SMFM Statement: Maternal serum cell-free DNA screening in low risk women
Maternal serum cell free DNA screening, or noninvasive prenatal testing (NIPT) for aneuploidy, uses cell free DNA from maternal serum to screen for common fetal aneuploidies with high sensitivity and specificity. NIPT uses next generation sequencing to directly measure fetal DNA in the maternal circulation, and clinical tests are now available using this technique. While there are differences in the methodologies employed by the commercial laboratories, overall the reported performance is similar, with detection rates for Down syndrome above 99% and false positive rates that are <1% (1-5). This makes this screening test an attractive alternative to traditional serum screening for aneuploidy for patients.
At the present time, professional organizations including SMFM have recommended that NIPT is most appropriate for high-risk patients (6-8). The five high-risk criteria currently include maternal age 35 years or older at delivery, sonographic findings indicating an increased risk of aneuploidy, history of a prior pregnancy with a trisomy, positive screening results for aneuploidy, including first trimester, sequential, integrated, or quadruple screen, or parental balanced Robertsonian translocation with increased risk for trisomy 13 or 21. This recommendation has been based primarily on the more limited evidence regarding the utility of NIPT in low- or average-risk pregnant women, and validation studies that have generally been limited to high-risk populations. Understandably, there is a keen interest in performing the same type of validation studies in a low risk population.
A recent paper published in the New England Journal of Medicine has garnered a great deal of media attention focused on the use of this technology in average risk patients (9). The authors, supported by one of the commercial laboratories, compared NIPT with traditional screening for aneuploidy using serum analytes on a relatively small number of average risk patients. The study was too small to compare detection rates, but the authors report that the false positive rate of NIPT is lower and therefore the test “merits serious consideration as a primary screening method for fetal autosomal aneuploidy.”
While this measured conclusion appears reasonable, the serious consideration that the authors propose requires further data, and the study by Bianchi et al has to be viewed in the context of its many limitations. Most importantly, the study is underpowered to compare the detection rates and it is generally not valid to compare false-positive rates in isolation. The authors compare only false positive rates for trisomies 18 and 21, although all commercially available products also include testing for trisomy 13 and the sex chromosomes, which have higher false positive rates (2, 10). A high percentage of the samples for NIPT were collected in the third trimester – at gestational ages when clinical aneuploidy screening is not performed and is not clinically relevant, yet when fetal DNA amounts are far higher allowing better test performance. The authors compare NIPT with “standard prenatal screening” with a variety of first and second trimester tests that have a broad range of performance characteristics. Fewer than 3% of patients had integrated screening, which is the prenatal screening method with the best performance, including the lowest false positive rate (11). In addition, traditional screening can detect risk for a broad array of structural, chromosomal and perinatal abnormalities. The importance of these in a low risk population may be far greater than the impact of trisomy 18 and 21, which are relatively rare in a younger maternal cohort. It is important to note that this study reported 5 Down syndrome cases in the population of 1909 patients, a rate of 1/381 and substantially higher than the population risk of 1/700 that would be expected in a truly “average” or “low risk” cohort. Finally and importantly, when considering population screening, many patients who choose NIPT will fail to obtain a result. While that number was just under 1% in this study, rates as high as 12% have been published, especially in overweight and obese women (12).
SMFM has reviewed the evidence, including this recent paper, and feels that while NIPT is a promising new technology, this new report is not enough to change current ACOG and SMFM recommendations. Given that just 8 aneuploidies were present in the entire cohort of patients, the true test performance is difficult to determine. Further evidence comparing costs, false positive rates for all included analyses, ability to obtain a result, and overall test performance for all detectable abnormalities in larger numbers of truly average risk patients are required to justify changing recommendations regarding population based prenatal screening from just high-risk pregnancies, to all pregnancies. We eagerly await the results of ongoing research studies which will address these issues.
1. Palomaki GE, Kloza EM, Lambert-Messerlian GM, et al. DNA sequencing of maternal plasma to detect Down syndrome: an international clinical validation study. Genet Med 2011;13(11):913–20.
2. Bianchi DW, Platt LD, Goldberg JD, et al. On behalf of the maternal blood is source to accurately diagnose fetal aneuploidy (MELISSA) study group. Genome-wide fetal aneuploidy detection by maternal plasma DNA sequencing. Obstet Gynecol 2012;119:890–901.
3. Ashoor G, Syngelaki A, Wagner M, et al. Chromosome-selective sequencing of maternal plasma cell-free DNA for first-trimester detection of trisomy 21 and trisomy 18. Am J Obstet Gynecol 2012;206(4):322.e1–5.
4. Sparks AB, Struble CA, Wang ET, et al. Noninvasive prenatal detection and selective analysis of cell-free DNA obtained from maternal blood: evaluation for trisomy 21 and trisomy 18. Am J Obstet Gynecol 2012;206(4):319.e1–9.
5. Norton ME, Brar H, Weiss J, et al. Non-invasive chromosomal evaluation (NICE) study: results of a multicenter prospective cohort study for detection of fetal trisomy 21 and trisomy 18. Am J Obstet Gynecol 2012;207(2):137.e1–8.
6. Position statement from the Aneuploidy Screening Committee on behalf of the Board of the International Society for Prenatal Diagnosis. Benn P, Borell A, Chiu R, et al. Prenat Diagn. 2013 Jul;33(7):622-9.
7. American College of Obstetricians and Gynecologists Committee on Genetics. Committee Opinion No. 545: Noninvasive prenatal testing for fetal aneuploidy. Obstet Gynecol. 2012 Dec;120(6):1532-4.
8. Wilson KL, Czerwinski JL, Hoskovec JM, et al. NSGC practice guideline: prenatal screening and diagnostic testing options for chromosome aneuploidy. J Genet Couns. 2013 Feb;22(1):4-15. doi: 10.1007/s10897-012-9545-3. Epub 2012 Nov 22.
9. Bianchi DW, Parker RL, Wentworth J, et al. N Engl J Med 2014;370:799-808.
10. Palomaki GE, Deciu C, Kloza EM, et al. 2012. DNA sequencing of maternal plasma reliably identifies trisomy 18 and trisomy 13 as well as Down syndrome: an international collaborative study. Genet. Med. 14:296–305
11. Malone FD, Canick JA, Ball RH, et al. 2005. First-trimester or second-trimester screening, or both, for Down's syndrome. N. Engl. J. Med. 353:2001–11.
12. Zimmermann B, Hill M, Gemelos G, et al. 2012. Noninvasive prenatal aneuploidy testing of chromosomes 13, 18, 21, X, and Y, using targeted sequencing of polymorphic loci. Prenat. Diagn. 32:1233–41.