Noninvasive prenatal testing: Where we are and where we’re going

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Noninvasive prenatal DNA testing: Who is using it, and how? Audiocast, June 2013
Noninvasive prenatal DNA tests are unproven and costly David A. Carpenter, MD (Comment & Controversy; September 2013)

Another concern about the published accuracy of NIPT clinical assays was recently sounded by Menutti and colleagues.⁸ The authors cited recent cases of positive NIPT outcomes for fetal trisomies 18 and 13 that were not confirmed by diagnostic testing of the pregnancies in question. The authors pondered whether such cases may reflect a limitation of the positive predictive values attributed to NIPT assays and that such limitations may carry profound inaccuracies in determining the accuracy of such protocols for rare aneuploidies.

While the improved detection rates for NIPT compared with conventional screening are not surprising, guidelines published by the American College of Obstetricians and Gynecologists still do not recommend the use of NIPT for the screening of low-risk women because of insufficient evaluation of ccfna technologies in the screening of such pregnancies.³ This also applies to twin pregnancies, despite preliminary studies showing comparable detection of trisomies 18 and 21 in such pregnancies compared with singleton pregnancies.^3,9

There are no direct comparative studies of the four commercially available screening products, thus precluding a robust comparison and determination of the best existing method to use.

SO, WHERE ARE WE WITH NIPT EXACTLY?
The recent introduction of NIPT into routine obstetric care has left many clinicians with a wide range of questions, many of which cannot be answered because of little or no information, robust or otherwise, to formulate an accurate and cogent response. So let’s state what we know based on the available evidence, recognizing that this will likely change, perhaps considerably, in the weeks and months ahead.

NIPT is a far superior approach, compared with conventional screening approaches, to screening for fetal trisomies 21, 18, and 13 in women carrying singleton pregnancies who are at an increased risk for fetal chromosome abnormalities.

In our current understanding of prenatal screening and diagnosis, NIPT does not provide either the comprehensive approach or the diagnostic accuracy associated with CVS and amniocentesis. As such, NIPT is not a suitable replacement for prenatal diagnostic procedures.

However, its application to screening a low-risk population for the common fetal aneuploidies, as well as in twin pregnancies, has been supported by initial studies, and the inclusion of other clinical outcomes—including other chromosome abnormalities, such as X and Y aneuploidies, trisomy 16, and triploidy^10,11 and certain genomic abnormalities (eg, 22q deletions)—in the screening algorithm will expand the future clinical applications of NIPT screening.

DOES NIPT CHANGE OUR CONCEPTS OF SCREENING AND DIAGNOSIS?
This question is simple but profound and is perhaps the most important to be asked and addressed. Is a screening algorithm that has a similar sensitivity and specificity to that of CVS and amniocentesis for the most common fetal trisomies in the first and second trimesters sufficient to replace invasive testing for most women? Does the ability to detect fetal genomic abnormalities with microarray analyses of fetal cells obtained by CVS or amniocentesis provide a far greater benefit than that possible with any screening algorithm?

With renewed interest in the cost of health-care screening and diagnosis, we need to consider how comprehensive and accurate our prenatal screening and diagnostic tests should be and whether such improvements are desired or even possible from a clinical or economic viewpoint. In addition, the development of new technologies, such as the capture and analysis of fetal cells in maternal blood, presents the potential for a direct diagnostic fetal assay without the risks of an invasive procedure.

BIAS-FREE COUNSELING CANNOT BE OVERLOOKED
That being said, the current role of NIPT and other screening protocols in obstetric care needs to be clearly communicated to women who are considering their fetal assessment options, with emphasis placed on the capabilities and limitations of prenatal screening (even the newer ccfna-based options), the actual risks associated with invasive testing, and the ability of invasive testing to provide expanded fetal information with the use of microarray analyses.

As it has been from the beginning of prenatal testing in the 1960s, counseling continues to be the most important part of the prenatal screening and diagnostic process and it is needed to facilitate clinical decisions made by women and couples. Counseling must include an accurate communication of the risks, benefits, and limitations of the aforementioned options and issues, and should be provided in a manner that strives to be free of bias, direction, and the personal opinions of the counselor.

In order to provide such counseling, we must remain informed of the ongoing work in the field of prenatal testing, a task that has become more challenging with the rapid release of a considerable amount of new information on prenatal screening technologies over the past 2 years. This will likely continue, and perhaps become even more frenetic, with the expected release of additional information on the clinical applications of ccfna technologies in the near future as well as the development of new technologies applicable for the screening and diagnosis of fetal abnormalities.