The effect of ultrasound findings on the risk of aneuploidy with a positive cell free DNA screen

The American College of Obstetricians and Gynecologists recommends that genetic counseling and aneuploidy screening be offered to all pregnant women regardless of their age, preferably at their first prenatal visit. The most... [ view full abstract ]

The American College of Obstetricians and Gynecologists recommends that genetic counseling and aneuploidy screening be offered to all pregnant women regardless of their age, preferably at their first prenatal visit. The most recent addition to the screening armamentarium is cell free DNA (cfDNA) screening through Next Generation Sequencing (NGS). While there is controversy on whether or not to use cfDNA screening in a low risk population, the arguments for its use include that it is noninvasive, has a superior sensitivity and specificity compared to conventional screening, and can be performed earlier in pregnancy than the prior screening options.
The false positive rate for the NGS is significantly less than one percent. The occurrence of a positive screen in a women who was believed to be at low risk required additional evaluation. When patients with a positive screen are referred for consultation, they are offered targeted ultrasound evaluation and invasive testing for confirmation of diagnosis.
We describe an IRB exempt retrospective review of data from unexpected positive noninvasive prenatal screens (NIPS) and a normal targeted scan, and we compare the karyotype information from this cohort with a high risk cohort where the NIPS was prompted by an abnormal ultrasound finding.

RESULTS: There were 48 NIPS performed for anomaly detected on ultrasound. These patients declined an initial offer of invasive testing. There were 14 abnormal NIPS results in this cohort. All cases had a confirmed abnormal on karyotype by either subsequent amniocentesis, neonatal blood, or placental karyotype evaluation. There was a 29% risk of aneuploidy in the cohort of infants with an anomaly. There was 100% concordance between the NIPS results and the karyotype information and no false negative screens in this group. There were 105 NIPS where the ultrasound failed to demonstrate any anomalies. Indications for screening included age, historical risk factors, soft markers for aneuploidy on ultrasound, maternal anxiety, or positive serum analyte screen. None of these patients had a positive NIPS and no post-natal abnormalities were reported. No post-natal karyotype was performed. A third group of patients (N=7) had NIPS by referring providers and were sent for consultation after the NIPS was reported as positive. (Monosomy X in 3 cases, one case each of partial Monosomy 13, 47 XXY, 47 XXX, and 48 XXY+13). In all 7 cases, the ultrasound was negative for anomalies. Of the 7 cases, all have either an amniocentesis which confirmed a normal karyotype or post-natal karyotype reported as normal. Using Fishers exact test, the probability of an abnormal karyotype following a positive NIPT was lower if the ultrasound fails to demonstrate any anomalies. (P=0.0035). Phi coefficient for association = 0.39. (p=.0001)
CONCLUSIONS: NIPS is a powerful new screening tool for common aneuploidies. The sensitivity and specificity are fixed test characteristics. The positive predictive value of the test is predicated upon the prevalence of the disease in the population being tested.
The widespread adoption of the NIPS in lower risk populations has presented a clinical challenge in counseling patients with an unexpected positive result. While best practice clearly dictate invasive testing for confirmation of the NIPS results, our findings suggest that a normal ultrasound after a positive NIPS is associated with a significantly reduced prevalence of aneuploidy and this information may be of some comfort to those women who are not prepared to proceed with invasive testing.