Aberrant right subclavian artery: embryology, prenatal diagnosis and clinical significance

Abstract

Introduction

The right subclavian artery normally arises as the first vessel from the brachiocephalic trunk. An aberrant right subclavian artery (ARSA) arises directly from the aortic arch and crosses behind the trachea towards the right arm. This variant occurs in approximately 1–2% of the population; however, the frequency increases in individuals with chromosomal abnormalities such as trisomy 21 and 22q11.2 microdeletion. Prenatal identification of ARSA therefore has a role in screening for such conditions.

Methods

Databases were searched for studies reporting the prenatal ultrasound evaluation of ARSA and its frequency in normal fetuses and in those with chromosomal abnormalities.

Results

A total of 23 studies were evaluated. Feasibility for the ultrasound evaluation of ARSA was 85–95%. The sonographic detection of ARSA is best in the three-vessel trachea view; however, sagittal and coronal imaging of the aortic arch may be useful. ARSA in isolation was not found to be associated with chromosomal abnormalities. The prevalence of ARSA in chromosomally abnormal fetuses was up to 24-fold higher than in normal fetuses, but the majority of chromosomally abnormal fetuses with ARSA had additional abnormal ultrasound findings, particularly cardiac abnormalities.

Conclusions

The prenatal detection of ARSA is a clinically useful prenatal marker for chromosomal abnormalities. In isolation, it is unlikely to be associated with pathogenic genetic variants. The ultrasound diagnosis of ARSA should prompt meticulous assessment of associated abnormalities. Invasive diagnostic testing should be offered to patients with non-isolated ARSA or in the presence of non-reassuring screening results or other risk factors.

Introduction

Abnormal development of the aortic arch occurs in approximately 1–2% of human fetuses and encompasses a range of anomalies, from complex cardiac defects to more subtle changes. ¹ These more subtle differences are classified as normal variants and are usually not associated with serious clinical sequelae in an otherwise normal-looking fetus. However, these variants are statistically positively associated with other structural cardiac anomalies and underlying chromosomal defects, particularly trisomy 21 and 22q11.2 deletion syndrome (22q11.2DS). Prenatal identification of these syndromes is clinically relevant and therefore these variants play a role as markers for these conditions. ² The most common anomaly of the branching of the aortic arch is the presence of an aberrant right subclavian artery (ARSA) with a normally sited left aortic arch. ¹ This article aims to summarise the embryological evolution of ARSA and the ultrasound techniques to image and diagnose it, as well as consider the literature regarding its frequency and association with structural cardiac defects and chromosomal abnormalities.

Embryology

The development of the aortic arch occurs in early gestation, following a series of complex steps that ultimately results in the formation of a left aortic arch from which three arteries (the brachiocephalic trunk, the left common carotid and the left subclavian) originate. ¹ In the developing embryo, a double aortic arch arises, with a left and right arch connected directly to each other, forming a vascular ring around the oesophagus and trachea (Figure 1). This double arch also connects with the neutrally positioned descending aorta.

Figure 1.

Schematic showing the embryological development of a left and right aortic arch surrounding the oesophagus and trachea (Adapted with permission from Chaoui R et al. ¹ ).

Each aortic arch gives rise to a common carotid and a subclavian artery. In normal development (Figure 2), the right aortic arch distal to the origin of the right subclavian artery regresses and the right common carotid artery and right subclavian artery merge to form the brachiocephalic trunk. The left aortic arch persists and descends on the left side of the spine, maintaining the origins of the left common carotid and left subclavian arteries. ¹ Aortic arch anomalies occur when there is persistence of structures that should have regressed, or regression of structures that should have persisted. ² The abnormal formation of the aortic arch can relate to the position, the branching pattern, or both simultaneously. ³ A list of these anomalies can be found in Table 1.

Figure 2.

Schematic showing the formation of a normal aortic arch. The distal part of the right arch regresses (dotted line) and the RSA (shaded) merges with the right common carotid artery to form the brachiocephalic trunk (Adapted with permission from Chaoui et al. ¹ ).

Table 1.

List of aortic arch anomalies.

Right aortic arch with mirror-image branching

Right aortic arch with aberrant left subclavian artery (ALSA)

Left aortic arch with aberrant right subclavian artery (ARSA)

Double aortic arch

Circumflex retroesophageal aortic arch

Cervical aortic arch

Double lumen aortic arch

An ARSA occurs when there is regression of the right aortic arch between the right common carotid and right subclavian artery rather than distal to them (Figure 3). This prevents the fusion of these arteries to form the brachiocephalic trunk and results in a left sided aortic arch giving rise to four rather than three arteries: the right common carotid, left common carotid, left subclavian and aberrant right subclavian arteries. ⁴ The aberrant right subclavian artery arises most distally from the origin of the aortic arch and therefore must course medially from the left side of the spine, behind the oesophagus and trachea to the right arm.

Figure 3.

Schematic showing the formation of a left aortic arch and ARSA. The right aortic arch regresses between (dotted line) the RSA (shaded) and the right common carotid artery. The right common carotid artery arises from the arch as the first vessel and the right subclavian artery will be aberrant and arise distally as the fourth vessel of the aortic arch, coursing behind the oesophagus and trachea (Adapted with permission from Chaoui et al. ¹ ).

Neural crest cells are responsible for the formation of the aortic arch, as well as other important structures such as the cardiac outflow tracts, thymus, parathyroid glands, palate, pharynx and face. ⁵ Several genes are important for the survival, proliferation and migration of neural crest cells. These genes are located within the commonly deleted region of chromosome 22q11.2. ⁵ Cardiovascular anomalies and variants, including ARSA, are therefore common in 22q11.2DS, affecting approximately 80% of individuals with the condition.

Demonstration of ARSA on prenatal ultrasound

The feasibility of identifying an ARSA is estimated to be approximately 82.4% in the first trimester ⁶ and 95.4% in the second trimester. ⁷ Factors such as operator experience, fetal size, fetal position and maternal body habitus impact the success in accurately diagnosing an ARSA. The majority of the literature regarding the prenatal ultrasound screening for an ARSA suggests the following ultrasound technique:^6–8

1. Ideally, the fetus is positioned with its spine on the left or right of the screen so that the course of the subclavian vessels is parallel to the beam.

2. Identify the ascending aorta in the transverse three-vessel trachea (3VT) view (Figure 4).

3. While still in the transverse plane, direct the ultrasound beam cephalad until the transverse aortic arch is identified.

4. Decrease the colour scale to approximately 20 cm/s to enable visualisation of flow within the subclavian artery.

5. Direct the ultrasound beam further cephalad in the transverse plane until the right subclavian artery is visualised coursing towards the upper right arm (Figure 5).

Figure 4.

Ultrasound image of a normal 3VT view in a 20-week fetus.

Figure 5.

Ultrasound image of a normal brachiocephalic and right subclavian artery in a 20-week fetus (top). Pulsed wave Doppler over the RSA (bottom).

In the normal fetus, the right subclavian artery courses anterior to the trachea and oesophagus. An ARSA will course behind the trachea, crossing to the right hemithorax towards the right arm (Figures 6 and 7).

Figure 6.

Ultrasound image of the 3VT view in a 13-week fetus. An ARSA (arrow) can be seen arising from the distal aortic arch, traversing the right hemothorax, in front of the spine, towards the right arm.

Figure 7.

Ultrasound image of the four chamber (top) and three-vessel trachea view (bottom) in a 20 week fetus. An ARSA (arrow) can be visualised arising from the distal aortic arch, coursing towards the right arm. Note the colour scale is set to approximately 20 cm/s to enable visualisation of flow within the subclavian artery.

Pulsed Doppler over the suspected subclavian artery is useful to confirm that the vessel is indeed arterial and not mistaken for the azygous vein ⁷ (Figure 8).

Figure 8.

Ultrasound image of the azygous vein (arrow), which may be mistaken for an ARSA. Pulsed Doppler over the vessel demonstrates a venous waveform.

Coronal and parasagittal views of the aortic arch can act as additional aids to confirm the diagnosis of an ARSA. Visualisation of the long axis or parasagittal view of the aorta is possible by rotating the transducer 90 degrees from the transverse view of the fetal thorax. An ARSA is suspected when there are four, rather than three vessels arising from the aortic arch. ⁹ Imaging of the aortic arch coronally, posterior to the trachea and anterior to the spine, enables visualisation of the thoracic descending aorta and an ARSA arising from the descending aorta at the level of the aortic isthmus. ¹⁰

Frequency and clinical significance of ARSA

ARSA is thought to affect approximately 0.4–2.3% of the general population. ¹¹ It has been reported, however, to be present in as many as 16–35% of postnatal individuals with Down Syndrome.^8,11 Chaoui et al. ⁸ were amongst the first to report the prevalence of ARSA in a population of fetuses with trisomy 21. They examined 14 fetuses with prenatally detected trisomy 21 and were able to detect the right subclavian artery in 100% of these fetuses. They found the incidence of ARSA in their population to be 35.7%. In one of these fetuses, the ARSA was the only abnormal ultrasound finding. Most of these fetuses, however, had additional ultrasound abnormalities. This preliminary study ultimately suggested that the prenatal identification of an ARSA may be a new ultrasound marker to identify fetuses with trisomy 21 and prompted numerous further studies to assess the incidence of ARSA in normal fetuses and the prevalence of ARSA in low risk, high risk and unselected populations.

Prevalence of ARSA in a low-risk population

In 2008, Zalel et al. ¹¹ evaluated the prevalence of ARSA in a low-risk population. They recruited 924 fetuses in women undergoing routine fetal ultrasound examinations between 13 and 26 weeks’ gestation. An ARSA was detected in 1.4% of fetuses with a normal karyotype and in 37.5% of fetuses with Trisomy 21. None of the trisomy 21 cases had ARSA as an isolated finding.

Gul et al. ¹² examined 4125 low risk patients during routine second trimester ultrasound. ARSA was detected in 17 cases (0.4%) and was an isolated finding in nine cases. Associated cardiac abnormalities were found in four cases of ARSA and associated soft sonographic markers were found in another four cases of ARSA. Of the 17 fetuses with ARSA, karyotypes were known for 13 fetuses. There was one case of trisomy 21 which occurred in a fetus where ARSA was an isolated finding.

Prevalence of ARSA in an unselected population

A Turkish study ¹³ in 2013 examined 2081 fetuses at routine ultrasound examination in the second trimester. ARSA was detected in 23 cases (1.1%). ARSA was an isolated finding in 11 cases and all of these fetuses had a normal karyotype. Seven fetuses with ARSA were confirmed to have trisomy 21 and all of these fetuses had associated ultrasound abnormalities. In 2014, a Spanish group ¹⁴ examined 8781 fetuses during routine antenatal ultrasound and detected 60 cases of ARSA (0.7%). ARSA was an isolated finding in 65% of cases and non-isolated in 35% of cases. No cases with isolated ARSA had chromosomal abnormalities. Of the 21 fetuses in the non-isolated ARSA group, seven were found to have trisomy 21 (33.3%).

A Korean study in 2017 ¹⁰ examined 7547 unselected pregnancies during routine antenatal ultrasound between 20 and 34 weeks. The incidence of ARSA was 0.4% (28 fetuses). The vast majority of fetuses with ARSA (96.4%) were euploid or morphologically normal. One fetus with ARSA had trisomy 18. ARSA was an isolated finding in 82.1% of fetuses. Three (10.7%) with ARSA had associated extracardiac findings, including choroid plexus cysts, cerebral ventriculomegaly, hyperechoic bowel, renal pelvis dilatation, small ears and clenched hands. Three (10.7%) with ARSA had associated cardiac malformations, including persistent left superior vena cava, Kommerell diverticulum, ventricular septal defect and coarctation of the aorta. A similar Turkish study in 2017 ¹⁵ looked at 1913 unselected fetuses. ARSA was detected in 20 fetuses (1.04%). ARSA was an isolated finding in 13 cases and all of these fetuses were euploid or morphologically normal. Five cases had associated ultrasound findings, including intracardiac hyperechoic foci, choroid plexus cysts and renal pyelectasis, but none of these neonates were found to have chromosomal abnormalities. Two cases had associated cardiac abnormalities (tetralogy of Fallot), both with a normal karyotype.

Prevalence of ARSA in a high-risk population

In 2008, Borenstein et al. ⁶ performed echocardiography in 516 fetuses with high risk combined first trimester screening results prior to planned chorionic villus sampling at 11 + 0 to 13 + 6 weeks’ gestation. An ARSA was observed in 0.6% of fetuses with a normal karyotype, in 7.5% of cases with Trisomy 21 and in 10% of cases with other chromosomal defects. They concluded that an ARSA is more common in chromosomally abnormal fetuses but that it is unlikely to be a useful marker for trisomy 21. In 2010, Borenstein et al. ⁷ examined the position of the right subclavian artery in all patients who attended for fetal cardiology assessment between 16 and 23 + 6 weeks’ gestation. They examined 2670 fetuses and found an ARSA in 43 (1.6%). The incidence of ARSA was 1.5% in normal fetuses, 28.6% in fetuses with trisomy 21 and 18.2% in fetuses with trisomy 18. Of the fetuses with ARSA, 3% had congenital heart disease (CHD) and a normal karyotype, suggesting an increased risk of CHD in the setting of ARSA. In the 12 fetuses with ARSA and a chromosomal anomaly, 11 had one or multiple other ultrasound abnormalities.

In 2012, Willruth et al. ¹⁶ performed a prospective study looking at a high-risk population. Pregnancies were deemed high risk due to maternal age, history of risk factors, abnormal ultrasound findings, chromosomal abnormalities and multiple pregnancies. They examined 1337 pregnancies between 16 and 28 weeks’ gestation and an ARSA was found in 14 fetuses (1.05%). In nine cases, ARSA was an isolated finding. Chromosomal abnormalities were associated with three cases. Two were associated with other sonographic abnormalities (hypoplastic left heart and Dandy-Walker malformation). A Chinese study from 2021 ¹⁷ specifically looked at the incidence of ARSA and the predictive value of ARSA for fetal chromosomal abnormalities in women of advanced maternal age (AMA). They retrospectively collected data from 13,690 singleton pregnancies, from 2015 to 2018. AMA was defined as conception and delivery greater than 35 years of age. They found that the overall incidence of ARSA was 0.69%, with no difference between the AMA and non-AMA groups. Unsurprisingly, the incidence of chromosomal abnormalities was much higher in the AMA group and the presence of ARSA increased the risk of chromosomal abnormalities in both groups.

ARSA and 22q11.2DS

The 22q11.2DS, also known as the velocardiofacial syndrome or DiGeorge syndrome is one of the most common microdeletion syndromes in humans. ¹⁸ Its prevalence is reported to be 1:1000–2000 newborns. 22q11.2DS encompasses extremely variable phenotypes including facial dysmorphism, velopharyngeal insufficiency, cleft palate, thymus hypoplasia, immune deficiency, parathyroid hypoplasia, developmental delay and other congenital anomalies. Congenital cardiac and conotruncal anomalies are the most prevalent anomalies detected in 22q11.2DS and are found in approximately 80% of individuals with the condition.^5,18 It has been suggested that the finding of an ARSA on a prenatal anatomy ultrasound may be an independent risk factor for 22q11.2DS. ¹⁸

A German study in 1999 ¹⁹ looked at 170 children with conotruncal defects. Four (2.4%) had an ARSA and, of those, one child had 22q11.2DS. Several more recent studies have reported on the association of congenital cardiac anomalies and 22q11.2DS.^5,20–26 In each study, tetralogy of Fallot was the most common, followed by tetralogy of Fallot with pulmonary atresia, ventricular septal defect, interruption of the aortic arch and truncus arteriosus. ARSA is present as an associated cardiovascular anomaly in approximately 20–35% of patients with 22q11.2DS and one of the above anomalies. ⁵

In 2017, Svirsky et al. ¹⁸ identified ARSA as a potential risk factor for 22q11.2DS and evaluated 62 pregnant women with a prenatal diagnosis of ARSA. Of these women, 55 underwent amniocentesis and all were evaluated with fluorescence in situ hybridisation and chromosomal microarray (CMA). Trisomy 21 was detected in 9.1% of cases and all of these fetuses had additional ultrasound abnormalities. No cases of 22q11.2DS were detected but there was one case of another pathogenic copy number variant (1.9%), in which ARSA was not an isolated finding. A similar study by Maya et al. ²⁷ identified 63 fetuses with ARSA, with or without additional ultrasound abnormalities. CMA results for these fetuses revealed that if found in isolation, no pathogenic CMA variant was identified. Five (7.9%) fetuses had a pathogenic CMA result, including one with trisomy 21, three with 22q11.2DS, and one with 22q11 duplication. All fetuses with pathogenic CMA results had additional ultrasound abnormalities.

Most recently, Sagi-Dain et al. ²⁸ performed a retrospective analysis of 246 pregnancies with isolated ARSA that underwent invasive diagnostic testing. CMA analysis revealed one fetus (0.4%) with a pathogenic result (trisomy 21), which was statistically similar to the control population. In the same study, there were 22 fetuses with non-isolated ARSA in which one (4.5%) had trisomy 21. A systematic review comprising data from 579 cases of isolated ARSA revealed 13 (2.2%) cases of trisomy 21 and no cases of 22q11.2 microdeletion. The authors concluded that ARSA diagnosed in isolation should be considered a soft marker and that non-invasive prenatal screening, such as cell-free fetal DNA (cfDNA), may be considered to decrease the probability of aneuploidy. Invasive testing and CMA analysis yielded no additional value and is not recommended for a truly isolated ARSA following a detailed morphology review looking for additional findings. In addition to invasive testing and CMA, effort has been made to analyse the performance of cfDNA to detect 22q11.2 microdeletions. Recently, a large prospective study ²⁹ found that a cfDNA platform utilising Digital Analysis of Selected Regions technology had a sensitivity of 69.6% and specificity of 100% in a high-risk study population. The authors concluded that cfDNA can enhance the identification of pregnancies at risk for 22q11.2DS.

Our article is focussed on a left sided aortic arch with ARSA, but an aberrant left subclavian artery (ALSA) can be found in association with a right sided aortic arch (RAA) (Figure 9). RAA has a positive statistical association with additional structural and chromosomal abnormalities. Invasive testing for microarray analysis should be offered to patients when RAA is diagnosed. ³⁰

Figure 9.

Ultrasound image of a 3VT view with a right sided aortic arch and aberrant left subclavian artery.

Conclusion

Ultrasound assessment of the right subclavian artery is feasible in most cases by experienced operators. The majority of the available evidence demonstrates that when diagnosed in isolation following low risk aneuploidy screening, ARSA is associated with chromosomal abnormalities in only a very small proportion of fetuses. However, the prevalence of ARSA in chromosomally abnormal fetuses is up to 24-fold higher than that in normal fetuses, making it an important and clinically useful marker for the detection of potential chromosomal abnormalities. The ultrasound diagnosis of ARSA should prompt the following course of action:

1. Meticulous and systematic anatomical assessment of the fetus looking for any other structural abnormality to determine whether the ARSA is isolated or not

2. Detailed fetal cardiology review and fetal echocardiography

3. Careful review of the aneuploidy screening tests the patient has undergone

Invasive testing such as amniocentesis or chorionic villus sampling should be offered to patients in cases of a non-isolated ARSA or if there are other risk factors or a non-reassuring screening test result.