Keywords
amniocentesis - ARSA - Down syndrome - trisomy 21
Introduction
Aberrant right subclavian artery (ARSA) is the most common aortic arch anomaly with
an incidence of 1 to 2.3%. It arises directly from the aorta, as its fourth branch
distal to the left subclavian artery and courses behind the trachea toward the right
shoulder.[1]
[2]
[3] The aortic arch normally gives rise to three branches, the right brachiocephalic
trunk, the left common carotid, and left subclavian artery. The right subclavian artery
(RSA) and right common carotid arises from right brachiocephalic trunk ([Fig. 1])
Fig. 1 Normal path of right subclavian artery in S-shaped manner.
Three vessel trachea view with low pulse repeatation frequency (PRF) settings has
made the diagnosis of ARSA relatively easy with the vessel seen originating at the
junction of aortic and ductal arch traversing behind the trachea.[3] Confirmation of the diagnosis can be achieved by additional coronal views allowing
direct visualization of ARSA coming from aorta toward the right shoulder ([Fig. 2]).
Fig. 2 (A) Axial section at three-vessel trachea view showing aberrant right subclavian artery
(ARSA) behind the trachea. (B) Coronal section showing ARSA arising directly from aorta.
The incidence of ARSA in trisomy 21 ranges from 28.5 to 37.5%.[4] Previous studies have showed high diagnostic performance of ARSA in detecting trisomy
21, with positive likelihood ratio (LR) ranging from (LR + ) 0 to 29.6 for isolated
anomaly and (LR + ) 12.6 to 42.04 for nonisolated anomaly. The estimated pooled global
positive LR (LR + ) and negative LR (LR–) for ARSA were 35.3 (95% confidence interval
[CI], 24.4–51.1) and 0.75 (95% CI, 0.64–0.87), respectively.[5]
[6]
[7]
[8]
[9]
However, a few recent studies have challenged this association, thereby creating a
dilemma toward the utility of ARSA in diagnosing trisomy 21.[1]
[3] This study addresses these disputes by retrospectively evaluating the structural
and chromosomal abnormalities associated with fetal ARSA along with its clinical outcome.
The aim of this study is to assess whether isolated fetal ARSA is associated with
Down syndrome or any other chromosomal abnormalities and to see whether or not invasive
testing should be considered.
Materials and Methods
After approval from institutional ethical board and taking informed consent, this
retrospective study was conducted at CIMAR Fertility Centre, Kochi and Edappal Hospital,
Kerala, from January 2017 to December 2021. All prenatally diagnosed cases of ARSA
were reviewed and their clinical data were collected.
The antenatal screening of ARSA was done as described by Chaoui et al, in 2005[6] at the three-vessel trachea view with simultaneous two-dimensional and color Doppler
images at low PRF settings. Normally, the RSA is seen at the level of clavicle running
anterior to trachea in an S-shaped fashion. ARSA has a relatively straighter course
traversing behind the trachea toward the right arm, originating from the V in the
three-vessel trachea view. The terminology of isolated ARSA was used when no other
associated structural anomalies were seen.
As per hospital protocol, upon detection of ARSA, dedicated fetal echocardiography
was done using International Society of Ultrasound in Obstetrics and Gynaecology (ISUOG)
guidelines and detailed anomaly scan was done to look for any additional abnormalities
using transabdominal and/or transvaginal route on GE VolusionS8, E8, and E10 machine.
Genetic counseling with invasive amniocentesis was offered to all patients. Genetic
testing is done by either karyotyping, comparative genomic hybridization (CGH) Microarray
and/or exome sequence.
Results
One hundred and thirteen patients with ARSA were detected from January 2017 to December
2021. The mean gestational age was 21.2 ± 2.4 weeks and the mean maternal age at diagnosis
was 28.9 ± 5.4 years. Five patients (4.4%) were diagnosed in first trimester, 2 patients
(1.75%) in third trimester, and remaining 106 patients (93.85 %) in second trimester
during anomaly scan. Of total 113 patients, 83 patients underwent amniocentesis, while
the remaining 30 patients refused, of which one agreed for noninvasive prenatal testing
(NIPT) and 6 patients underwent genetic sonogram for further evaluation. The fetuses
for whom karyotyping was not done had no complaints in postnatal life thus excluding
any major chromosomal anomalies. Eighty-eight of one hundred and thirteen cases had
isolated ARSA, while remaining 25 patients had either associated cardiac, extracardiac
anomalies, or had high risk in combined testing.
Of 83 patients who underwent amniocentesis chromosomal rearrangements were seen in
nine patients. Six patients with ARSA had Down syndrome, one had high risk on combined
testing (1:90), while three had low screening risk but had few additional soft markers
like echogenic intracardiac focus (EIF), absent nasal bone (NB), and tricuspid regurgitation
(TR). Lastly, the remaining two patients had isolated ARSA, with no other associated
abnormalities and low risk on combined tests ([Table 1]). The association of feta ARSA with Down syndrome was, however, not significant
(p-value = 0.998).
Table 1
All cases of ARSA with associated chromosomal abnormalities
|
Sl. no.
|
GA (wk)
|
Maternal age (y)
|
Indication
|
Associated abnormalities
|
Diagnosis
|
Management
|
|
1
|
25
|
23
|
Second opinion for multiple soft markers
|
TR with EIF
|
Trisomy 21
|
Terminated
|
|
2
|
16
|
25
|
Early anomaly
|
None
|
Trisomy 21
|
Terminated
|
|
3
|
22
|
19
|
Anomaly scan
|
None
|
Trisomy 21
|
Terminated
|
|
4
|
16
|
28
|
Anomaly scan
|
Absent nasal bone
|
Trisomy 21
|
Terminated
|
|
5
|
20
|
21
|
Anomaly scan
|
EIF
|
Trisomy 21
|
Terminated
|
|
6
|
21
|
25
|
2nd opinion CT T21 high risk
|
None
|
Trisomy 21
|
Terminated
|
|
7
|
26
|
32
|
Anomaly scan
|
None
|
Turner syndrome
|
Terminated
|
|
8
|
20
|
27
|
Anomaly scan
|
None
|
Inversion of chromosome 9
|
2 years old normal child
|
|
9
|
20
|
29
|
Anomaly scan
|
TR with EIF
|
Inversion of chromosome 9
|
3.5 years old, normal child
|
Abbreviations: ARSA, aberrant right subclavian artery; CT, combined test; EIF, echogenic
intracardiac focus; GA, gestational age; TR, tricuspid regurgitation.
Three fetuses had other chromosomal abnormalities besides Down syndrome, one had Turner
syndrome that was associated only with isolated ARSA, while other two had normal variants
(inversion of chromosome 9) of which one was associated with EIF and TR.
Various structural anomalies were seen in association with ARSA, most common being
soft markers (n = 17; [Table 2]) followed by cardiovascular anomalies (n = 3), limb abnormalities (n = 2), central nervous system malformations (n = 2), and facial abnormalities (n = 1; [Table 2]).
Table 2
Distribution of various structural abnormalities with ARSA
|
Soft markers
|
|
|
Absent/hypoplastic NB
|
6
|
|
Bilateral pelvicalyceal dilatation
|
4
|
|
Increased NF
|
2
|
|
Echogenic bowel
|
2
|
|
CP cyst
|
3
|
|
Cardiovascular anomalies
|
|
|
AVSD
|
1
|
|
Coarctation of aorta with left SVC
|
1
|
|
Dilated and tortuous pulmonary artery
|
1
|
|
Skeletal abnormalities
|
|
|
Bilateral club foot
|
2
|
|
CNS anomalies
|
|
|
Partial/complete agenesis of corpus callosum
|
2
|
|
Facial abnormalities
|
|
|
Retrognathia
|
1
|
Abbreviations: ARSA, aberrant right subclavian artery; AVSD, atrioventricular septal
defect; CNS, central nervous system; CP, choroid plexus; NB, nasal bone; NFT, nuchal
fold thickness; SVC, superior vena cava.
Ten patients opted for the termination of pregnancy as a result of trisomy 21 (6),
Turner syndrome (1), complete corpus callosum (CC) agenesis with bilateral club foot
(1), partial agenesis of CC with hypoplastic NB (1), and absent NB with increased
nuchal fold thickness (1). Intrauterine fetal demise occurred in one fetus having
ARSA along with coarctation of aorta and left superior vena cava and one fetus with
ARSA and atrioventricular septal defect expired at 18 months of age.
Postnatal follow-up was done in all infants except for those who did not progress
to term. The mean age of follow-up was 2.2 years. Only one patient with isolated ARSA
had complaints of respiratory distress with stridor, which resolved spontaneously
thereafter.
Discussion
In this retrospective study, the presence of Down syndrome was seen in 6.6% of the
cases with ARSA. ARSA is considered one of the major soft markers for Down syndrome
along with absent NB, increased nuchal fold, and ventriculomegaly.[10] The incidence of Down syndrome in our study was in agreement with studies done previously
ranging from 7 to 30%.[2]
[4]
[5]
[6]
[7]
[8]
[9]
[11]
[12]
[13]
[14]
[15]
The technique for prenatal visualization of normal/aberrant RSA has been described
by several groups in the past. In studies by Borenstein et al[7] and Rembouskos et al,[13] identification of RSA was successfully done in 84 and 85% of cases in the first
trimester ultrasound and 95 and 98% of cases in the second trimester, respectively.
In our experience, though assessment of ARSA is not as simple as other major soft
markers (increased NF, absent NB, and ventriculomegaly), with special skill and proper
learning curve the assessment of RSA was possible in all our cases.
Four cases of isolated ARSA with no other ultrasound findings had associated chromosomal
malformations in our study. In all four cases, maternal age was less than 35 years.
One case of trisomy 21 had high combined risk (1/90) while remaining three cases including
two of Down syndrome and one of Turner syndrome that were totally isolated had no
other abnormalities.
Similar results have been mentioned before in literature ([Table 3]). In the study conducted by Chaoui et al,[6] Gul et al,[13] and Esmer et al[8] (total 8 cases), the maternal age was more than 35 years in 6/8 cases and the remaining
2 cases had high combined risk. Both Borenstein et al[7] and Paladini et al[2] reported total nine cases of chromosomal aberrations with isolated ARSA. In our
study, there was no associated risk factor other than isolated ARSA.
Table 3
Comparison of various studies with chromosomal abnormalities and ARSA
|
Author
|
Year
|
Isolated ARSA and chromosomal abnormalities
|
Maternal age (y)
|
NT
|
Combined risk
|
|
Chaoui et al6
|
2005
|
1
|
42
|
< 95th centile
|
NK
|
|
Borenstein et al7
|
2010
|
1
|
NK
|
NK
|
NK
|
|
Paladini et al2
|
2012
|
8
|
NK
|
NK
|
NK
|
|
Gul et al13
|
2012
|
1
|
37
|
NK
|
1/39
|
|
Rembouskos et al12
|
2012
|
2
|
NK
|
> 95th centile
|
1/402
|
|
Esmer et al8
|
2013
|
6
|
37
39
29
38
42
35
|
≤ 95th percentile ≤ 95th percentile ≤ 95th percentile ≤ 95th percentile ≤ 95th percentile
≤ 95th percentile
|
NP
Positive Positive
NP
Positive Positive
|
|
Our study
|
2022
|
4
|
25
19
25
32
|
≤ 95th percentile ≤ 95th percentile
≤ 95th percentile
≤ 95th percentile
|
Low risk
Low risk
1/90
Low risk
|
Abbreviations: ARSA, aberrant right subclavian artery; NK, not known; NP, not performed.
However, few recent studies by Pico et al[14] and Ranzini et al[3] reported no association of isolated ARSA and Down syndrome. Pico et al reported
108 cases of ARSA of which 54 were isolated. Fetal karyotyping was performed in 59/108
(54%) fetuses. Chromosomal abnormalities were seen in 22 cases of which 11 had other
ultrasound findings, 10 had ultrasound findings with congenital heart disease (CHD),
and 1 case had only CHD. In the study by Ranzini et al,[3] there were total 43/79 cases of isolated ARSA and 11 cases of chromosomal malformations.
Seven of eleven cases had trisomy 21 and 4/11 cases had other chromosomal abnormalities.
All 11 cases had associated ultrasound abnormalities and 6/7 cases of Down syndrome
had high adjusted priori risk.
Interestingly, of the six cases with Down syndrome and one with Turner syndrome no
other structural abnormalities were seen. Only one case of Down syndrome had a significant
marker, that is, unossified NB, which means even though the association of ARSA with
Down syndrome was not significant, if we had overlooked ARSA, five of seven cases
in this group would not have had invasive testing and would have undiagnosed Down
syndrome neonate at birth. Hence, the diagnosis of ARSA significantly modified the
risk of patients in this group thereby enabling timely detection.
Previous studies conducted by Shah, Ranzini et al, and Martínez-Payo et al[1]
[3]
[16] that also had nonsignificant results did not find any single cases of isolated ARSA
with Down syndrome. However, in our study we had two truly isolated cases associated
with Down syndrome and one with Turner syndrome, still the result came not significant
(p-value = 0.998). Thus, this study provides a better understanding of correlation of
ARSA with chromosomal abnormalities as it removes the assumption which may arise that
previous researchers might be dealing with low-risk population. Larger prospective
trials may be needed to assess the cost-effectiveness of routine evaluation of the
ARSA but till then its effect and utility as significant marker for Down syndrome
are reconfirmed with this study.
In our study, ARSA was associated with other structural abnormalities in 25/113 cases,
which is slightly less as compared with the reports published by Ranzini et al (36/79)
and Pico et al (54/108).[3]
[14] This can be due to variation in the study population.
Lastly, 22q11.2 deletion has been associated with ARSA in literature; however, we
could not find any such case, suggesting low incidence in our population.
Only one patient had few episodes of respiratory distress with mild stridor that resolved
by itself. No neonatal intensive care unit admissions were reported in any case. Unlike
right aortic arch with aberrant left subclavian artery and double aortic arch that
forms a vascular ring around tracheoesophageal axis, ARSA patients are usually asymptomatic.
There are some limitations in this study including its retrospective nature which
did not allow us to calculate the incidence of ARSA in study population. Also being
a tertiary center, a greater number of high-risk cases are being dealt with accounting
association of isolated ARSA with chromosomal malformations. Despite these limitations,
this study has various strengths. One is an adequate sample size that gave us the
broader picture of cases with ARSA. Second, all the scans were performed by our experienced
and competent fetal medicine specialists and these patients were kept on close follow-up
and delivered at our own hospital, thereby ruling out the possibility of any associated
missed abnormalities.
Conclusion
ARSA can be identified relatively easily with proper learning curve and should be
screened in every fetus. The presence of ARSA should mandate an advanced ultrasound
to look for any associated structural anomalies with simultaneous close follow-up.
Isolated cases of ARSA can be associated with trisomy 21, but this association was
not significant and therefore invasive testing can be deferred in these patients and
cell-free DNA testing can suffice. Presence of multiple soft markers, however, should
command invasive testing. More prospective studies are needed so that standardized
protocol is established
