Prenatal Diagnosis

Cover image for Vol. 33 Issue 7

Special Issue: Noninvasive Prenatal Testing Using Maternal Plasma DNA: Part II

July 2013

Volume 33, Issue 7

Pages 619–710

Issue edited by: Lyn S. Chitty, Diana W. Bianchi

  1. Editorial

    1. Top of page
    2. Editorial
    3. Correspondence
    4. Position Statement
    5. Original Articles
    6. Research Letter
    1. You have free access to this content
      The 2012 Malcolm Ferguson-Smith Young Investigator Award (pages 619–620)

      Diana W. Bianchi, Lyn S. Chitty, Jan Deprest, Alessandro Ghidini, Lisa G. Shaffer and Rupert K. J. Cousens

      Version of Record online: 4 JUL 2013 | DOI: 10.1002/pd.4169

  2. Correspondence

    1. Top of page
    2. Editorial
    3. Correspondence
    4. Position Statement
    5. Original Articles
    6. Research Letter
  3. Position Statement

    1. Top of page
    2. Editorial
    3. Correspondence
    4. Position Statement
    5. Original Articles
    6. Research Letter
    1. Position statement from the Aneuploidy Screening Committee on behalf of the Board of the International Society for Prenatal Diagnosis (pages 622–629)

      Peter Benn, Antoni Borell, Rossa Chiu, Howard Cuckle, Lorraine Dugoff, Brigitte Faas, Susan Gross, Joann Johnson, Ron Maymon, Mary Norton, Anthony Odibo, Peter Schielen, Kevin Spencer, Tianhua Huang, Dave Wright and Yuval Yaron

      Version of Record online: 21 MAY 2013 | DOI: 10.1002/pd.4139

  4. Original Articles

    1. Top of page
    2. Editorial
    3. Correspondence
    4. Position Statement
    5. Original Articles
    6. Research Letter
    1. The role of noninvasive prenatal testing as a diagnostic versus a screening tool – a cost-effectiveness analysis (pages 630–635)

      Mika Ohno and Aaron Caughey

      Version of Record online: 17 JUN 2013 | DOI: 10.1002/pd.4156

      What's already known about this topic?

      • Noninvasive prenatal testing has improved sensitivity and specificity for detecting Down syndrome compared with current screening.

      What does this study add?

      • This cost-effectiveness analysis supports the role of noninvasive prenatal testing as a screening tool, not a diagnostic tool.
      • The number of false-positive terminations, if noninvasive prenatal testing were used as a diagnostic tool, far outweighs the number of procedure-related losses if it were used as a screening tool.
    2. Maternal cfDNA screening for Down syndrome – a cost sensitivity analysis (pages 636–642)

      Howard Cuckle, Peter Benn and Eugene Pergament

      Version of Record online: 9 JUN 2013 | DOI: 10.1002/pd.4157

      What's already known about this topic?

      • Two studies have shown that the use of cfDNA testing for fetal Down syndrome can be economically justified if offered as a secondary screening test for high-risk women, the cost of the cfDNA test was below the cost of an invasive test, and there was no major change in the uptake of conventional screening.
      • A third study showed that cfDNA testing was economically justified if, in addition, it is offered as a primary screening test to women 35 years or older.

      What does this study add?

      • On the basis of modeling, it was concluded that expansion of cfDNA testing would be economically justifiable if offered as a contingent test to 10% to 20% of women at moderate or high risk.
      • The cost of cfDNA testing needs to fall substantially before it should be offered to all women, regardless of risk.
    3. SNP-based non-invasive prenatal testing detects sex chromosome aneuploidies with high accuracy (pages 643–649)

      Carole Samango-Sprouse, Milena Banjevic, Allison Ryan, Styrmir Sigurjonsson, Bernhard Zimmermann, Matthew Hill, Megan P. Hall, Margaret Westemeyer, Jennifer Saucier, Zachary Demko and Matthew Rabinowitz

      Version of Record online: 20 JUN 2013 | DOI: 10.1002/pd.4159

      What's already known about this topic?

      • Current routine prenatal screening methods are not designed to detect sex chromosome aneuploidies. Although increased nuchal translucency may indicate Turner syndrome, maternal serum markers are not consistent indicators and are not used to screen for either Turner or the sex chromosome trisomies. Thus, diagnoses are often missed. Current non-invasive prenatal aneuploidy testing methods either do not detect sex chromosome aneuploidy or do not detect them with accuracies comparable with trisomy 21 and 18.

      What does this study add?

      • We accurately detect 45,X (Turner) with 91.7% sensitivity (CI: 61.5–99.8%) and 100% specificity (CI: 97.9–100%), as well as 47,XXY and 47,XYY, by using a novel non-invasive and informatics-based prenatal method for detecting fetal aneuploidy. The method identified copy number at chromosomes 13, 18, 21, X, and Y with high accuracy across all five chromosomes.
    4. Variability of ffDNA in maternal plasma does not prevent correct classification of trisomy 21 using MeDIP-qPCR methodology (pages 650–655)

      Skevi Kyriakou, Elena Kypri, Christiana Spyrou, Evdokia Tsaliki, Voula Velissariou, Elisavet A. Papageorgiou and Philippos C. Patsalis

      Version of Record online: 28 MAY 2013 | DOI: 10.1002/pd.4140

      What's already known about this topic?

      • The ffDNA level in maternal plasma varies between pregnancies and this poses limitations in trisomy 21 classification using next generation sequencing-based NIPD methodology. MeDIP-qPCR-based NIPD methodology for trisomy 21 is proved accurate, reproducible, and promising to be introduced in the clinical practice.

      What does this study add?

      • This study evaluates ffDNA and total DNA in 83 maternal plasma samples and tests whether these influence the D-value and enrichment ratios of DMRs reflecting the correct classification of trisomy 21 using the MeDIP-qPCR methodology.
    5. Best ethical practices for clinicians and laboratories in the provision of noninvasive prenatal testing (pages 656–661)

      M. A. Allyse, L. C. Sayres, M. Havard, J. S. King, H. T. Greely, L. Hudgins, J. Taylor, M. E. Norton, M. K. Cho, D. Magnus and K. E. Ormond

      Version of Record online: 21 MAY 2013 | DOI: 10.1002/pd.4144

      What's already known about this topic?

      • Noninvasive prenatal genetic testing using cell-free fetal DNA or whole fetal cells has ethical implications pertaining to its commercial and clinical provision.

      What does this study add?

      • This paper provides a set of best ethical practices for clinicians and companies providing noninvasive prenatal genetic testing.
    6. You have free access to this content
      Gestational age and maternal weight effects on fetal cell-free DNA in maternal plasma (pages 662–666)

      Eric Wang, Annette Batey, Craig Struble, Thomas Musci, Ken Song and Arnold Oliphant

      Version of Record online: 9 MAY 2013 | DOI: 10.1002/pd.4119

      What's already known about this topic?

      • Previous literature indicates no significant change in average percentage of fetal cell-free DNA between 10 and 22 weeks when using Next-Generation Sequencing technology.

      What does this study add?

      • This is the largest sample set reporting changes in percent fetal cell-free DNA in relation to maternal weight and gestational age.
    7. The impact of maternal plasma DNA fetal fraction on next generation sequencing tests for common fetal aneuploidies (pages 667–674)

      Jacob A. Canick, Glenn E. Palomaki, Edward M. Kloza, Geralyn M. Lambert-Messerlian and James E. Haddow

      Version of Record online: 31 MAY 2013 | DOI: 10.1002/pd.4126

      What's already known about this topic?

      • The fetal fraction is a well described measurement of the proportion of circulating cell-free DNA in maternal plasma derived from the fetal/placental unit.
      • Fetal fraction is related to several characteristics of testing for common autosomal trisomies including test failure rate and detection rate.

      What does this study add?

      • An existing dataset was used to create a model that fits the observed distributions of euploid and Down syndrome z-scores by stratifying results by fetal fraction and to further explore the association between increasing maternal weight and lower fetal fractions; that effect is not due solely to dilution.
      • A modified estimate of ‘effective’ fetal fraction may be helpful in understanding test performance when mosaicism is present.
    8. Noninvasive twin zygosity assessment and aneuploidy detection by maternal plasma DNA sequencing (pages 675–681)

      Tak Y. Leung, James Z. Z. Qu, Gary J. W. Liao, Peiyong Jiang, Yvonne K. Y. Cheng, K. C. Allen Chan, Rossa W. K. Chiu and Y. M. Dennis Lo

      Version of Record online: 29 APR 2013 | DOI: 10.1002/pd.4132

      What's already known about this topic?

      • By using massively parallel maternal plasma DNA sequencing, noninvasive prenatal detection of fetal chromosomal aneuploidies has been achieved. The sensitivity of the maternal plasma DNA sequencing test for aneuploidy detection is governed by the fractional fetal DNA concentration.

      What does this study add?

      • We have recently developed a maternal plasma DNA sequencing-based method for the noninvasive assessment of twin zygosity. The method also allows the determination of the fetal DNA fraction contributed by each member of a pair of dizygotic twin in maternal plasma. In this study, we applied the new method to two dizygotic twin pregnancies involving one aneuploid fetus each. We confirmed that each fetus contributed adequate amounts of DNA into maternal plasma so that the aneuploidy test result could be interpreted with confidence.
    9. RASSF1A in maternal plasma as a molecular marker of preeclampsia (pages 682–687)

      Nikolas Papantoniou, Vassilis Bagiokos, Kostantinos Agiannitopoulos, Aggeliki Kolialexi, Aspasia Destouni, Georgia Tounta, Emmanuel Kanavakis, Aris Antsaklis and Ariadni Mavrou

      Version of Record online: 22 MAR 2013 | DOI: 10.1002/pd.4093

      What's already known about this topic?

      • A previous survey study prior to the clinical availability of cell-free DNA analysis for aneuploidy detection indicated uncertainty among providers about the implementation of this technology.

      What does this study add?

      • This study indicates that within a year of clinical availability of NIPT in the United States obstetricians have a high awareness about the technology, have used the testing clinically and are optimistic about its use in the future.
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      Routine testing of fetal Rhesus D status in Rhesus D negative women using cell-free fetal DNA: an investigation into the preferences and information needs of women (pages 688–694)

      Kerry Oxenford, Caroline Silcock, Melissa Hill and Lyn Chitty

      Version of Record online: 20 JUN 2013 | DOI: 10.1002/pd.4135

      What's already known about this topic?

      • Technological advances mean that there is now potential to offer routine fetal RhD typing using cell-free fetal DNA to all Rhesus negative women. This will mean that anti-D can be targeted to women carrying a Rhesus positive baby.

      What does this study add?

      • This unique study shows that women and health professionals hold positive views regarding the introduction of routine fetal RhD genotyping using cell-free fetal DNA. Women's current knowledge of Rhesus blood groups and anti-D administration was found to be limited. Development of information leaflets and health professional training will therefore be critical for successful implementation.
    11. Cell-free fetal DNA in maternal circulation after chorionic villous sampling (pages 695–699)

      Mariarosaria Di Tommaso, Viola Seravalli, Francesca Salvianti, Cecilia Bussani, Lucia Pasquini, Adalgisa Cordisco and Pamela Pinzani

      Version of Record online: 31 MAY 2013 | DOI: 10.1002/pd.4155

      What's already known about this topic?

      • It is still unclear whether the amount of fetal DNA in maternal blood increases after invasive procedures. No significant changes in DNA levels after chorionic villous sampling (CVS) have been detected in one study.

      What does this study add?

      • This is the second study to quantify circulating cffDNA after CVS by use of real-time polymerase chain reaction but is the first to examine cffDNA levels with a universal fetal marker independent from fetal gender (the methylated form of the promoter of RASSF1A gene).
    12. Noninvasive prenatal testing of fetal aneuploidies by massively parallel sequencing in a prospective Chinese population (pages 700–706)

      Yijun Song, Congcong Liu, Hong Qi, Yunping Zhang, Xuming Bian and Juntao Liu

      Version of Record online: 17 JUN 2013 | DOI: 10.1002/pd.4160

      What's already known about this topic?

      • The existence of cell-free fetal DNA in maternal circulation and the noninvasive prenatal testing (NIPT) by massively parallel sequencing present a new era of prenatal screening. However, previously reported studies were primarily conducted on high-risk and advanced maternal age (AMA) pregnancies.

      What does this study add?

      • We collected 1916 maternal blood samples from women younger than 35 years old in a prospective clinical setting. NIPT outperforms second trimester triple serum screening in sensitivity, specificity, and positive prediction values for fetal chromosome aneuploidy detection and is a promising choice for pregnant women as a primary prenatal screening method.
  5. Research Letter

    1. Top of page
    2. Editorial
    3. Correspondence
    4. Position Statement
    5. Original Articles
    6. Research Letter
    1. A robust second-generation genome-wide test for fetal aneuploidy based on shotgun sequencing cell-free DNA in maternal blood (pages 707–710)

      N. Guex, C. Iseli, A. Syngelaki, C. Deluen, G. Pescia, K. H. Nicolaides, I. Xenarios and B. Conrad

      Version of Record online: 3 MAY 2013 | DOI: 10.1002/pd.4130

      What's already known about this topic?

      • Non-invasive genome-wide screening of fetal aneuploidy by shotgun sequencing cell-free DNA in maternal blood has been shown to effectively identify fetal trisomy 21, but the performance of screening for other aneuploidies is variable.

      What does this study add?

      • Optimizing all individual steps in the procedure and performing rigorous quality control provides a test capable of replacing invasive testing for the major aneuploidies.

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