patients. The results of the studies allowed the test be integrated into the clinical practice and used specifically for high-risk women. The question still remained, though, of how effective the screening test was in low-risk patients. A few studies had been conducted and showed promising results, however, they were conducted outside of the US and did not represent the approaches used in the US. The article published by the NEJM describes the results of the Comparison of Aneuploidy Risk Evaluation (CARE) which was a prospective, blinded study that compared the results of the cfDNA for aneuploidy with the current standard screening for trisomy 21 and 18 in the general population. The primary objective of the study was the comparison of false positive rates in each screening method.

Methods

Patients and Data Collection - The women enrolled for the study came from 21 different medical centers in 14 different states. To be eligible for the study, pregnant women needed to be at least 18 years old, carrying a fetus at least 8 weeks gestational age and had planned to undergo a standard prenatal serum screening test.

Clinical Outcomes - Patients were followed and categorized as having a live birth or a nonlive birth. For the live births, a pediatrician would examine the baby and document the baby as affected or not affected for trisomy 21 or 18. For nonlive births, cytogenetic testing or physical exam was performed.

Sample Collection, Sequencing and Aneuploidy Classification - At enrollment, a peripheral venous blood sample was obtained from all the participants. The sample was eligible for analysis if it was no more than 5 days old and contained at least 7 ml of blood. All the personnel were unaware of the clinical data and outcomes. For autosomal aneuploidy of chromosome 21, 18 and 13, samples with a normalized chromosome value of 4.0 or more were classified as affected and values of 3.0 or less classified as unaffected.

Aneuploidy Classification on Standard Screening - First trimester markers (pregnancy-associated plasma protein (PAPP-A), free beta subunit, human chorionic gonadotropin (hCG)) were combined with sonographic measurement of fetal nuchal translucency to formulate a risk score. Second-trimester serum values (maternal serum alpha-fetoprotein (MSAFP), hCG, unconjugated estriol and inhibin A) could be evaluated alone, in combination with first-trimester screening. Certified genetic counselors, who were unaware of the results of cfDNA and clinical outcomes, reviewed all the laboratory reports and trisomy 21 and 18 were classified as positive or negative for individual risk scores.

Results - Both methods (cfDNA and standard) detected all cases of aneuploidy but cfDNA had significantly lower false positive rates and higher positive predictive values for trisomy 21 and 18 than the standard screening test.

Discussion - This study set out to determine if this test would be valid in the general population rather than in high-risk women only and in the clinical setting in the US. The study was representative of the general population of women seen in clinical practice and showed that the performance of the cfDNA was better than the standard screening. The major advantage of using the cfDNA was the reduction of false positives! Although it is uncertain how cost-effective this test would be compared to the standard testing, the findings in the study merit further investigation as this may be overall, a superior test for fetal aneuploidy screening.