母血非侵襲性唐氏症篩檢NIFTY，敲起了產前檢查包括2指4指的喪鐘了嗎？

2014.06.13

 母血非侵襲性唐氏症篩檢NIFTY，敲起了產前檢查包括2指4指的喪鐘了嗎？Has noninvasive fetal trisomy testing (NIFTY) rung the death knell for other forms of prenatal testing?

這個論文報告的題目真的是很令人驚訝，這是2014年05月30日的不孕與節育期刊，Firuza Rajesh Parikh, M.D.面回顧了NIPTY的發展，
他指出了在新生兒裡面21、13、18是最容易產生體顯性染色體異常的，而大概有160個新生兒就有一個，
而其他的像特諾氏症候群45XO、克林菲爾氏症候群47XXY和XYY症候群，也是非常常見的，也就是說在其他的性染色體包括X染色體少一個或X染色體多一個，或者Y染色體多一個，這個在新生兒裡面尤其是男生裡面也有1/500到1/850的女性新生兒，
 
因此任何的產前檢查-母血，非侵襲性篩檢至少要把以上提到的這6種染色體異常，包括13、18、21、45X、47XXY、XXY這6個找出來，否則的話就不叫產前非侵襲性檢查，
 
或者是有任何取代現階段2指或4指或羊水穿刺的意義，因此在目前全世界有關NIFTY的檢查，包括亞洲全球都有突飛猛進的進步，這份寫的非常聳動的是來自於美國約翰霍普京斯醫學研究中心Jaslok Hospital and Research Centre登在生育與節育期刊2014年05月30日。
 
Has noninvasive fetal trisomy testing (NIFTY) rung the death knell for other forms of prenatal testing?
Firuza Rajesh Parikh, M.D.
, 
 Madhavi Panpalia, M.S.
, 
Meenal Khandeparkar, M.B.B.S.
Department of Assisted Reproduction and Genetics, Jaslok Hospital and Research Centre, Mumbai, India
Published Online: May 30, 2014
Publication stage: In Press Corrected Proof
 
  •  
  •  
 
Obstetric vigilance for early pregnancy screening has become imperative for all pregnancies, regardless of the risk for chromosomal anomalies.
Down syndrome (trisomy 21), Edward syndrome (trisomy 18), and Patau syndrome (trisomy 13) are the most significant autosomal aneuploidies, occurring in as many as 1 in 160 live births. Turner syndrome (45,X), Klinefelter syndrome (47,XXY), and XYY syndrome are common sex chromosomal aneuploidies occurring in 1 out of 500 male births and 1 out of 850 female births.
A conglomeration of tests, such as biochemical marker testing, nuchal translucency by ultrasound, morphology by sonography, and other invasive testing, such as chorion villus sampling and amniocentesis, help clinch the diagnosis in high-risk pregnancies. Because average and low-risk pregnancies account for 75% of chromosomal abnormalities, the question that needs to be addressed is whether a noninvasive modality can adequately diagnose chromosomal abnormalities in the low-risk group of patients.
Noninvasive fetal trisomy testing (NIFTY) is a recent molecular test to detect fetal trisomies 21, 18, and 13 based on detection of cell-free fetal DNA (cfDNA) and intact fetal cells in the maternal blood. The technology of massively parallel sequencing of cfDNA uses a highly sensitive assay to quantify millions of DNA fragments in the maternal blood. Quantitative differences in chromosomal fragments or a chromosome type in excess of a 1:1 ratio relative to all other pairs can identify fetuses affected with trisomy. This test was endorsed by the American College of Obstetricians and Gynecologists (ACOG) in 2011 for women at high risk of aneuploidy. Subsequent research has validated its use in women at low and average risk. The purpose of the present paper is to examine whether NIFTY, which is considered to be a noninvasive screening test, can attract the confidence of clinicians and replace invasive testing. A paradigm shift in its utility would be acceptable if the test gives fewer false positive results than standard screening procedures and is affordable.
The Comparison of Aneuploidy Risk Evaluations (CARE) study was carried out by Bianchi et al. (1) at the Tufts Medical Center, comparing the current standard-of-care tests using biochemical markers and nuchal translucency on ultrasound against cfDNA testing. Their main objective was to compare the rate of false positives. The study included 1,914 blood samples from women with a mean age of 29.6 years undergoing routine screening at 21 centers. The study found that in a head-to-head comparison of noninvasive prenatal testing with the use of cfDNA versus standard screening methods, cfDNA testing significantly reduced the rate of false positive results for fetal trisomies 21 (0.3% vs. 3.6%) and 18 (0.2% vs. 0.6%) and had significantly higher positive predictive values for the detection of trisomies 21 (45.5% vs. 4.2%) and 18 (40.0% vs. 8.3%). cfDNA testing was more specific than standard testing for both trisomies 21 (99.7% vs. 96.4%) and 18 (99.8% vs. 99.4%). cfDNA had a sensitivity and negative predictive value of 100% for both trisomies 21 and 18.
A negative NIFTY result obviates the use of invasive testing, thus narrowing the window of uncertainty that women face when they are offered invasive testing to clarify their first- or second-trimester screening results. Many women would prefer to undergo initial screening to assess the risk of fetal birth defects to justify the risks of invasive testing; chorionic villus sampling has a 1%–2% risk of miscarriage, and amniocentesis has a 0.5%–2% risk of miscarriage, according to various studies. Because cfDNA has a low rate of false positive results, using this test would decrease unnecessary invasive testing. A positive NIFTY test would indicate those who require invasive testing. One of the important points of the present paper is that if NIFTY were used by all pregnant women as a primary screening method, and if all women with positive results on NIFTY were to undergo invasive screening, there would be a relative reduction of 89% in the number of diagnostic invasive procedures required to confirm a positive screening result.
Jiang et al. (2) applied the NIFTY test to 903 pregnancies and compared the diagnostic results with those of full karyotyping. They observed that the NIFTY test performed with 100% sensitivity and 99.9% specificity for detecting autosomal aneuploidies and with 85.7% sensitivity and 99.9% specificity for detecting sex chromosomal aneuploidies.
The review by Langlois et al. (3) in 2013 of published studies on the use of cfDNA in maternal plasma for the noninvasive diagnosis of trisomies 21, 18, and 13 looked at systematic reviews, randomized controlled trials/controlled clinical trials, and observational studies and concluded that noninvasive prenatal testing should be an option available to women at increased risk instead of amniocentesis. Pretest counseling of these women should include a discussion of the limitations of noninvasive prenatal testing. They concluded that no irrevocable obstetrical decision should be made in pregnancies with a positive noninvasive prenatal testing result without confirmatory invasive diagnostic testing.
Other screening methods give higher false positives and false negatives. A morphology scan can detect about 97% of neural tube defects, such as spina bifida. A quadruple marker test has an 81% sensitivity and 5% false positive rate for detecting Down syndrome when performed at 15–18 weeks of gestational age.
There are some pitfalls of NIFTY that preclude its universal use. The accuracy of the test in multiple-gestation pregnancies is not known. The test can be done as early as 10 weeks, but if the maternal blood is sampled too early, the fraction of fetal DNA can be too low, making the test inconclusive. The plasma of obese women may carry a smaller fetal fraction of DNA, and therefore the test may be inconclusive. Also, the test provides information on three autosomal aneuploidies, sex chromosome abnormalities, and translocations. It does not screen for neural tube defects, nor has it been validated in multiple gestations. Currently this technology can not detect other trisomies, triploidy, unbalanced translocations, deletions and duplications, single gene mutations, or confined placental mosaicism. Therefore, at the present time, ACOG guidelines have validated the test for high-risk women with advanced maternal age (>35 years), a positive triple or quadruple or first-trimester screen, a structural finding on ultrasonography suggesting aneuploidy, a previous trisomy birth, or a known balanced translocation in a parent or the parent of the partner.
Although testing of fetal cfDNA in maternal plasma appears to be very promising as a screening test for Down syndrome and other trisomies, studies in average-risk pregnancies and a significant reduction in the cost of the technology are needed before it can replace the current maternal screening approach using biochemical serum markers with or without fetal nuchal translucency ultrasound. Confidence in using NIFTY as a diagnostic test rather than a screening test would also increase if the technology becomes more watertight.
Patient counseling is important when offering NIFTY. The physician needs to educate patients that its utility is currently as a genetic screen. It can become a genetic test with further refinement and affordability. However, recent developments in technology allow a complete microarray analysis of a single cell. Reducing the high cost would allow this test to be offered on a diagnostic platform for prenatal diagnosis. It will take time for guidelines and recommendations on the use of this type of screening to be formulated and disseminated. However, these tests have made so many headlines that clinicians have to be ready with answers for women who may want to consider this test to know about the genetic health of their baby.
References