ORIGINAL RESEARCH
Aberrant Right Subclavian Artery
Correlation Between Fetal and Neonatal Abnormalities
and Abnormal Genetic Screening or Testing
Angela C. Ranzini, MD, Francine Hyman, MD, Emily Jamaer, MD, Tim van Mieghem, MD, PhD
Videos online at wileyonlinelibrary.com/journal/jum
Received May 23, 2016, from the Department
of Obstetrics and Gynecology, Saint Peter’s Uni-
versity Hospital, New Brunswick, New Jersey
USA (A.C.R., F.H.); and Department of
Obstetrics and Gynecology, University Hospitals
Leuven, Leuven, Belgium (E.J., T.M.). Revised
manuscript accepted for publication July 8,
2016.
Presented at the 14th World Congress in
Fetal Medicine, Crete, Greece, June 24, 2015.
Address correspondence to Angela C.
Ranzini, MD, 4th Floor MOB, 254 Easton
Ave, New Brunswick, NJ 08903 USA.
E-mail: aranzini@saintpetersuh.com
Abbreviations
ARSA, aberrant right subclavian artery;
cfDNA, cell-free fetal DNA; CVS, chorionic
villous testing; QF-PCR, quantitative fluo-
rescent–polymerase chain reaction; VSD,
ventricular septal defect
doi:10.7863/ultra.16.05028
C 2017 by the American Institute of Ultrasound in Medicine | J Ultrasound Med 2017; 00:00–00 | 0278-4297 | www.aium.org
V
Objectives—To determine whether fetuses with an isolated aberrant course of the
right subclavian artery (ARSA) have increased risk for chromosomal abnormalities,
including trisomy 21 or 22q11 deletion.
Methods—We performed a retrospective chart review of all fetuses with antenatally
diagnosed ARSA. Data were collected from fetal anatomic surveys, fetal echocardio-
grams, noninvasive trisomy 21 screening programs, invasive genetic studies, and
neonatal records.
Results—Seventy-nine fetuses with ARSA were identified at 20.3 6 3.8 weeks’ ges-
tation. Forty-eight fetuses underwent chromosomal evaluation. Of those, seven had
trisomy 21. Four other fetuses had unusual karyotype abnormalities. All fetuses with
genetic anomalies had additional aberrant ultrasound findings. There were three
spontaneous fetal deaths (trisomy 21-2 and Wolf-Hirshhorn-1). Nine pregnancies
were terminated because of abnormalities and one died as a result of hypoplastic left
heart syndrome. No neonate was found or suspected to have 22q11.2 deletion. The
ARSA was isolated in 43 fetuses; all had unremarkable neonatal outcomes, and
none were readmitted within 6 months after discharge.
Conclusions—As an apparently isolated finding, ARSA is benign and not associated
with trisomy 21 or 22q11.2 deletion. The finding of ARSA, however, warrants a
detailed fetal ultrasound. All fetuses with ARSA and genetic anomalies had addi-
tional ultrasound findings.
Key Words—aberrant right subclavian artery; aneuploidy; cell-free fetal DNA;
chromosomes; prenatal diagnosis; 22q11.2 deletion
A
n aberrant right subclavian artery (ARSA) is the most com-
mon branching abnormality of the aortic arch, and is a variant
in 1 to 1.5% of the healthy population.1–3 In contrast to the
normal aortic arch branching pattern, in which the right subclavian
artery branches off the brachiocephalic trunk, an ARSA arises as a
fourth aortic arch vessel and passes behind the trachea and esophagus
and courses to the right arm.3,4 In general, an ARSA is a benign find-
ing, although it is one cause of dysphagia5 or dyspnea6 in the pediat-
ric population as a result of compression of the trachea or esophagus
by the aberrant vessel.
In the fetus, an ARSA can easily be identified at the level of the
transverse 3-vessel tracheal view arising at the junction of the aortic
arch and ductal arches of the heart by adjusting color velocities
downward to the 15 to 30 cm/s range, and ensuring that the
expected course of the aberrant vessel behind the trachea is toward
or away from the transducer7 (Figure 1A and B, and Video 1). Using
Ranzini et al—ARSA: Fetal, Neonatal Abnormalities and Chromosomal Abnormalities
pulsed Doppler, an arterial signal should be sought,
which can avoid confusing an ARSA (Figure 1B) with
the normally seen azygous vein that courses toward the
Figure 1. A, Transtracheal view with color Doppler. Arrow demonstrates
ARSA, which courses toward right fetal shoulder. B, Transtracheal view
with color Doppler and pulsed Doppler gate demonstrating arterial flow
in ARSA. C, Same fetus in (B) demonstrating venous signal from azygous
vein (normal structure). (Note that this vessel points toward the SVC
(arrow) and has a venous waveform.)
2 J Ultrasound Med 2017; 00:00–00
SVC7 and demonstrates a venous waveform (Figure
1C). The course of the ARSA can also be followed
toward the right shoulder in real time, which makes it
easy to determine whether the vessel of interest is an
ARSA (see Video 1) or the azygous vein (see Video 2).
Over the last 10 years, ARSA has emerged as a
marker of trisomy 21, increasing the fetal risk for tris-
omy 21 with a likelihood ratio of 21.5.8 Most fetuses
with trisomy 21, however, have additional anatomic
abnormalities7,9–12 in addition to the ARSA. An ARSA
has also been reported in fetuses with other, less com-
mon, genetic anomalies,9,13–15 including 22q11.2 dele-
tion.14,16,17 However, neither the incidence of ARSA
in fetuses with these genetic anomalies, nor the inci-
dence of these genetic anomalies in fetuses with
ARSA, has been established.14,15
The purpose of this study was to determine whether
in fetuses with ARSA, in the absence of other ultrasound
findings, the likelihood of trisomy 21 or other genetic
anomalies (in particular 22q11.2 deletion) is increased,
and whether cell-free fetal DNA (cfDNA) screening or
invasive testing should be considered.
Materials and Methods
After internal review board approval, we performed a
retrospective chart review of all fetuses diagnosed ante-
natally with ARSA between 2009 and 2014 in the fetal
ultrasound units of Saint Peter’s University Hospital,
New Brunswick, New Jersey, and the University Hospi-
tals Leuven, Leuven, Belgium. Cases were ascertained
from institutional databases, and hospital charts were
reviewed. We collected data from first trimester and
targeted fetal anatomy ultrasound scans, fetal echo-
cardiograms, genetic studies (preimplantation genetic
screening, karyotype, microarrays, cfDNA, and FISH)
for 22q11.2 deletion as available, and reviewed all neona-
tal and pediatric cardiac records through 1 year of age.
Fetuses were excluded if they delivered outside our hos-
pitals without karyotype or cfDNA screening and neona-
tal records were not available, or if the patient declined
all forms of genetic screening or testing and autopsy.
As per institutional protocols, when an ARSA was
identified, a targeted ultrasound examination was per-
formed, searching for aneuploidy markers or genetic syn-
dromes. An advanced fetal cardiac ultrasound was
performed either at the time of diagnosis or within 1 to
2 weeks. Women were counseled about the risk for
 Ranzini et al—ARSA: Fetal, Neonatal Abnormalities and Chromosomal Abnormalities

aneuploidy and offered amniocentesis at the time of
diagnosis if prior chromosome testing with chorionic vil-
lous testing (CVS) or amniocentesis had not been previ-
ously performed.
For this study, we also retrieved the patient’s best
risk calculation for trisomy 21, using the prenatal screen-
ing technique with the highest detection rate available
for the patient (maternal age, first trimester nuchal trans-
lucency, and biochemical testing [first screen] in the first
trimester, or nuchal translucency and biochemistry in
both the first and second trimesters [sequential screen]).
We used sequential screen, first screen and maternal age,
in that order, as the best a priori risk. Using the patient’s
best a priori risk, the patient’s final risk for trisomy 21
was adjusted by the ultrasound findings using a risk
assessment calculator.8
Results
Seventy-nine fetuses with ARSA were identified during
routine or targeted ultrasound examinations at an aver-
age gestational age of 20.3 6 3.8 weeks. The mean
maternal age was 32 (range 21–42) years. Two fetuses
were excluded as they delivered outside our institutions,
without karyotype, cfDNA, or neonatal records available.
An additional fetus that had multiple findings consistent
with trisomy 21 was excluded, as the patient declined all
genetic screening, testing, and autopsy after intrauterine
fetal death at 26 weeks of gestation.
Of the 76 fetuses with evaluable data, 48 (63.2%)
had chromosome screening or testing. One patient had
preimplantation genetic screening for aneuploidy during
the in vitro fertilization procedures and declined further
testing, 5 had cfDNA as the only test, 3 had CVS, 38
had amniocentesis, and one had a neonatal microarray.
Thirty-eight fetuses (50%) had 22q11.2 deletion eval-
uated either by quantitative fluorescent–polymerase
chain reaction (QF-PCR) or microarray. The remainder
of the fetuses were discharged from the nursery without
a suspicion of a chromosome abnormality. No fetus or
neonate was found to have evidence of 22q11.2 deletion
by QF-PCR, microarray, or neonatal examination.
Seven (9.2%) fetuses were diagnosed with trisomy
21, six with full trisomy 21, and one with a translocation
(Table 1). All but one fetus with trisomy 21 had abnor-
mal screening results (maternal age, first screen, or
sequential screen) and fulfilled criteria for invasive test-
ing, even without the detection of the ARSA. One fetus
(Case 3, Table 1) had a low screening risk and would
not have been diagnosed had it not been for an

Table 1. Cases of Confirmed Down Syndrome (N 5 7)

A Posteriori Risk
Gestational Best a Priori Risk for Trisomy 21,
Age at Method of Anatomic for Trisomy 21 Not Including
Case Karyotype Diagnosis Karyotype Abnormalities (Basis for Risk) ARSA

1 47 1 21 13 CVS NT 6 mm, hypoplastic NB, 1/1110 (age) 1/4

ARSA, cardiac axis
deviation, pericardial
effusion
2 47 1 21 12 CVS NT 3.2 mm, ARSA, VSD, 1/685 (age) 1/2
pyelectasis, short FL,
short HL, hypoplastic NB,
EIF
3 47 1 21 21 Amnio ARSA, EIF, 8 days smaller 1/10,000 (first 1/10,000
than expected from trimester NT
12-week CRL /biochemistry/age)
4 47 1 21 20.1 Amnio ARSA, absent NB, EIF 1/274 (age) 1/2
5 47 1 21 22.8 sono Amnio ARSA, AVSD, absent NB, 1/114 (age) 1/2
30.6 amnio flat face, sandal gap
6 47 1 21 20 Amnio ARSA, absent NB, short 1/48 (sequential 1/2
femur screen)
7 6,XX,t(4;21) 21 amnio ARSA, VSD, Hypoplastic 1/227 (sequential 1/34
(q25;q22.11) NB, ACC screen)

CRL, crown rump length; EIF, echogenic intracardiac focus; FL, femur length; HL humerus length; NB, nasal bone; NT, nuchal
translucency.

J Ultrasound Med 2017; 00:00–00 3

Ranzini et al—ARSA: Fetal, Neonatal Abnormalities and Chromosomal Abnormalities

amniocentesis triggered by the combination of ARSA Excluding cases that did not progress to term, the
with an echogenic intracardiac focus in a fetus that was 7 gestational age at birth was 37.5 6 3.3 weeks and the
days smaller than expected in the second trimester after birth weight was 2947 6 931 g. Two neonates were
accurate dating by first trimester ultrasound. unexpectedly admitted to the neonatal ICU for poor
Four fetuses (5%) had abnormal microarray results respiratory effort and feeding difficulties for 5 days, unre-
other than trisomy 21 or 22q11.2 deletion, three were lated to the ARSA. They were discharged without an
identified in the antenatal period, and one in the neona- additional diagnosis. Three others were admitted for pre-
tal period (Table 2). All had additional structural anoma- maturity. There was one neonatal readmission for sepsis
lies identified on ultrasound. However, one fetus (Case evaluation at 9 months of age, but none for suspected
1, Table 2) only had an echogenic intracardiac focus and chromosome abnormalities including 22q11.2 deletion.
would not have undergone invasive testing if the ARSA No neonate had respiratory issues in the newborn
had not been identified. period, and none were readmitted for feeding or respira-
The ARSA was apparently isolated in 43 fetuses, tory issues up to 1 year of age.
none of whom had or were suspected to have trisomy
21 or 22q11.2 deletion. Of these fetuses, 17 (39.5%)
Table 3. Additional Anomalies Seen Without Evidence of
underwent invasive genetic testing, and 6 (14.0%) had Aneuploidy
cfDNA.
Anomaly No. of Patients
Among all fetuses with structural anomalies, the
most common associated findings were soft markers for Findings associated with increased
trisomy 21 risk:
trisomy 21 (n 5 25), cardiac malformations (n 5 11; Echogenic intracardiac focus 5
ventricular septal defect (VSD) 6, complex cardiac dis- Pyelectasis 4
ease 3, atrioventricular septal 1, abnormal cardiac axis 1), Short long bones 3
and a single umbilical artery (n 5 5) (Tables 1 and 2). Abnormal nuchal region 2
Echogenic bowel 1
Additional anomalies not associated with aneuploidy Ventriculomegaly 1
were found in 22 fetuses (28.9%), including 9 (11.8%) Cardiac anomalies:
with a single anomaly and 13 (17.1%) with multiple Complex cardiac disease 2
abnormalities (Table 3). When additional markers were Ventricular septal defect 2
Single umbilical artery: 4
seen, 23 of 33 (66.7%) fetuses had karyotyping. Lung/gastro-intestinal tract: 2
Nine women chose to interrupt the pregnancy as a Other:
result of trisomy 21 (5), de novo deletion (1), retinoic Arachnoid cyst 1
acid embryopathy (1), VATER (1), and arachnoid cyst Choroid plexus cyst 1
Sandal gap 1
(1). Neonatal death occurred in two cases: one as a Face (wide maxilla) 1
result of extreme prematurity (24 weeks of gestation), Oligohydramnios 1
and one because of hypoplastic left heart syndrome.

Table 2. Other Chromosome Abnormalities (N 5 4)

Best a Priori Risk for Trisomy

Case Karyotype/Array Result Ultrasound Findings 21 (Screening Method)
1 5p15.2p15.1(14,444,119- ARSA, EIF 1/49,987 (first trimester
16,375,547)x1 de novo biochemistry/NT/age)
2 4p-(Wolf-Hirshhorn) ARSA, IUGR, VSD, persistent LSVC, 1/106 (first trimester
small thymus biochemistry/NT/age)
3 deletion 8p23.1 ARSA, aortic stenosis, LSVC, 1/810 (sequential screen)
hypoplastic left heart and aortic
arch
4 arrXp22.33q28(216,519- ARSA, postaxial polydactyly (not 1/1600 (sequential screen)
154,881,514) (Mosaic Turner) familial)

EIF, echogenic intracardiac focus; IUGR, intrauterine growth restriction; LSVC, left superior vena cava.

4 J Ultrasound Med 2017; 00:00–00

 Ranzini et al—ARSA: Fetal, Neonatal Abnormalities and Chromosomal Abnormalities
Discussion
This study shows that an apparently isolated ARSA is
not associated with genetic anomalies. This is consistent
with the conclusion of a recent large study12 and meta-
analysis,13 and confirms that an isolated ARSA is a likely
a normal variant.
In association with other malformations, however,
the risk of chromosomal anomalies in a fetus with ARSA
is elevated. Indeed, 12 of the 27 fetuses (44%) with
ARSA and other (minor) structural anomalies in our
series had genetic anomalies, two-thirds of which were
trisomy 21. Our data therefore confirm the findings of
others that all cases of Down syndrome with ARSA had
associated ultrasound findings.7,18–20
Recently, noninvasive genetic screening using cfDNA
has been introduced into clinical practice. This test has
excellent sensitivity for trisomy 21, and good sensitivities
for trisomies 18 and 13,21 but does not screen for other
aneuploidies. From the present data, it seems inappro-
priate to recommend cfDNA testing as a second line
investigation in fetuses diagnosed with ARSA and other
malformations or soft markers, as about a third of genetic
anomalies will be missed. Similarly, QF-PCR for 22q11.2
deletion, which was used before the widespread availabil-
ity of microarray, and regular karyotyping clearly appear
to be inferior to microarray in this population.
Strikingly, 2 of the 12 fetuses with genetic anomalies
in our study would likely not have been identified, had it
not been for the presence of an ARSA (Case 3, Table 1;
Case 1, Table 2). This points to the potential clinical
relevance of incorporating the ARSA in routine screen-
ing, and the necessity of an excellent, structured ana-
tomic survey that looks for additional soft markers and
an echocardiogram in all fetuses with ARSA. From our
study, an echogenic intracardiac focus, which is typically
considered a normal variant,22 a hypoplastic nasal bone
or a VSD, may be of relevance in the fetus with ARSA.
Finally, although 22q11.2 deletion has been reported
in a fetus with ARSA,14 we did not identify a single case
with 22q11.2 deletion in our series of 76 cases, suggesting
that its incidence in this population is low.
Our study certainly has some limitations. As this is a
retrospective study in two referral centers, we were
unable to calculate the incidence of ARSA in the general
population. Moreover, some fetuses with isolated ARSA
may not have been referred to us, as they either went
undiagnosed on routine screening in other hospitals or
J Ultrasound Med 2017; 00:00–00
were considered irrelevant. It is unlikely, however, that
we missed ARSAs in fetuses with anomalies, as anoma-
lous fetuses are carefully screened in our centers and
ARSA is typically looked for on targeted ultrasound
examinations and fetal echocardiography in both of our
units.
In summary, ARSA can easily be identified on a
screening ultrasound examination and is a normal vari-
ant in most fetuses. Apparently, isolated ARSA is not
associated with trisomy 21 or 22q11.2 deletion; how-
ever, the presence of an ARSA mandates advanced ultra-
sound. If other soft markers or major anomalies are
identified, cfDNA is not sufficient for screening. Invasive
genetic testing by microarray is recommended.
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