DSJUOG

Critical Assessment of Noninvasive Prenatal 10.5005/jp-journals-10009-1574

Critical Assessment of Noninvasive Prenatal Testing:

How to cite this article: Zalel Y. Critical Assessment of I have published in 2015 an article named: NIPT–it is
Noninvasive Prenatal Testing: Before or after Anomaly Scan. all a matter of timing.6 I have described, during the first
Donald School J Ultrasound Obstet Gynecol 2018;12(4):255-257.
year after the introduction of the technique to Israel,6
Source of support: Nil
women with various malformations (including severe
Conflict of interest: None heart, brain, and renal abnormalities) found in anomaly
Noninvasive prenatal test (NIPT) analyzes cell-free DNA scan a few days after a normal NIPT. These women were
(cfDNA) in the maternal serum. Approximately, 3–15% of falsely reassured of the “normality” of their pregnancies,
cfDNA in the maternal blood is of fetal origin. eventually either underwent a further invasive procedure
The NIPT examination, based on the existence of this or terminated the pregnancy and even paid considerable
cfDNA, is accurate in screening for Down syndrome and sums of money for the blood test.
less for other trisomies, as well as other structural chro- While preparing this opinion, I have turned to G-Med
mosomal abnormalities. The commercial companies offer raising the same issue.
this technique as early as 10 weeks of gestation. Global Online Medical Community (G-Med) is the
The purpose of this critical assessment is to challenge largest community for physicians, true medical crowd-
the timing of offering the NIPT to women at 10 weeks sourcing enabled by peer-to-peer consultation of hundred
gestation, emphasizing the limitations of this technique thousands of physicians worldwide (www.g-med.info).
before the anomaly scan is done. I have added a recent case of mine (a 41 years old
The utilization of NIPT for genetic screening has woman, para 0, after normal NIPT examination at 10
increased rapidly since the introduction of the first clinical weeks gestation, who was diagnosed with multiple
test in October 2011. However, its performance early in anomalies, including a large omphalocele containing
pregnancy hasnot been recommended by the commer- liver, complex heart disease and IUGR (Figs 1 to 4) found
cial companies only. Likewise, Bianchi et al.1 have even at early anomaly scan that led to a termination of preg-
examined their patients from 8 weeks gestation, Lo et al.2 nancy) and raised the question of timing of the NIPT.
stated that it can be done after 9–10 weeks' gestation and These were the results:
the Israeli Society of Medical Genetics NIPT Committee
Opinion 0720133 stated that it can be done as early as 10
weeks of gestation.
Furthermore, although the 99% detection rate for
trisomy 21, using cfDNA screening, one should remem-
ber, that cfDNA analysis is a screening test and is not
considered diagnostic because of the potential for false-
positive results. Positive results require secondary testing
with invasive techniques.
Moreover, 17% of chromosomal abnormalities
detected by a traditional screening test were not detect-
able by cfDNA screening.4,5 These abnormalities included
rare trisomies, unbalanced rearrangements, and large
deletions or duplications.
So, although we have succeeded to raise the impor-
tance of performing an anomaly scan before the NIPT,
Professor
there are still 38% of the physicians worldwide that would
Expert Clinic, Habarzel 9a Tel-Aviv, Israel
send their patients for NIPT first.
Corresponding Author: Yaron Zalel, Professor, Expert Clinic, Furthermore, in various countries, including
Habarzel 9a Tel-Aviv, Israel, Phone: 972-52-6666462, e-mail:
the US, there are many NIPT examinations done
zalel1954@ gmail.com

Donald School Journal of Ultrasound in Obstetrics and Gynecology, October-December 2018;12(4):255-257 255
Yaron Zalel

Fig. 1: The fetus “watches” large omphalocele in front of its face (2D) Fig. 2: Large omphalocele containing liver (2D)

Fig. 3: Fetal abdomen (axial view, 3D color Doppler)—Blood Fig. 4: Whole fetus (3D) with large omphalocele
vessels within the omphalocele

primarily in general OB offices, leading to a subop- Lately, Allyse and Wick,8 at the JAMA clinical update,
timal discussion regarding limitations and benefits have stated that cfDNA screening can detect chromosome
with the patient. The problem is, however, much aneuploidy in pregnancy after 10 weeks' gestation but is
more serious than that. The false-reassurance given less effective at screening for other genetic abnormalities.
to these low-risk patients after a normal NIPT for They also added that cfDNA tests are more expensive
9–10 weeks gestation, leads in many cases to elimi- than other approaches.
nate the Nuchal scan at 11–13 weeks or even the When we recommend an early anatomy scan done
early anomaly scan for 14–16 weeks due to inappro- before the NIPT examination, we have to ask are we
priate counseling regarding the importance of an ana- capable of performing an anatomy scan so early in
tomic evaluation than just "A Down syndrome test". pregnancy?
This technique has its obvious advantages—the In most of the cardinal chromosomal syndromes:
ability to get quite accurate results of the fetal DNA, trisomy 21, 13 ,18, Xo, triploidy–there is a severe struc-
especially regarding trisomy 21 and so early in pregnancy. tural anomaly, especially cardiac abnormality.
Nevertheless, current guidelines from the American Concerning congenital heart diseases (CHD), Yagel et
College of Medical Genetics, the American College of al.9 have found that 64% of CHD are detectable during
Obstetricians and Gynecologists, and the Society for the first TVS at 13–16 weeks, and Moyano et al.10 have
Maternal Fetal Medicine advise that cfDNA may be stated that diagnosis of heart malformations can be made
offered to all women to screen for common aneuploi- reliably, even in the first trimester at the time of nuchal
dies and fetal sex, but it is not considered the standard translucency measurement.
approach in pregnancies that are not considered high Bronshtein et al.11 have found while evaluating
risk.7 fetuses with increased nuchal translucency (NT) at

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 DSJUOG

Critical Assessment of Noninvasive Prenatal Testing: Before or after Anomaly Scan

an early (11–14 gestational weeks), that overall, there also eliminate (hopefully) the trend towards performing
were 27% fetuses with severe structural anomalies. the NIPT alone while avoiding additional important
The remaining 73% underwent CVS which was found information gained by the structural anomaly scan and
abnormal in 33%. thus turning the pre-natal care to “Down syndrome
Zalel et al.12,13 share the same experience. We have test alone”.
examined 32 patients with a mean gestational age at a Author thinks this message should be communicated
scan of 12.3 weeks (11–14 weeks) with mean NT of to the commercial companies as well as to the physician
4.6 mm (range 3.4–9). Overall, our study has found that consult their patients regarding the timing of the
major abnormalities in 78% of the cases. The presence NIPT technique.
of malformations yielded a positive predictive value
of 53%,8 and 96.7% for having abnormal karyotype or REFERENCES
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evaluation for VCF in cases of heart malformations). timing. Ultrasound Obstet Gynecol. 2015 Jan;45(1):115-116
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Given the above data, I challenge the timing of offering 8. Allyse MA, Wick MJ. Noninvasive prenatal genetic screening
using cell-free DNA. Jama. 2018 Aug 14;320(6):591-592.
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results until after the anomaly scan. However, there is Diagn. 2008 Nov;28(11):1037-1041.
little difference between termination of pregnancy at 12 12. Zalel Y. Increased NT- to scan or to karyotype? P01.24. 24th
World Congress on ultrasound in Obstetrics and Gynecology,
weeks and 14 weeks of gestation. Moreover, this will
Barcelona, Spain, September 2014.
save the money spent on this test, will spare the patient 13. Zalel Y, Zemet R, Kivilevitch Z. The added value of detailed
"false reassurance" of the normality of the pregnancy, early anomaly scan in fetuses with increased nuchal translu-
and in cases where major abnormalities were excluded, cency. PrenatDiagn. 2017 Mar;37(3):235-243.
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it will allow further evaluation of the pregnancy either
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by NIPT or invasive karyotyping. This approach will Ultrasound Obstet Gynecol. 2013 Jul;42(1):15-33.

Donald School Journal of Ultrasound in Obstetrics and Gynecology, October-December 2018;12(4):255-257 257