The study of Nicolaides et al, “Noninvasive prenatal testing for fetal trisomies in a routinely screened first-trimester population,” demonstrates that techniques analyzing cell free fetal DNA in the maternal circulation can perform well to detect aneuploidy in a general obstetric population. However, we must consider the impact of false-positive results before promoting this technique as a primary screening tool. The proportion of false- to true-positive results will be much higher among pregnancies in low-risk women. The study of Nicolaides et al confirms this problem, but does not highlight it.

Noninvasive prenatal tests (NIPT) are being aggressively marketed directly to the public and to obstetric clinicians. Companies prominently cite >99% sensitivity and specificity for trisomy 21 and trisomy 18 on their reports and promotional materials. While these figures are based on results from published trials, they may be misleading to both patients and physicians, due to the common confusion of high specificity with high positive predictive value. With the perception that NIPT is highly accurate, there is a real danger that positive test results will be interpreted as diagnostic, leading couples to terminate pregnancies without waiting for a confirmatory karyotype.

Since NIPT became commercially available in the United States we are aware of 13 fetal samples received at 6 US cytogenetics laboratories (ACL Laboratories, Park Ridge, IL; Brigham and Women’s Hospital, Boston, MA; Case Western Reserve, Cleveland, OH; Greenwood Genetic Center, Greenwood, SC; Johns Hopkins, Baltimore, MD; Stanford, Palo Alto, CA) that were positive for trisomy using NIPT but not confirmed by conventional chromosome analysis. Seven NIPT were positive for trisomy 18, 5 positive for trisomy 21, and 1 for trisomy 13. Normal karyotypes for 11 were obtained on amniocentesis and for 2 through chorionic villus sampling. Although we cannot calculate a false-positive rate without knowing the denominator from which these samples were drawn, the study of Nicolaides et al itself provides some information about the rate of false-positive findings. They identified 2 cases of euploid fetuses with “risk scores” for trisomy 18 above their screening cutoff, representing a false-positive rate of 2 of 1949 (0.10%). The prevalence of confirmed trisomy 18 in first trimester in their unselected population was only 3 of 2049 women (0.15%), and will be still lower in a low-risk population or in pregnancies screened later in gestation. Thus for rarer trisomies, the false-positive rate may exceed the true-positive rate.

The authors correctly suggest that confined placental mosaicism may explain some apparent false-positive results. Other possibilities include low-frequency fetal or maternal mosaicism. However, as with any screening test, some false-positive results are inherent in need to choose cutoffs to minimize false-negative findings. Systematic evaluation of cases with discordance between positive NIPT results and cytogenetic results should be undertaken before these tests are applied generally, or analysis is extended to more chromosomes. Postnatal evaluation of the newborns, their placentas, and possibly the mother’s karyotype from cases with discordance is needed. We recommend initiating a registry for discordant cases to allow systematic assessment of false-positive results. Meanwhile physicians and midwives offering NIPT must themselves understand and convey to their patients that positive results must be confirmed by diagnostic tests before pregnancies are terminated.