The New Genetics: Is Ultrasound Dead?

There are those who pretend that we do not need ultrasound anymore to detect fetal anomalies, “Just use maternal blood and with various forms of genetic testing and you will be able to detect the majority of fetal anomalies.”

Well, let me rebuke this insinuation.

3D ultrasound image of a fetus.
Acrania in a fetus at 11 weeks.


There is no doubt that prenatal genetic testing has come a long way from using only maternal age to assume a risk of Down syndrome (for instance 1 in 1250 at age 25 and 1 in 385 at age 35). Maternal serum screening came next. At first, levels of alpha-feto-protein (AFP) were found to be lower in mothers carrying fetuses affected with Down syndrome.

Then, other markers, such as human chorionic gonadotropin (hCG), unconjugated estriol, and dimeric inhibin A, were determined to display characteristic patterns in pregnancies with Down syndrome, with the introduction of the double, triple, and quadruple screening in the second trimester. This moved to the first trimester, with incorporation of fetal nuchal translucency (NT), pregnancy-associated plasma protein A (PAPP-A), and the beta subunit of human chorionic gonadotropin (β-hCG). A high detection rate of 85–90% was attained for Down syndrome and 90–95% for trisomy 18, with a 5% false-positive.

A combination of both the first and second trimester was introduced, to further improve the detection rate and, at the same time, decrease the false-positive rate.  In some of these tests only serum fetal-placental protein markers were considered (integrated) and in others ultrasound findings (NT) and various serum markers were combined (integrated, sequential, and contingent).   

It is widely accepted that testing of the type used nowadays originated from a Lancet paper in 1997 by Lo and colleagues, describing circulating cell-free fetal DNA (ccffDNA) in the plasma of pregnant women. It took almost 15 years for the technology to become clinically available1. At first, it was used to determine the risk of trisomies and sex chromosome anomalies. Originally designed as noninvasive prenatal diagnosis (NIPD) or noninvasive prenatal testing (NIPT), the general opinion is that these are still screening (and not diagnostic) tests, hence the designation noninvasive prenatal screening (NIPS). I prefer noninvasive DNA screening (NIDS) because, after all, ultrasound is NIPT!

Nowadays, NIDS can be used to identify Rhesus group and some single-gene fetal conditions, autosomal dominant, recessive or sex-linked (eg, cystic fibrosis, achondroplasia, thanatophoric dysplasia, sickle cell disorder, congenital adrenal hyperplasia, spinal muscular atrophy, and hemophilia). Most conditions require using a maternal blood sample only but many require a paternal blood sample. Normal karyotype doesn’t mean everything is fine, hence chromosomal microarray, introduced in the prenatal diagnosis clinical setting in 2005. Looking for submicroscopic aberrations <5Mb can provide additional diagnostics in about 10% of fetuses with multiple anomalies1. The latest reiteration of the technology is genome-wide monogenic NIDS2.

Screening beyond the common trisomies is currently not recommended by the American College of Obstetricians and Gynecologists3. So where does ultrasound stand?

Ultrasound is alive and doing fine, thank you

In the general population, chromosomal abnormalities are less frequent than structural abnormalities. A large number of fetal structural abnormalities, especially many lethal ones, can be diagnosed in the first trimester of pregnancy, therefore, ultrasound remains an essential part of the story. Ultrasound diagnosis of fetal anomalies has now moved from the mid-second trimester (18–22 weeks) to the late first–early second-trimester (approximately 11–14 weeks). It should be noted that a repeat scan at the “classical” time (18–22 weeks) is still recommended by most.

Ultrasound image of a fetus with the NT measurement marked.
Image courtesy of Sergiu Puiu, MD

Two major reasons for the early scan: it’s a perfect time to perform a nuchal translucency (NT) measurement and, at that stage, most structural anomalies that are already present are detectable. A few examples of what is observable include all 4 limbs and all digits, cranial anatomy, estimation of the cardiac axis, and omphalocele (which is associated with Beckwith-Wiedemann and CHARGE syndromes, limb-body stalk anomaly, and Pentalogy of Cantrell, to name a few). Amputations or other unusual cleft due to amniotic band syndrome are visible and cardiac position and orientation can also be determined. In incidences of heart defects, dextrocardia is associated with 90% and situs inversus with levocardia with over 95%.

Most of the above anomalies will be associated with an increased NT, as will pulmonary, gastrointestinal and genitourinary conditions, diaphragmatic hernia, skeletal dysplasia, fetal anemia, and abnormal lymphatic drainage4. A third of congenital abnormalities occurring in fetuses with increased NT may remain undetected in the first trimester of pregnancy, unless cfDNA is used in combination with fetal sonographic NT assessment. When karyotype is normal, 10% of fetuses with an increased NT (>95th percentile) have structural abnormalities5.

In one study5, 65% of structural abnormalities would have potentially been missed in the first trimester if cfDNA had been used as a first-trimester screening test without an early ultrasound scan. Furthermore, if cfDNA only was used, besides structural defects, one third of other anomalies would have been missed: sex chromosome abnormalities, triploidy, single gene disorders, and submicroscopic aberrations <5Mb. In addition to NT measurements and detection of structural anomalies, several other sonographic markers have been described: nasal bone, ductus venosus Doppler anomalies and tricuspid regurgitation, helping to determine a high-risk group for whom genetic screening will have a high yield.

When these or/and other ultrasound-diagnosed fetal anomalies are present, whole-exome-sequencing can add relevant information in cases when an etiology could not be elucidated by fetal karyotype testing or chromosomal microarray6.

In a very recent article, Bedei et al. propose several conclusions, one of them being: “NIPT should always be combined with a skilled ultrasound examination.”7

My thoughts, exactly8.

I purposely do not wish to initiate a discussion on the ethical, moral, philosophical, religious, or emotional values or demerits of prenatal diagnosis. While some will say that all this is a veiled “search and destroy” exercise, others will explain that knowledge is power. Power to choose but also power to be ready when the baby is born or power to correct certain anomalies in the womb or intervene immediately at birth. Both sides of this argument may be defensible, but that is for another blog.


1. Talkowski ME, Rehm HL. Introduction of genomics into prenatal diagnostics. Lancet 2019 Feb 23; 393(10173):719–721.

2. Rabinowitz T, Shomron N. Genome-wide noninvasive prenatal diagnosis of monogenic disorders: Current and future trends. Comput Struct Biotechnol J 2020; 18:2463–2470.

3. American College of Obstetricians and Gynecologists screening for fetal chromosomal abnormalities: ACOG practice bulletin summary, number 226. Obstet Gynecol 2020; 136:859–867.

4.  Baer RJ, Norton ME, Shaw GM, et al. Risk of selected structural abnormalities in infants after increased nuchal translucency measurement. Am J Obstet Gynecol 2014; 211:675.e1–19.

5. Bardi F, Bosschieter P, Verheij J, et al. Is there still a role for nuchal translucency measurement in the changing paradigm of first trimester screening? Prenat Diagn 2020; 40:197–205.

6. Petrovski S, Aggarwal V, Giordano JL, et al. Whole-exome sequencing in the evaluation of fetal structural anomalies: a prospective cohort study. Lancet 2019;393(10173):758-767

7. Bedei I, Wolter A, Weber A, Signore F, Axt-Fliedner R. Chances and challenges of new genetic screening technologies (NIPT) in prenatal medicine from a clinical perspective: A narrative review. Genes (Basel) 2021; 12:501. 8. Rauch KM, Hicks MA, Adekola H, Abramowicz JS. Aneuploidy screening: the changing role of ultrasound. In: Abramowicz JS (ed). Ultrasound in the First Trimester, a Comprehensive Guide. Switzerland: Springer International Publishing AG; 2016:131–152.

Jacques S. Abramowicz, MD, FACOG, FAIUM, is a professor of OB-GYN and Director of Ultrasound Quality Assurance in the Department of Obstetrics and Gynecology at the University of Chicago.

More from Jacques Abramowicz, MD:
COVID-19: How to Prepare Yourself and Your Ultrasound Equipment During the Pandemic, an on-demand webinar from the AIUM (a collaborative activity with Samsung).

Interested in learning more about obstetric ultrasound? Check out the following posts from the Scan:

The Best of the Scan, 5 Years in the Making

The Scan has been a home for all things ultrasound, from accreditation to zoos, since its debut 5 years ago, on February 6, 2015.MISC_SCAN_5_YR_ANN_DIGITAL_ASSETS_FB

In its first 5 years, the Scan has seen exponential growth, in large part due to the hard work of our 110 writers, who have volunteered their time to provide the 134 posts that are available on this anniversary. And it all began with Why Not Start? by Peter Magnuson, the AIUM’s Director of Communications and Member Services, who spearheaded the blog’s development.

In honor of this 5th Anniversary, here are some of your favorites:

Top 5 Most Viewed Posts


1. Ultrasound Can Catch What NIPT Misses
by Simcha Yagel
(August 4, 2015)

Sonographer Stretches2. Sonographer Stretches for an ‘A’ Game
by Doug Wuebben and Mark Roozen
(January 31, 2017)

Keepsake3. The Issue with Keepsake Ultrasounds
by Peter Magnuson
(April 30, 2015)

Hip Flexor Stretch4. 3 Stretches All Sonographers Should Do
by Doug Wuebben and Mark Roozen
(January 19, 2016)

Anton5. From Sonographer to Ultrasound Practitioner: My Career Journey
by Tracy Anton
(October 23, 2018)

The Fastest Growing Posts
That Are Not Already in the Top 5

And we have plenty more great posts, such as:

Ultrasound Can Catch What NIPT Misses

A few months ago a young couple, Michele and Dan, came to my office for a mid-trimester fetal anatomic survey at 21 weeks’ gestation. They were excited to see their fetus in 3D-4D ultrasound, and were wowed by the 3D image of their baby’s face. During the scan the couple related that they were sure their baby was OK “because the blood test came back negative,” and had decided to forego first trimester screening, despite their OB strongly recommending it.

unnamedThe blood tests, nuchal translucency measurement, and other sonographic parameters evaluated in first trimester screening are considered together to provide a risk profile for fetal chromosomal anomaly, particularly the risk of Down syndrome. If there is an increased risk, the parents may be advised to undergo invasive testing, such as chorionic villus sampling (CVS) or amniocentesis. In addition, first trimester screening can raise warning flags for structural anatomic malformations in the fetus, as well as other problems for the pregnancy. If first trimester screening includes a full fetal anatomic survey, it can spot about 40% of fetal malformations at a very early stage.

While I was reassured that Michele and Dan’s results on noninvasive prenatal testing (NIPT) meant the risk of their baby having Down syndrome and certain other aneuploidies was extremely low, I explained that structural malformations were still a much more common concern than chromosomal anomalies, and that a negative NIPT result did not rule out other conditions. Michele protested, “On the Internet it said that the blood test rules out Down syndrome 100%, that we didn’t have to worry.”

“The screening tests only give you a risk profile,” Dan insisted, “they don’t tell you if the baby is really affected. So we thought the blood test was the way to go.”

“I don’t want to have an amnio,” Michele continued, “I had a miscarriage in my last pregnancy,” she continued, as I proceeded to the echocardiography portion of the examination.

“Your baby appears to have a heart defect,” I said, as gently as I could, and began to explain the nature of transposition of the great arteries (TGA).

NIPT is the name applied to new techniques that use a sample of a pregnant woman’s blood to examine her fetus’s chromosomes. As early as 10 weeks of pregnancy there is sufficient fetal genetic material, called cell-free DNA, found in the maternal serum to allow analysis. A negative result from NIPT is a very good test to rule out Down syndrome in the fetus: it is highly specific, meaning that in almost all cases, a negative result is truly negative. NIPT is also highly sensitive, which means that in almost all cases, a positive result is truly positive. However, because there is a chance (however small) of a false positive (a healthy fetus may have a result showing him/her to have Down syndrome), a positive test result always needs to be confirmed with invasive testing, such as CVS or amniocentesis, before any decisions are made regarding the further management of the pregnancy. NIPT has also been found useful in identifying fetuses with other chromosomal anomalies and certain other genetic conditions. NIPT can also be used to determine the fetal sex.

However, while NIPT does a very good job at what it is designed for: looking at fetal chromosomal complement in specific conditions, it does not examine all the fetal chromosomes, nor does it look at the anatomy of the fetus. Fetal anatomy is examined in detail by ultrasound scanning. There is some debate among practitioners regarding the optimal week of pregnancy when full early fetal anatomy scanning should be performed. Some practitioners prefer performing the scan at the time of nuchal translucency screening, 11-13 weeks, while others prefer 14-16 weeks, when the fetal organs are more developed. The important point to remember: a fetus with a normal (negative) NIPT result can have an anatomic structural malformation. It has been shown that while fetuses with malformations may be at increased risk of chromosomal anomaly, the majority have healthy chromosomes. The diagnosis of a malformation by ultrasound should prompt invasive testing such as CVS or amniocentesis. In some centers, more detailed investigation by chromosomal microarray analysis (CMA), which may discover subtle anomalies, will also be ordered. CMA detects duplicated or deleted chromosomal segments and translocations—rearrangements of chromosomal structure, which may not be evident on traditional karyotyping.

NIPT is a very reliable test. But patients may have a false sense of security regarding their baby’s well-being. A negative NIPT result cannot rule out anatomic structural malformations in the fetus, nor does it rule out all chromosomal anomalies. There is ongoing debate surrounding the integration of NIPT into existing screening programs.

I continued to follow Michele and Dan in the weeks and months that followed. They were, of course, shocked and dismayed by their diagnosis. With Michele at 21 weeks, we immediately arranged multidisciplinary consultation with the cardiologists, who explained the procedures the baby would have to undergo, and how Michele’s plans for the birth would have to change. Prenatal diagnosis of TGA can improve the baby’s surgical outcome, and with prompt intervention, prognosis is excellent. They met with a genetic counselor, and despite Michele’s fears, underwent amniocentesis. CMA is performed in all such cases in our center. Testing ruled out genetic syndromes that we suspected based on the anatomic malformation, none of which could have been diagnosed by NIPT.

With comprehensive information in hand about their baby’s prognosis and the options open to them, Michele and Dan decided to continue the pregnancy, despite the difficult road they knew was ahead. They made arrangements for delivery in the tertiary care center where the baby would undergo surgery, so she would not have to be transferred from their community hospital and would be under constant surveillance. “I fell in love when I first saw the baby’s face in 3D,” she told me. “Whatever comes, we’ll handle it together.”

How do you think NIPT should be integrated into prenatal care? How do you advise your patients who ask about NIPT? Have you encountered patients with negative NIPT results whose fetus has a structural anomaly? Have you encountered patients with false negative or false positive NIPT? Comment below or let us know on Twitter: @AIUMultrasound.

Simcha Yagel, MD, is Head of the Division of Obstetrics and Gynecology Hadassah-Hebrew University Medical Centers, Jerusalem, Israel, and Head of the Center for Obstetric and Gynecological Ultrasound at the Hadassah-Hebrew University Medical Centers, Mt. Scopus, Jerusalem. He served as moderator for a panel discussion, “Noninvasive Prenatal Testing and Fetal Sonographic Screening,” that appeared in the March 2015 issue of the Journal of Ultrasound in Medicine.