Non-Invasive Prenatal Testing: For everyone? REALLY??? Michelle Y. Owens, MD Maternal Fetal Medicine

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1 Non-Invasive Prenatal Testing: For everyone? REALLY??? Michelle Y. Owens, MD Maternal Fetal Medicine

2 I have no financial disclosures.

3 Objectives Differentiate between NIPT and other antenatal screening tests. Discuss the application of NIPT in the evaluation of high risk women. Discuss the limitations of NIPT.

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5 Diagnostic versus screening tests A diagnostic test determines the presence or absence of a disease when a subject shows signs or symptoms of the disease. A screening test identifies asymptomatic individuals who may have the disease. The diagnostic test is performed after a positive screening test to establish a definitive diagnosis.

6 Simple Stats Sensitivity: Correctly identify affected individual (true positive rate) Specificity: Correctly identify disease-free individual (true negative rate)

7 Types of Prenatal Testing Invasive testing (Diagnostic) Chorionic villus sampling (CVS) Amniocentesis Percutaneous Umbilical Cord Blood Sampling (PUBS) Chromosomal Microarray Non-Invasive testing Maternal serum analyte screening First trimester Second trimester Cell free fetal DNA/RNA Ultrasound Nuchal translucency Targeted sonogram

8 Ultrasound screening options Nuchal translucency 10w4d-13w6d Increased NT: risk for aneuploidy, CHD, and adverse pregnancy outcomes DS DR: 60-82% T18 DR: 71-82% No ONTD risk assessment Fetal anatomic survey 18-20w6d (ideal) Structural defects, soft markers DS DR: 50-70% T18 DR: 80% ONTD risk assessment

9 First trimester aneuploidy screening options NT only 10 4/7-13 6/7 Detection rates (DR): 80% First trimester analyte screening PAPP-A, free β-hcg /7weeks DR Down: 62-63% DR T18: 82% Does not address ONTD Combined first trimester screening NT plus analytes /7 weeks DSDR: 78-91% T18 DR: 91-96% No ONTD risk

10 Aneuploidy screening options Integrated 1 st and 2 nd trimester analytes (9-13w6d, 15-21w6d) + NT DS DR: 94-96% T18 DR: 91-96% ONTD risk assessment Results not given until second trimester Serum Integrated 1 st and 2 nd trimester analytes (9-13w6d, 15-21w6d) DS DR: 87-88% T18 DR: 82% ONTD Risk assessment Results not given until second trimester

11 Aneuploidy screening options Stepwise sequential All maternal serum analytes (9-13w6d, 15-21w6d) + NT 1 st trimester result for highest risk patients DS DR: 91-95% T18 DR: 91-96% ONTD risk assessment Contingency All maternal serum analytes (9-13w6d, 15-21w6d) + NT 1 st trimester results for high and low risk patients, low and moderate risk groups require second visits. DS DR: 91-92% T18 DR: 91-96% ONTD risk assessment

12 Aneuploidy screening options Multiple marker serum screening (Triple, Quad, Penta) AFP, hcg, ue3, DIA, +/- ITA (15-21w/6d) DS DR: 72-83% T18 DR: 60-70% ONTD risk assessment Non-invasive prenatal testing 10-21w6d Circulating cell free fetal DNA (cfdna) DS DR: %* T18 DR: %* No ONTD risk assessment

13 NIPT: The Physiology Basics Fetal genetic material can be found in the maternal circulation. Fetal cells and cell-free fetal DNA/RNA (cfdna). Fetal DNA comprises 10-15% of the total DNA in the maternal circulation.

14 Physiology The primary source of cfdna is the placenta (syncytiotrophoblasts). The primary source of cfmdna is apoptotic hematopoietic cells.

15 Physiology Can be detected from 4 weeks gestation. Rapid clearance Pure fetal DNA extraction from the maternal circulation is not currently possible.

16 NIPT The basics Uses circulating cell free fetal DNA in maternal plasma to evaluate for T21, T18, and T13. Low FPR (<1% ) and very high DR for DS (99-100%), T18 (97-100%) and T13 (79-92%)

17 Applications of NIPT Fetal gender determination Rhesus typing Single gene disorders Aneuploidy testing

18 High Risk or Low Risk? Nicolaides, et al (Ultrasound Obstet Gyneol 2013) FMF 1005 women (37), 10 wks gestation, one center cfdna superior to standard screening Song, et al (Prenat Diagn 2013) 1741 pregnant women <35 yo, 2 clinical sites cfdna testing vs. standard screening Sensitivity (100% vs. 54.5%) Specificity (99.9% vs. 85.9%) PPV (91.7% vs. 2.4%)

19 High Risk or Low Risk? Comparison of Aneuploidy Risk Evaluations (CARE study) NEJM women (30), 21 centers T21 and T18 Sensitivity (100% vs. 100%) T21 Specificity (99.7 vs. 96.4) T21 PPV (45.5% vs. 4.2%) T21 and T18 NPV (100% vs. 100%) T18 Specificity (99.8% vs. 99.4%) T18 PPV (40% vs. 8.3%)

20 Low Risk: Cell-free DNA Analysis for Noninvasive Examination of Trisomy (NEXT) 18,955 enrolled 15,841 analyzed Pregnant women of all risk levels (76% under 35) Avg 12.5 weeks Testing had higher sensitivity and specificity than standard first trimester screening (FTS) detection of T21. FPR was over 90 times lower than that of standard FTS (0.06% vs. 5.4%).

21 The recommendations: ACOG NIPT that uses cfdna offers tremendous potential as a screening tool for fetal aneuploidy. cfdna testing should be an informed patient choice after pretest counseling and should not be a part of routine laboratory assessment.

22 ACOG recommendations Should not be offered to women with multiple gestations because it has not been sufficiently evaluated in these groups. A negative cfdna test does not ensure an unaffected pregnancy. A patient with a positive result should be referred for genetic counseling and should be offered prenatal diagnosis for confirmation of test results.

23 SMFM 2014 While NIPT is a promising new technology, [the available data] is not enough to change the current recommendations. Further evidence is required to justify changing recommendations regarding population based prenatal screening from just high-risk pregnancies, to all pregnancies.

24 SMFM (October 2015) For front-line clinicians, challenges still exist for determining the most appropriate implementation of cell free DNA (cfdna) aneuploidy screening. The purpose of this statement is to clarify that SMFM does not recommend that cfdna aneuploidy screening be offered to all pregnant women, nor does it suggest a requirement for insurance coverage for cfdna screening in women at low-risk of aneuploidy.

25 ISUOG (Consensus Statement) In very high risk women, NIPT should not replace invasive testing. In presence of fetal anomaly, NIPT should not change invasive indications. If normal NIPT, genetic sonogram should not be performed.

26 What constitutes High Risk? Advanced maternal age Positive maternal serum screen Positive family history Parent carrying balanced robertsonian translocation Fetal anomaly identified on ultrasound/increased risk of aneuploidy

27 The Challenges Need for professional standards and guidelines Non-informative results (NIPT), clinical meaning of copy number (CNV) variants in microarrays Resource allocation Advanced training and education for providers Direct-to-consumer testing Detection of mistaken paternity and incest Confidentiality of information obtained Coercion to have test Role of industry promoting research Legal concerns (IP)

28 Things to remember: NIPT is a screening test. Remember ONTD. Serum screening does not replace ultrasound screening.

29 The Future Further expansion in single gene disorders Potential use in microarray analysis Expansion to include additional chromosome abnormalities Possibly as diagnostic testing

30 Summary Cell free fetal DNA found in maternal blood during pregnancy can be used for non-invasive prenatal diagnosis. NIPT is a screening test. Appropriate counseling and diagnostic testing for confirmation is needed for any positive result and should be considered in cases of no call test results.

31 Summary This technology offers safer, earlier, and easier antenatal testing than current standard practice. Research into non-invasive prenatal diagnosis is ongoing, and the public and healthcare professionals must be kept informed about the progress and limitations of this technology.

32 Summary NIPT does not replace ultrasound. However, ultrasound should not be used as a screen for aneuploidy when NIPT results are known. Likewise, the use of multiple serum screening tests is not recommended.

33 The End!!

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