Use o f C ell-Free Fetal D NA in Mater n al Plasma for N o n i n v a s i v e P ren a t a l Sc re e n i n g Amy J. Wagner, MDa, Michael E. Mitchell, Aoy Tomita-Mitchell, PhDb,*

MD

b

,

KEYWORDS  Noninvasive prenatal testing  Screening  Cell-free DNA  Aneuploidy KEY POINTS  Noninvasive prenatal testing (NIPT) using cell-free fetal (cfDNA) offers potential as a screening tool for fetal anomalies; it is more accurate than maternal serum markers and nuchal translucency tests.  The accuracy of NIPT using cfDNA, with a lower false-positive rate than previous standard aneuploidy testing, decreases the overall number of invasive tests needed for a definitive diagnosis, subjecting fewer pregnancies to the risk of the invasive procedures.  Women who undergo NIPT need informed consent before testing and accurate, sensitive counseling after results are available.

INTRODUCTION

Prenatal screening for aneuploidy has been available to pregnant women for more than three decades. Accurate prenatal screening is important for several reasons. It can provide reassurance early in pregnancy in some cases. For those receiving less encouraging news, it allows the opportunity to consider options, have ample time to make difficult decisions, and manage expectations. It also may help to predict the postnatal course and make appropriate delivery plans when needed. An ideal prenatal test is one that is accurate, can be completed early in gestation, and poses minimal or

Disclosures: M.E. Mitchell and A. Tomita-Mitchell are co-founders of Ariosa Diagnostics, a company that offers a noninvasive prenatal screening test in which they have a significant financial interest. Any financial conflicts of interest that may be related to the work presented here have been disclosed to The Medical College of Wisconsin as required per Federal Regulation(s) 42 CFR Part 50, Subpart F and 45 CFR Part 94. A.J. Wagner has no disclosures. a Division of Pediatric Surgery, Department of Surgery, Medical College of Wisconsin, 999 North 92nd Street, Suite C320, Milwaukee, WI 53226, USA; b Division of Cardiothoracic Surgery, Department of Surgery, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA * Corresponding author. E-mail address: [email protected] Clin Perinatol - (2014) -–http://dx.doi.org/10.1016/j.clp.2014.08.013 perinatology.theclinics.com 0095-5108/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.

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no risk to the fetus and the mother. Over the past several years, the discovery of cellfree fetal DNA (cfDNA) in the maternal circulation has revolutionized prenatal screening and changed the standard of care. Noninvasive maternal blood testing began in the early 1980s with the maternal serum test for a-fetoprotein (AFP). Since that time, many serum factors have been studied as screening tests for fetal anomalies. Maternal serum markers tested in the second trimester utilized the double (maternal serum beta-human chorionic gonadotropin [hCG] and AFP), triple (maternal serum beta-hCG, AFP, unconjugated estriol), and eventually quadruple (maternal serum beta-hCG, AFP, unconjugated estriol, and inhibin A) screens. The quadruple screen is associated with a false-positive rate of 7% and a sensitivity of less than 80%.1 In 2007, the American College of Obstetricians and Gynecologists released guidelines that included nuchal translucency (a measurement of the thickness of the back of the fetal neck), serum pregnancy-associated plasma protein A (PAPP-A), and serum beta-hCG in the first trimester in addition to the quadruple screen in the second trimester. The nuchal translucency test has an overall sensitivity of 77% for trisomy 21 and a false-positive rate of 6%.2 Combining the nuchal translucency and quad screens improves sensitivity, but there continues to be a 3% to 5% false-positive rate.3 The maternal serum markers AFP, beta-hCG, unconjugated estriol, and inhibin A (the quad screen) are now routinely utilized in screening pregnancies for trisomy 21. AFP is a major fetal plasma protein and has a structure similar to albumin that is found in postnatal life. AFP is made initially by the yolk sac, gastrointestinal tract, and liver. Fetal plasma levels peak at approximately 10 to 13 weeks gestation and then decline progressively until term, whereas maternal levels peak in the third trimester. Maternal and amniotic fluid levels of AFP are increased in pregnancies in which the fetus has a neural tube defect (ie, anencephaly and open spina bifida) or certain other fetal malformations, such as abdominal wall defects. Screening of maternal blood samples usually is done between weeks 16 and 18 of gestation.4,5 Although neural tube defects have been associated with elevated levels of AFP, decreased levels have been associated with Down syndrome. A complex glycoprotein, beta-hCG is produced exclusively by the outer layer of the trophoblast shortly after implantation in the uterine wall. It increases rapidly in the first 8 weeks of gestation, declines steadily until 20 weeks, and then plateaus. Unconjugated estriol is produced by the placenta from precursors provided by the fetal adrenal glands and liver. It increases steadily throughout pregnancy to a higher level than that normally produced by the liver. Unconjugated estriol levels are decreased in Down syndrome and trisomy 18. The last maternal serum marker that makes up the quadruple screen is inhibin-A. Inhibin A, which is secreted by the corpus luteum and fetoplacental unit, is also a maternal serum marker for fetal Down syndrome when levels are reduced.6 Another first trimester serum screening test for trisomy 21, or Down syndrome, is PAPP-A. PAPP-A, which is secreted by the placenta, has been shown to play an important role in promoting cell differentiation and proliferation in various body systems. The PAPP-A concentration increases with gestational age until term. Decreased PAPP-A levels in the first trimester (between 10 and 13 weeks) have been shown to be associated with Down syndrome. When used along with free b-hCG and ultrasound measurement of nuchal translucency, serum PAPP-A levels can reportedly detect 82% to 87% of affected pregnancies with a false-positive rate of approximately 5%.7 The limitations of these standard prenatal screening tools include high false-positive and false-negative rates. Additionally, the quadruple screen is drawn in the second

Use of Fetal DNA for Prenatal Screening

trimester, which gives the patient less time to make challenging decisions regarding the pregnancy. Last, these screening tests need to be confirmed by an invasive test to obtain a sample of fetal tissue and a definitive diagnosis, either through chorionic villus sampling (CVS) or an amniocentesis. Both tests have a known risk of fetal loss to be approximately 1 in 200 to 1 in 300 procedures.8,9 As a positive screening test requires a confirmatory invasive CVS or amniocentesis, the high false-positive rate of these tests results in unnecessary procedures that put the fetus at risk (Table 1). Because of these limitations, other approaches with better diagnostic accuracy and without the invasive risk have been investigated. FETAL CELL-FREE DNA

A major breakthrough in the approach to accurate, noninvasive prenatal screening occurred after the discovery of fetal cfDNA in the maternal serum in 1997.10 Circulating cfDNA fragments are short fragments of DNA found in the blood. During pregnancy, there are cfDNA fragments from both the mother and fetus in the maternal circulation. Fetal cfDNA can be detected as early as 4 weeks gestation.11 The total amount of fetal cfDNA in the maternal serum is known as the fetal fraction. The fetal fraction varies between pregnancies and is affected by multiple factors including maternal weight, ethnicity, smoking status, gestational age, singleton versus Table 1 Down syndrome screening tests and detection rates Screening Test

Detection Rate (%)

First trimester NT measurement

64–70

NT measurement, PAPP-A, free or total beta-hCG

82–87

Second trimester Triple screen (maternal serum alpha-fetoprotein, hCG, unconjugated estriol)

69

Quadruple screen (maternal serum alpha-fetoprotein, hCG, unconjugated estriol, inhibin A)

81

First and second trimesters Integrated (NT, PAPP-A, quadruple screen) Serum integrated (PAPP-A, quadruple screen)

94–96 85–88

Stepwise sequential First-trimester test result Positive: Diagnostic test offered Negative: Second-trimester test offered Final: Risk assessment incorporates first- and second-trimester results

95

Contingent sequential First-trimester test result Positive: Diagnostic test offered Negative: No further testing Intermediate: Second-trimester test offered Final: Risk assessment incorporates first- and second-trimester results

88–94

Note: Detection rates are based on a 5% positive screen rate. Abbreviations: hCG, human chorionic gonadotropin; NT, nuchal translucency; PAPP-A, pregnancy-associated plasma protein A. Adapted from ACOG Committee on Practice Bulletins. Screening for fetal chromosomal abnormalities. Obstet Gynecol 2007;109:218; with permission.

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multiples, and fetal chromosomal abnormalities. The fetal fraction is about 10% of total circulating cfDNA on average and can range from 7% to 19%.12 Levels of cfDNA have been shown to increase moderately during a normal pregnancy,13 as well as during pathologic conditions of pregnancy such as preeclampsia.14 The majority of cfDNA in plasma is thought to originate from the natural turnover of hematopoietic cells via apoptosis.15,16 cfDNA has a rapid turnover, with the mean half-life estimated to be 16.3 minutes (range, 4–30). Therefore, to maintain a constant fetal fraction despite a relatively short half-life, fetal DNA must be released into the maternal circulation at a rate of 2.24  104 copies per minute.17 Because the half-life is so short, the fetal fragments are no longer detectable in the maternal circulation soon after birth.18,19 Therefore, the cfDNA test should also be accurate in multigravid women with the results reflecting the current pregnancy, because cfDNA from previous pregnancies would have cleared.20 Initially, cfDNA was able to be detected in the maternal plasma using paternally inherited loci or loci on the Y chromosome.21,22 This allowed maternal DNA to be differentiated from the male fetal DNA. However, the utility of the test was thus limited because it would be applicable only to male fetuses, loci on the Y chromosome, and heterozygous paternally inherited polymorphisms.23 In 2007, an advance in technology occurred that allowed aneuploidy detection from the maternal plasma regardless of fetal gender and theoretically to all chromosomes. This technology involved parallel shotgun DNA sequencing, also known as nextgeneration sequencing, followed by counting statistics.24–26 A variety of other methods have demonstrated proof of concept for detecting fetal DNA including placentally expressed mRNA and others. The first four companies to offer noninvasive cfDNA tests employ next-generation sequencing. Two of the tests use whole-genome shotgun sequencing27,28 and two use a targeted approach.29,30 Advantages of a targeted approach include reduced cost as well as shorter bioinformatics analysis.31 Although, theoretically, wholegenome shotgun sequencing would be more comprehensive, there is uncertainty about clinically reportable findings which could result in a greater burden for clinicians and their patients.32 Before the commercial availability of these products, proof of concept studies were completed, which proved that noninvasive prenatal testing (NIPT) is feasible using cfDNA in the maternal plasma. These studies were completed in both aneuploid and euploid pregnancies.20,24,33–35 The methods used included shotgun DNA sequencing in trisomies 13, 18,35,36 and 21.24,35,37 Tandem single nucleotide polymorphism analysis (short haplotype analysis) was also shown to be an effective and accurate means of diagnosing trisomy 21.34 Additionally, an alternate method called digital analysis of selected regions was developed to detect fetal trisomies 21 and 18 in the maternal plasma. Digital analysis of selected regions has the benefits of increasing mapping efficiency and selective analysis of specific chromosomes, while decreasing cost and improving throughput.33 Finally, an approach that assesses placentally expressed mRNA present in maternal plasma has shown moderate success for detecting trisomy 21.38 Using single nucleotide polymorphisms on the PLAC4 gene, 9 out of 10 trisomy 21 patients were identified (90% sensitivity).38 However, there are inherent issues of RNA-based approaches. Limitations include the instability of RNA, currently only one gene seems to be reliably suitable for such analysis on chromosome 21, the number of potentially informative single nucleotide polymorphisms on the PLAC4 gene is limited, and false positives are likely with certain maternal illnesses. Furthermore, because the approach is not DNA-based and

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requires more than a thousand-fold differential between placental RNA expression and maternal hematopoietic cells, the ability to expand toward other chromosomal regions and assays for trisomies 13 and 18 is limited. After publication of these proof-of-concept trials, several clinical trials were published in women who were deemed high risk for trisomy 21, another aneuploidy, or any disorder.28,29,39–43 Patients were defined as high risk if they had a positive screening test, advanced maternal age, ultrasound findings, or positive family history. The studies included results on trisomies 13, 18, and 21. A systematic review was published regarding the diagnostic accuracy of noninvasive detection of fetal trisomy 21 in high-risk patients.44 This included a total of 681 pregnancies with an overall sensitivity of 125 of 125 (100%; 95% CI, 97.5%–100%) and specificity of 552 of 556 (99.3%; 95% CI, 98.7%–99.3%). This revealed that there is a high diagnostic accuracy to detect trisomy 21 in high-risk patients using fetal nucleic acids in the maternal plasma. More recently, there have been studies investigating the accuracy of NIPT using cfDNA in non–high-risk subjects. It was important to examine the utility in low-risk patients, because the results of studies completed on high-risk individuals could not necessarily be generalized to the rest of the obstetric population. These studies also found that NIPT is highly accurate in this population to detect fetal aneuploidy.45–49 Bianchi and colleagues49 reported results from 1914 women with singleton pregnancies who were undergoing standard aneuploidy testing using serum biochemical assays with or without nuchal translucency measurement. They used massively parallel sequencing of maternal cfDNA. The false-positive rates with cfDNA testing were lower than those that had standard screening for trisomies 21 and 18 (0.3% vs 3.6% for trisomy 21 [P 5 .001]; 0.2% vs 0.6% for trisomy 18 [P 5 .03]).49 Therefore, cfDNA was shown to have lower false-positive rates and higher positive predictive values than standard screening in the general obstetric population. A meta-analysis was also recently published that reviewed cfDNA for aneuploidy screening. The results for pooled detection rates and false-positive rates were 99.0% (95% CI, 98.2–99.6) and 0.08% (95% CI, 0.03–0.14) respectively, for trisomy 21; 96.8% (95% CI, 94.5–98.4) and 0.15% (95% CI, 0.08–0.25) for trisomy 18; and 92.1% (95% CI, 85.9–96.7) and 0.2% (95% CI, 0.04–0.46) for trisomy 13.50 Although cfDNA screening studies are promising and demonstrate high sensitivity and specificity with low false-positive rates, there are limitations to NIPT. Specificity and sensitivity are not uniform for all chromosomes, in part owing to differing content of cytosine and guanine nucleotide pairs.51 False-positive screening results occur. Furthermore, the sequences derived from NIPT are derived from the placenta and, like CVS, may not reflect the true fetal karyotype. Therefore, invasive testing is recommended for confirmation of a positive screening test and should remain an option for patients seeking a definitive diagnosis.51 Despite these known limitations and the requirement for invasive testing to confirm a definitive diagnosis, the American College of Obstetricians and Gynecologists, the Society for Maternal-Fetal Medicine, the National Society of Genetic Counselors, and the International Society for Prenatal Diagnosis state that cfDNA testing should be offered to pregnant women at high risk for fetal aneuploidy as a screening test.52–54 In addition to advances in prenatal screening for aneuploidy, recent developments in the clinical application of genomic technologies have impacted prenatal diagnosis. Chromosomal microarray analysis allows identification of microdeletions and microduplications of chromosomes that are too small to be identified by karyotyping.55 Another advantage of chromosomal microarray analysis is the rapidity of results. Standard cytogenetic karyotype requires 5 to 7 days of tissue culture, whereas

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chromosomal microarray analysis is able to be completed on uncultured samples. This more rapid result time is important in prenatal testing and counseling.55 CONTROVERSIES

Prenatal testing and counseling are inherently emotionally complex endeavors. The development of NIPT and the ability to provide additional information about the fetus earlier in gestation has raised many ethical issues including informed consent, terminations, changes in perceptions of those with disabilities, and appropriate counseling. Practitioners discussing invasive testing such as CVS or an amniocentesis have a clear need to obtain informed consent because there is an inherent risk to the procedure. However, when the same emotionally complex issues regarding aneuploidy results are garnered through a peripheral blood draw, the question arises of whether or not the patient was properly prepared for the information she will receive. The first issue is the need for a confirmatory invasive test; NIPT is simply screening and not meant as a definitive diagnostic test. After a woman receives results that are concerning for aneuploidy, she needs to make the decision of whether or not to pursue an invasive test (CVS or amniocentesis) for a definitive diagnosis. It is important that the patient understand this will be recommended, and not be surprised when that is the next recommended step.31 In addition to the concern regarding appropriate informed consent for women undergoing NIPT, the concern has been raised that it may lead to an increase in the number of terminations. More accurate and reliable prenatal testing will likely lead to a greater number of fetuses diagnosed with not only aneuploidy, but also the possibility of diagnosing other genetic conditions early in the pregnancy. This will likely result in more pregnancy terminations. There is rarely an issue more passionately debated or contentious than that of reproductive rights. The concern is that NIPT will make abortion more common because the diagnoses will be available to a woman earlier in her pregnancy.56 Fears of eugenics and termination over qualities such as gender, trait selection, or even the concern of creation of “savior siblings” have also been raised.57 Additionally, implications have been raised that there may be a negative effect on the status and worth of those people currently living with disabilities as more people decide to terminate pregnancies with similar diagnoses. There have also been concerns raised about funding, research, treatment, awareness, and support of those with disabilities or aneuploidy.57 Women who are pregnant with a fetus with a prenatal diagnosis of aneuploidy or any disability require careful, thorough, and understandable prenatal counseling in a nondirective fashion. The question arises of how best to provide appropriate pretest genetic counseling before the decision to pursue NIPT is made. Currently, in California approximately two thirds of pregnant women undergo noninvasive screening for trisomy 21 and neural tube defects. If the same proportions of women in the United States choose to have NIPT, the number of genetic tests will go from 100,000 per year to more than 3 million.57 If more women undergo NIPT, it is important to ensure that there are a sufficient number of genetic counselors to provide appropriate information regarding interpretation of results and expectations. As more patients opt for NIPT, the responsibility of delivering the information will increasingly fall to the obstetricians because the information will exceed the number of genetic counselors available. Genetic counselors traditionally receive formal training on how to deliver a prenatal diagnosis to a pregnant mother.58 In a 2004 survey of American College of Obstetricians and Gynecologists fellows, 45% rated their training regarding prenatal diagnosis and counseling as “barely adequate or

Use of Fetal DNA for Prenatal Screening

nonexistent.”59 Unfortunately, as more of the NIPT responsibility falls to obstetricians who have not had the benefit of formal training, the mothers’ experience when receiving the news has been reported to be less than positive. Mothers with a prenatal diagnosis of trisomy 21 state that the diagnosis was delivered to them in an “incomplete” or “inaccurate” fashion by their obstetrician.60 Ideally, obstetricians and pediatricians should coordinate their counseling to deliver news as parents preferred to receive the diagnosis together in a joint meeting with both providers.61 When this is not possible, the obstetrician and the pediatrician should communicate to ensure that a consistent message is being conveyed.61 SUMMARY

NIPT using cfDNA offers tremendous potential as a screening tool owing to its increased accuracy over maternal serum markers and nuchal translucency tests. The American College of Obstetricians and Gynecologists recommends that all pregnant women, regardless of age, be offered prenatal screening and diagnostic testing by their obstetrician.7 The recent and rapid adoption of NIPT in high-risk pregnancies in the United States suggests that NIPT may change the standard of care for genetic screening. This allows the advantages of an accurate test with results available early in the pregnancy. The accuracy of NIPT using cfDNA, with a lower false-positive rate than previous standard aneuploidy testing, decreases the overall number of invasive tests needed for a definitive diagnosis, subjecting fewer pregnancies to the risk of the invasive procedures. Women who undergo NIPT need informed consent before testing and accurate, sensitive counseling after results are available. REFERENCES

1. Wald NJ, Huttly WJ, Hackshaw AK. Antenatal screening for Down’s syndrome with the quadruple test. Lancet 2003;361(9360):835–6. 2. Malone FD, D’Alton ME, Society for Maternal-Fetal Medicine. First-trimester sonographic screening for Down syndrome. Obstet Gynecol 2003;102(5 Pt 1): 1066–79. 3. Malone FD, Canick JA, Ball RH, et al. First-trimester or second-trimester screening, or both, for Down’s syndrome. N Engl J Med 2005;353(19):2001–11. 4. Nassbaum RL, McInnes RR, Willard HF, editors. Thompson & Thompson genetics in medicine. 7th edition. Philadelphia: Saunders Elsevier; 2007. 5. Graves JC, Miller KE, Sellers AD. Maternal serum triple analyte screening in pregnancy. Am Fam Physician 2002;65(5):915–20. 6. Lambert-Messerlian GM, Canick JA. Clinical application of inhibin a measurement: prenatal serum screening for Down syndrome. Semin Reprod Med 2004;22(3):235–42. 7. ACOG Committee on Practice Bulletins. ACOG practice bulletin no. 77: screening for fetal chromosomal abnormalities. Obstet Gynecol 2007;109(1): 217–27. 8. Antsaklis A, Papantoniou N, Xygakis A, et al. Genetic amniocentesis in women 20-34 years old: associated risks. Prenat Diagn 2000;20(3):247–50. 9. Evans MI, Andriole S. Chorionic villus sampling and amniocentesis in 2008. Curr Opin Obstet Gynecol 2008;20(2):164–8. 10. Lo YM, Corbetta N, Chamberlain PF, et al. Presence of fetal DNA in maternal plasma and serum. Lancet 1997;350(9076):485–7. 11. Illanes S, Denbow M, Kailasam C, et al. Early detection of cell-free fetal DNA in maternal plasma. Early Hum Dev 2007;83(9):563–6.

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12. Ashoor G, Poon L, Syngelaki A, et al. Fetal fraction in maternal plasma cell-free DNA at 11-13 weeks’ gestation: effect of maternal and fetal factors. Fetal Diagn Ther 2012;31(4):237–43. 13. Lo YM, Tein MS, Lau TK, et al. Quantitative analysis of fetal DNA in maternal plasma and serum: implications for noninvasive prenatal diagnosis. Am J Hum Genet 1998;62(4):768–75. 14. Zhong XY, Laivuori H, Livingston JC, et al. Elevation of both maternal and fetal extracellular circulating deoxyribonucleic acid concentrations in the plasma of pregnant women with preeclampsia. Am J Obstet Gynecol 2001;184(3):414–9. 15. Suzuki N, Kamataki A, Yamaki J, et al. Characterization of circulating DNA in healthy human plasma. Clin Chim Acta 2008;387(1–2):55–8. 16. Lui YY, Chik KW, Chiu RW, et al. Predominant hematopoietic origin of cell-free DNA in plasma and serum after sex-mismatched bone marrow transplantation. Clin Chem 2002;48(3):421–7. 17. Lo YM, Zhang J, Leung TN, et al. Rapid clearance of fetal DNA from maternal plasma. Am J Hum Genet 1999;64(1):218–24. 18. Hui L, Vaughan JI, Nelson M. Effect of labor on postpartum clearance of cell-free fetal DNA from the maternal circulation. Prenat Diagn 2008;28(4):304–8. 19. Smid M, Galbiati S, Vassallo A, et al. No evidence of fetal DNA persistence in maternal plasma after pregnancy. Hum Genet 2003;112(5–6):617–8. 20. Benn P, Cuckle H, Pergament E. Non-invasive prenatal testing for aneuploidy: current status and future prospects. Ultrasound Obstet Gynecol 2013;42(1): 15–33. 21. Dhallan R, Guo X, Emche S, et al. A non-invasive test for prenatal diagnosis based on fetal DNA present in maternal blood: a preliminary study. Lancet 2007;369(9560):474–81. 22. Lo YM. Noninvasive prenatal detection of fetal chromosomal aneuploidies by maternal plasma nucleic acid analysis: a review of the current state of the art. BJOG 2009;116(2):152–7. 23. Sifakis S, Papantoniou N, Kappou D, et al. Noninvasive prenatal diagnosis of Down syndrome: current knowledge and novel insights. J Perinat Med 2012; 40(4):319–27. 24. Fan HC, Quake SR. Detection of aneuploidy with digital polymerase chain reaction. Anal Chem 2007;79(19):7576–9. 25. Lo YM, Lun FM, Chan KC, et al. Digital PCR for the molecular detection of fetal chromosomal aneuploidy. Proc Natl Acad Sci U S A 2007;104(32):13116–21. 26. Bianchi DW, Wilkins-Haug L. Integration of noninvasive DNA testing for aneuploidy into prenatal care: what has happened since the rubber met the road? Clin Chem 2014;60(1):78–87. 27. Canick JA, Kloza EM, Lambert-Messerlian GM, et al. DNA sequencing of maternal plasma to identify Down syndrome and other trisomies in multiple gestations. Prenat Diagn 2012;32(8):730–4. 28. Bianchi DW, Platt LD, Goldberg JD, et al. Genome-wide fetal aneuploidy detection by maternal plasma DNA sequencing. Obstet Gynecol 2012;119(5): 890–901. 29. 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. 30. Zimmermann B, Hill M, Gemelos G, et al. Noninvasive prenatal aneuploidy testing of chromosomes 13, 18, 21, X, and Y, using targeted sequencing of polymorphic loci. Prenat Diagn 2012;32(13):1233–41.

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31. Morain S, Greene MF, Mello MM. A new era in noninvasive prenatal testing. N Engl J Med 2013;369(6):499–501. 32. Dewey FE, Grove ME, Pan C, et al. Clinical interpretation and implications of whole-genome sequencing. JAMA 2014;311(10):1035–45. 33. Sparks AB, Wang ET, Struble CA, et al. Selective analysis of cell-free DNA in maternal blood for evaluation of fetal trisomy. Prenat Diagn 2012;32(1):3–9. 34. Ghanta S, Mitchell ME, Ames M, et al. Non-invasive prenatal detection of trisomy 21 using tandem single nucleotide polymorphisms. PLoS One 2010;5(10): e13184. 35. Sehnert AJ, Rhees B, Comstock D, et al. Optimal detection of fetal chromosomal abnormalities by massively parallel DNA sequencing of cell-free fetal DNA from maternal blood. Clin Chem 2011;57(7):1042–9. 36. Chen EZ, Chiu RW, Sun H, et al. Noninvasive prenatal diagnosis of fetal trisomy 18 and trisomy 13 by maternal plasma DNA sequencing. PLoS One 2011;6(7): e21791. 37. Chiu RW, Chan KC, Gao Y, et al. Noninvasive prenatal diagnosis of fetal chromosomal aneuploidy by massively parallel genomic sequencing of DNA in maternal plasma. Proc Natl Acad Sci U S A 2008;105(51):20458–63. 38. Lo YM, Tsui NB, Chiu RW, et al. Plasma placental RNA allelic ratio permits noninvasive prenatal chromosomal aneuploidy detection. Nat Med 2007;13(2):218–23. 39. Chiu RW, Akolekar R, Zheng YW, et al. Non-invasive prenatal assessment of trisomy 21 by multiplexed maternal plasma DNA sequencing: large scale validity study. BMJ 2011;342:c7401. 40. Ehrich M, Deciu C, Zwiefelhofer T, et al. Noninvasive detection of fetal trisomy 21 by sequencing of DNA in maternal blood: a study in a clinical setting. Am J Obstet Gynecol 2011;204(3):205.e1–11. 41. 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. 42. 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. 43. 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. 44. Verweij EJ, van den Oever JM, de Boer MA, et al. Diagnostic accuracy of noninvasive detection of fetal trisomy 21 in maternal blood: a systematic review. Fetal Diagn Ther 2012;31(2):81–6. 45. Lau TK, Chan MK, Lo PS, et al. Clinical utility of noninvasive fetal trisomy (NIFTY) test–early experience. J Matern Fetal Neonatal Med 2012;25(10):1856–9. 46. Nicolaides KH, Syngelaki A, Ashoor G, et al. Noninvasive prenatal testing for fetal trisomies in a routinely screened first-trimester population. Am J Obstet Gynecol 2012;207(5):374.e1–6. 47. Dan S, Wang W, Ren J, et al. Clinical application of massively parallel sequencingbased prenatal noninvasive fetal trisomy test for trisomies 21 and 18 in 11,105 pregnancies with mixed risk factors. Prenat Diagn 2012;32(13):1225–32. 48. Gil MM, Quezada MS, Bregant B, et al. Implementation of maternal blood cell-free DNA testing in early screening for aneuploidies. Ultrasound Obstet Gynecol 2013;42(1):34–40. 49. Bianchi DW, Parker RL, Wentworth J, et al. DNA sequencing versus standard prenatal aneuploidy screening. N Engl J Med 2014;370(9):799–808.

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50. Gil MM, Akolekar R, Quezada MS, et al. Analysis of cell-free DNA in maternal blood in screening for aneuploidies: meta-analysis. Fetal Diagn Ther 2014; 35(3):156–73. 51. Gregg AR, Gross SJ, Best RG, et al. ACMG statement on noninvasive prenatal screening for fetal aneuploidy. Genet Med 2013;15(5):395–8. 52. Benn P, Borell A, Chiu R, et al. Position statement from the aneuploidy screening committee on behalf of the board of the international society for prenatal diagnosis. Prenat Diagn 2013;33(7):622–9. 53. Devers PL, Cronister A, Ormond KE, et al. Noninvasive prenatal testing/noninvasive prenatal diagnosis: the position of the national society of genetic counselors. J Genet Couns 2013;22(3):291–5. 54. American College of Obstetricians and Gynecologists Committee on Genetics. Committee opinion no. 545: noninvasive prenatal testing for fetal aneuploidy. Obstet Gynecol 2012;120(6):1532–4. 55. Wapner RJ, Levy B. The impact of new genomic technologies in reproductive medicine. Discov Med 2014;17(96):313–8. 56. Benn PA, Chapman AR. Ethical challenges in providing noninvasive prenatal diagnosis. Curr Opin Obstet Gynecol 2010;22(2):128–34. 57. Greely HT. Get ready for the flood of fetal gene screening. Nature 2011; 469(7330):289–91. 58. Skotko BG, Kishnani PS, Capone GT, Down Syndrome Diagnosis Study Group. Prenatal diagnosis of Down syndrome: how best to deliver the news. Am J Med Genet A 2009;149A(11):2361–7. 59. Cleary-Goldman J, Morgan MA, Malone FD, et al. Screening for Down syndrome: practice patterns and knowledge of obstetricians and gynecologists. Obstet Gynecol 2006;107(1):11–7. 60. Skotko BG. Prenatally diagnosed Down syndrome: mothers who continued their pregnancies evaluate their health care providers. Am J Obstet Gynecol 2005; 192(3):670–7. 61. Skotko BG, Capone GT, Kishnani PS, Down Syndrome Diagnosis Study Group. Postnatal diagnosis of Down syndrome: synthesis of the evidence on how best to deliver the news. Pediatrics 2009;124(4):e751–8.

Use of cell-free fetal DNA in maternal plasma for noninvasive prenatal screening.

Noninvasive prenatal testing (NIPT) using cell-free fetal (cfDNA) offers potential as a screening tool for fetal anomalies. All pregnant women should ...
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