The Value of a Repeat Nasal Bone Evaluation in First-Trimester Screening for Down Syndrome

First-trimester screening for Down syndrome, a genetic disorder caused by the presence of an extra chromosome, usually involves a combination of maternal blood tests and an ultrasound exam (ie, a combined first-trimester screening [FTS]), which is performed between 11 and 14 weeks of pregnancy.

During the ultrasound exam, the healthcare provider evaluates various markers that can indicate an increased risk of Down syndrome, such as the thickness of the nuchal translucency (a fluid-filled space at the back of the fetus’s neck) and the presence of certain physical features, including the nasal bone. Because research has shown that fetuses with Down syndrome are less likely to have a visible nasal bone on ultrasound than fetuses without the condition, evaluating the nasal bone can help healthcare providers assess the risk of Down syndrome more accurately.

Although visualizing the nasal bone is not a mandatory component of the screening, the inclusion of fetal nasal bone evaluation in the screening improves the clinical performance of the screen for the detection of fetal Down syndrome. Unfortunately, factors such as maternal body habitus (such as increased body mass index [BMI]), poor acoustic windows, unfavorable fetal position, delayed nasal bone ossification, and early gestational age can hinder nasal bone visualization then. In addition, ethnicity may also affect the visualization of the fetal nasal bone as the development of the fetal nasal bone differs between populations. Acknowledging and integrating the differences in facial structure between different racial and ethnic groups can help to promote equity in prenatal imaging and ensure the provision of accurate, personalized risk counseling across patient populations.

Therefore, a recent study aimed to determine if repeat nasal bone evaluation provided a significant improvement in refining the specificity of Down syndrome risk assessment by combined FTS, as well as determine the efficacy of a repeat nasal bone evaluation across various maternal ethnicities.

The study reviewed the medical records of patients who underwent a first-trimester ultrasound evaluation in an American Institute of Ultrasound in Medicine (AIUM)-accredited center between January 2015 and January 2018. The study focused on patients with fetal nasal bone labeled as “absent or hypoplastic” or “unable to be adequately visualized” during the ultrasound. The researchers reviewed the records to assess factors such as patient age, ethnicity, follow-up evaluations, and fetal anomalies. They analyzed the combined FTS results and followed up with patients with abnormal results. They then conducted statistical analyses to compare patient ethnicity and nasal bone visualization on the second exam, as well as to compare patient ethnicity and fetal Down syndrome risk by combined FTS.

The study identified 589 cases (8.7%) of absent or uncertain fetal nasal bone on initial nuchal translucency (NT) ultrasound evaluation among the 6780 total NT ultrasounds performed, with the most frequently represented ethnicities being African American/Caribbean (46.2%) and White (36.8%). Of the total, 125 patients (21.2%) did not complete a repeat nasal bone evaluation, and 105 patients with additional risk factors pursued genetic counseling. Of these patients, 20 pursued chorionic villus sampling (CVS), and 11 of these cases (55.0%) reported abnormal karyotypes. Of the 376 eligible patients who completed a second nasal bone evaluation (exam 2), 82 patients (21.8%) had an absent fetal nasal bone, 26 (6.9%) had an uncertain fetal nasal bone, and 268 (71.2%) had a present fetal nasal bone. White patients were statistically significantly more likely than African American/Caribbean patients to have a present nasal bone on exam 2 (82.9% and 59.2% respectively, P < .0001), as were Asian Indian patients (100% and 59.2%, respectively, P < .0001).

Combined FTS can identify fetuses at high risk for aneuploidy, but it has a relatively high false positive rate. Therefore, proper identification of the absence or presence of the fetal nasal bone during FTS plays a critical role in identifying and counseling patients at increased risk for fetal aneuploidy. The study found that repeat nasal bone evaluation could reduce false positive FTS results, particularly in African American/Caribbean populations.

Even with the widespread use of cell-free DNA screening, combined FTS, including nasal bone assessment, remains an important tool for first-trimester aneuploidy risk assessment.

To read more about this study, download the Journal of Ultrasound in Medicine article, “Follow Your Nose: Repeat Nasal Bone Evaluation in First-Trimester Screening for Down Syndrome” by Kristen A. Miller, MGC, et al. Members of the American Institute of Ultrasound in Medicine (AIUM) can access it for free. Join the AIUM today!

Interested in reading more about obstetric ultrasound? Check out these posts from the Scan:

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: