An interrupted aortic arch (IAA) is a rare, but serious,nomaly in which a proportion of the systemic circulation isuctal dependent in the neonatal period.1,2 Imaging of theortic arch in the fetus can be challenging, and it can beifficult to distinguish the ductal arch from the aortic arch.he current recommendations for screening on the obstetric
etal anomaly scan include identification of a 4-chamberiew, all 4 valves, and the outflow tracts, all of which canppear to be normal to the ultrasonographer in fetuses withonotruncal anomalies.3,4
Other than case reports, essentially no published data arevailable concerning the prenatal diagnosis of IAA, and, asuch, the frequency, accuracy, outcomes, and specific ana-omic features of fetuses with an IAA have not been char-cterized.4–10 The aim of the present study was to determinehe frequency of prenatal detection among liveborn patientsith an IAA, the accuracy of the prenatal diagnosis of an
AA, and the specific anatomic features associated with anAA in the fetus that should alert ultrasonographers to theresence of a significant heart defect. The ascending aorticow might be lower than normal in fetuses with an IAA,
aDepartment of Cardiology, Children’s Hospital Boston, Boston, Mas-achusetts; and bDepartment of Pediatrics, Harvard Medical School, Bos-on, Massachusetts. Manuscript received August 12, 2009; revised manu-cript received and accepted October 25, 2009.
This study was supported by contributions from the Kenrose Kitchenable Foundation, Gig Harbor, Washington.
wing to the ductal supply of the entire lower body circu-ation and often the left subclavian artery. Therefore, it wasypothesized that the Z-scores for the aortic valve (AoV)nnulus and ascending aortic diameters would be lower thann the normal population, that the pulmonary valve annulusnd main pulmonary artery Z-scores would be greater thann the normal population, and that the AoV/pulmonaryalve and ascending aorta/main pulmonary artery ratiosould be abnormally low.
ethods
Fetuses and neonates diagnosed with an IAA werescertained by searching the database of the cardiovas-ular program at the Children’s Hospital Boston (Boston,assachusetts), using the diagnostic codes for all types
f IAA. Patients suspected to have an IAA prenatallyho were found to have another diagnosis after birthere also included. The postnatal cohort only includedatients who presented to our institution at �1 month ofge. Patients with additional major cardiac anomaliesho also had IAA, such as transposition of the great
rteries, double-outlet right ventricle, and truncus arteri-sus, were excluded. The following demographic andistorical data were obtained: gestational age at diagno-is, family history of congenital heart disease, a previouserious fetal anomaly or chromosomal defect, pregnancyutcome, and postnatal outcome.
The assigned prenatal and postnatal diagnoses wereaken from the official echocardiogram report. The diag-
osis of IAA was specified as type A (interruption after
728 The American Journal of Cardiology (www.AJConline.org)
he origin of the left subclavian artery), type B (interrup-ion after the origin of the left common carotid artery), ornspecified. The presence and type of ventricular septalefect (VSD) was recorded. Echocardiographic measure-ents were made off-line by one observer who was
naware of the patient outcomes. All studies obtainedfter 2004 were recorded in Digital Imaging and Com-unications in Medicine format. For earlier echocardio-
rams that were stored on videotape, the studies wereigitized and measurements made from the digital ver-ion. The anatomic structures measured included the mi-ral and tricuspid valve diameters (valve hinge points at
igure 1. Fetal echocardiographic images showing (A) 4-chamber view wientricle; (B) 3-vessel view, with a large pulmonary artery juxtaposed aguperior vena cava (S); and (C) modified 4-chamber view showing large
he annulus during the maximum opening in diastole), m
eft ventricular (LV) and right ventricular lengths at end-iastole, LV short-axis dimension at end-diastole, AoVnd pulmonary valve, and ascending aorta and main pul-onary artery diameters in systole. Gestational age-
ased Z-scores were calculated from unpublished norma-ive data collected at Children’s Hospital Boston from005 to 2007 from 232 normal fetuses. To optimize theeporting of the diagnostic accuracy of the fetal echocar-iographic findings and the estimates of the frequency ofhe prenatal diagnosis, the data from newborns with anAA not diagnosed prenatally at our center were alsoollected to ascertain whether a fetal diagnosis had been
al relative dimensions of right atrium, left atrium, right ventricle, and leftsmall ascending aorta (arrow), which is located immediately anterior totricular septal defect (*).
th normainst a
ade elsewhere. The postnatal echocardiograms and re-
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729Congenital Heart Disease/Interrupted Aortic Arch in the Fetus
orts were reviewed to assess for discrepancies betweenhe pre- and postnatal diagnosis.
The diagnostic and outcome data are reported in descrip-ive fashion. A comparison of the gestational age at diag-osis between the liveborn and terminated pregnancies waserformed using the Wilcoxon rank sum test. A comparisonf categorical data between groups (eg, pre- and postnatallyiagnosed patients) was performed using Fisher’s exact test.
igure 2. Echocardiographic images in fetus with IAA showing (A) ductaescending aorta (DAo); (B) ascending aorta separating from the ductal arY appearance); (C) another view of the Y appearance, with the ascendingifurcation); and (D) separation of ascending aorta (AAO) and ductal arch
he echocardiographic data from the fetuses with an IAA were a
ompared with a normative population (mean Z-score � 0)sing a 1-sample t test. A comparison of the serial echocar-iograms in fetuses with 2 studies was performed using aaired t test analysis.
esults
From June 1988 through April 2009, 26 fetuses and 56
(arrows), which can be mistaken for the aortic arch, continuing into theing straight cranially, and branching into the first brachiocephalic vesselsranching into the innominate and left common carotid arteries (arrow at
lor flow imaging.
l archch, runn
aorta b
dditional neonates �30 days old were diagnosed with an
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730 The American Journal of Cardiology (www.AJConline.org)
AA at Children’s Hospital Boston. Of the 26 fetusesith a prenatal diagnosis of IAA, 21 were liveborn and 5
amilies elected to terminate the pregnancy without fe-opsy. The median gestational age at diagnosis was 25.7eeks (range 17.0 to 37.3) overall and 19.8 weeks (range8.8 to 20.1) for the terminated pregnancies (p �0.001or comparison of terminated pregnancies with those con-inued to birth). Of the 21 liveborn patients, 17 wereemale and 3 were male; for 1 infant, who was born andied at an outside hospital, the gender was unknown.llustrative echocardiographic images are depicted inigures 1 and 2.
All 21 liveborn patients diagnosed prenatally with IAAor whom postnatal echocardiograms were available had aostnatal diagnosis of an IAA or severe coarctation ofhe aorta (COA). Of the 21 liveborn patients, 18 (86%) wereonfirmed to have an IAA after birth (Table 1), and 3 wereound to have severe COA instead of an IAA. In 2 of these 3,he prenatal diagnosis was “either IAA or severe COA,” and in
IAA type B and VSD IAA type B and VSD 4*IAA type B and VSD IAA type A and VSD 1IAA type B and VSD Severe COA with
hypoplastic aorticarch and VSD
1
IAA type A IAA type B and VSD 1IAA unspecified and VSD IAA type B and VSD 4IAA type A or severe
COA and VSDIAA type A and VSD 1
IAA type A or severeCOA and VSD
Severe COA andVSD
1
IAA unspecified or severeCOA, VSD, small leftventricle
COA and Shonecomplex
1
IAA unspecified or severeCOA and VSD
IAA type A and VSD 2†
IAA unspecified or severeCOA and VSD
IAA type B and VSD 5
regnancy terminated afterprenatal diagnosis ofIAA
IAA type B and VSD pregnancy terminated 2IAA unspecified pregnancy terminated 2IAA unspecified or severe
COApregnancy terminated 1
renatal echocardiogramincorrect, postnataldiagnosis of IAA‡
Large VSD, small AoV‡ IAA type A and VSD 1Normal IAA type A and VSD 1Possible COA and mild
ventricular discrepancyIAA type B and VSD 1
* Co-existing left-sided congenital diaphragmatic hernia in 1, diagnosedrenatally and confirmed postnatally.
† Patient also had dextrocardia.‡ Prenatal echocardiography was performed at another institution in the
rst of these patients and at our institution in the other 2.
he third, the prenatal diagnosis was IAA type B. In 2 cases, g
he prenatal diagnosis specified a particular type of IAA (eg,ype A or B), and the postnatal imaging revealed the IAA toe a different type. In 4 cases, the type of IAA was notpecified prenatally and was found to IAA type B postna-ally. In 8 other cases, the prenatal diagnosis was listed aseither IAA or severe COA” and was found postnatally toe IAA type B (n � 5) or type A (n � 3). Those patientsere considered to have had the correct antenatal diagnosis.
n the other 4 cases, the prenatal diagnosis of IAA type Bas correct.In all 21 liveborn patients, a VSD was diagnosed prena-
ally. In 16 cases, all correctly characterized on the prenatalcan, the VSD was a posterior malalignment defect. Ofhese 16 patients, 14 had type B IAA confirmed postnatally,
had type A IAA, and 1 had COA. Of the other 5 patients,had muscular VSDs and 1 a membranous defect. None of
hese patients had a type B IAA; 3 had type A IAA and 2ad COA. All 5 fetuses in which the pregnancy was termi-ated were diagnosed with a posterior malalignment VSD.
Of the 56 patients diagnosed with an IAA in the newborneriod (27 males and 29 females), 53 had not undergonerenatal echocardiography and 3 had a prenatal echocardio-
able 2atients with a family history of cardiac or noncardiac malformation orhromosomal anomaly
amily History Patient Diagnosis Prenatal or NeonatalDiagnosis of IAA
ather with 22q11deletion
IAA type B, 22q11deletion
Prenatal
ather with tetralogyof Fallot andprobably 22q11deletion
IAA type B, 22q11deletion
Prenatal
other and maternalaunt withtetralogy of Fallotand 22q11deletion
* Prenatal scan at 20 weeks’ gestation was interpreted as showingormal cardiac anatomy.HLHS � hypoplastic left heart syndrome.
ram that did not include the correct diagnosis. Of these 3
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731Congenital Heart Disease/Interrupted Aortic Arch in the Fetus
atients, 1 had a fetal echocardiogram from a differentnstitution and was diagnosed with a small AoV and a largeSD but was found to have type A IAA and a VSD onostnatal scanning. The other 2 fetuses were scanned at ournstitution: 1 was reported to have normal findings but hadype A IAA; the other was diagnosed prenatally with apossible COA” and a VSD and was found to have type BAA and a VSD postnatally.
The frequency of the prenatal diagnosis over time wasssessed by dividing the 21-year study period into 3 equiv-lent periods. Of the liveborn patients with a confirmedostnatal diagnosis of IAA (n � 74), 24% were diagnosedrenatally. This frequency increased from 11% during therst 7-year period to 16% during the second and 43% during
he third (p � 0.01). In 2 (40%) of 5 fetuses diagnosed withn IAA during the first 7-year period, the pregnancy waserminated compared to 1 (17%) of 6 during the seconderiod and 2 (13%) of 15 during the most recent period. Ofhe 56 patients first diagnosed during the neonatal period, 24ere diagnosed during the first 7-year period and 16 eachere diagnosed in the second and third periods.Of the 18 prenatally diagnosed patients with postnatally
onfirmed IAA, 12 (67%) had an identified chromosomal
able 3etal echocardiographic data
ariable Total (n � 26) p Value*
estational age at diagnosis (weeks) 25.7 (17.0, 37.3) NAoV diameter Z-score �2.4 � 1.2 �0.001
V long-axis dimension Z-score 0.3 � 0.9 0.130.5 (�1.7, 1.7)
V short-axis dimension Z-score 0.01 � 1.1 0.970.1 (�2.3, 1.5)
ight ventricular long-axisdimension Z-score
0.7 � 0.9 0.0010.5 (�1.2, 1.9)
V/right ventricular length ratio 1.04 � 0.07 NA1.03 (0.86, 1.22)
Data are presented as mean � SD and/or median (range) or as number%) of fetuses in respective column.
* p Values reflect comparison of entire 26-patient cohort with normalopulation (mean Z-score � 0) using 1-sample t test; comparisons withormal data were only performed for variables with Z-scores.
bnormality or syndrome, chromosome 22q11 deletion in 2
0 patients, Turner syndrome in 1, and VACTERL associ-tion (vertebral anomalies; anal atresia; cardiac defect, mostften VSD; tracheoesophageal fistula with esophageal atre-ia; renal abnormalities; and limb abnormalities, most oftenadial dysplasia) in 1. One of the patients diagnosed withAA in utero who was found to have COA after birth hadurner syndrome. The genetic status was unknown in 1 of1 liveborn patients with a prenatal diagnosis of IAA and inof the 5 in which the pregnancy was terminated. A mal-
ormation syndrome or chromosome abnormality was diag-osed in 30 of 56 patients with a neonatal diagnosis of IAA.f the 30 patients, 27 had a chromosome 22q11 deletion (1ith Klippel-Feil syndrome in addition and 1 withACTERL association), and 1 patient each had CHARGE
yndrome, trisomy 21, and chromosome 4 deletion. Theenetic status was unknown in 9 of 56 patients with aonfirmed neonatal diagnosis of IAA. The chromosomalbnormalities were similarly common in patients diagnosedre- and postnatally.
A known family history of cardiac, severe noncardiac, orhromosomal/genetic abnormalities was reported in 10 pa-ients, including 4 (15%) of those with a prenatal diagnosisTable 2).
The fetal echocardiographic data are summarized inable 3. Overall, the Z-scores for the AoV, ascending aorta,nd mitral valve were significantly (p �0.001) lower in thetudy cohort than in normal fetuses, and were less thanormal (Z-score �2) in 69%, 73%, and 19% of fetuses,espectively (Figure 3 and Table 3). The LV short- and LVong-axis Z-scores, however, were normal. The pulmonaryalve, main pulmonary artery, and right ventricular length-scores were all larger than normal, although only mod-stly so for the right ventricle (Table 3). The AoV/pulmo-ary valve diameter ratio (0.54 � 0.11) and the ascendingorta/main pulmonary artery diameter ratio (0.50 � 0.09)ere lower than normal, but both were noticeably greater
nd closer to normal in fetuses diagnosed earlier in gestationFigure 3). The fetuses found to have IAA type A and COAostnatally tended to have greater ascending aorta/mainulmonary artery diameter ratios on the prenatal scan thanhose with IAA type B.
In 10 fetuses, serial prenatal echocardiograms were per-ormed with a median duration between the first and lastchocardiograms of 58.5 days (range 28 to 98). In this smallubset of patients, no significant differences were found inhe Z-scores of the cardiac structures between the first andast studies.
Of the 21 liveborn patients diagnosed with IAA prena-ally, including those found to have a COA postnatally, theedian gestational age at birth was 39 weeks (range 35 to
1) and the median birth weight was 2.83 kg. Of those 21atients, 5 (24%) died in infancy. Nineteen patients (91%)nderwent cardiac surgery for IAA and 2 patients diedithout surgery. Of the 56 patients diagnosed with an IAA
n the newborn period, 3 (5%) died in infancy.
iscussion
As with other conotruncal anomalies, the prenatal di-gnosis of IAA is relatively uncommon. During the past
1 years at our center, 24% of patients born with an IAA
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732 The American Journal of Cardiology (www.AJConline.org)
ere diagnosed in utero.8,11,12 However, during theourse of the study, the frequency of the prenatal diag-osis increased from 11% in the first 7-year period to3% in most recent 7-year period. Despite a high asso-iation of chromosomal anomalies and that the outcomesf IAA remain suboptimal,13 the rate of termination was25% overall and decreased from 40% during the first 7
ears to 15% in the subsequent 14 years. Fourteen per-ent of infants born with the diagnosis of an IAA in thiseries had a positive family history of cardiac, noncar-iac, or chromosomal anomalies. As described in previ-us studies, type B IAA is commonly associated with the2q11 deletion; however, fetuses with CHARGE syn-rome, VACTERL association, Klippel-Feil syndrome,urner syndrome, and other syndromes/anomalies couldlso have an IAA.6,7,14,15 The increasing frequency of therenatal diagnosis over time, consistent with trends forther complex anomalies, is likely to be related to aombination of factors, including improving image qual-
igure 3. Scatterplots showing distribution of (A) AoV diameters accordinorta/main pulmonary artery diameter ratio according to gestational age. Inean (Z-score � 0) and the narrow lines indicating the limits of normal (
iagnosis: IAA type B (solid circles), IAA type A (open circles), and COAot confirmed) indicated by solid triangles.
ty, increased awareness of the cardiac defect, experience a
f the primary sonographer, and more frequent referralor echocardiography for various indications.
The most prominent anatomic hallmarks of IAA in theresent series were a small AoV with a normal-size LV,ildly enlarged right-sided structures, small AoV/pulmo-
ary valve, and ascending aorta/pulmonary artery diameteratios (Figure 1), and the universal presence of a VSD,hich was always correctly identified as a posterior mal-
lignment defect in cases of IAA type B. A significant sizeiscrepancy between the AoV and pulmonary valve or aortand main pulmonary artery might not be pathognomonic ofAA, but it should alert the ultrasonographer to the possibleresence of an aortic arch anomaly such as COA or IAA.lthough the numbers of patients with IAA type A or COAostnatally were small, a tendency for greater ascendingorta/main pulmonary artery diameter ratios in these fetusesompared to those with IAA type B. This observation isonsistent with the larger volume of blood flow that woulde expected to pass through the ascending aorta in these
tational age; (B) AoV/pulmonary valve diameter ratio; and (C) ascending(B), the normal range is depicted with the broad line indicating the normal
s �2 and �2). In (C), data from individual fetuses indicated by postnatalsquares). Fetal data from terminated pregnancies (ie, postnatal diagnosis
g to ges(A) andZ-score
(open
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733Congenital Heart Disease/Interrupted Aortic Arch in the Fetus
lied by flow from the LV and AoV compared to IAA type, in which the ascending aorta supplies flow only to the
nnominate and left common carotid arteries. The presencef a VSD in utero, particularly a moderate to large cono-entricular VSD, should not be assumed to be an isolatedefect (Figure 1). A conoventricular VSD is rarely isolatednd additional significant defects including IAA, transposi-ion of the great arteries, double-outlet right ventricle, andetralogy of Fallot should specifically be sought. A posterioralalignment VSD is often, although not always, associatedith IAA type B. Positive testing for chromosome 22q11eletion should further alert the physician to the possibleiagnosis of IAA type B.
Diagnosing IAA in the fetus can be challenging. Inost cases all 4 chambers are present (Figure 1). Cross-
ng of the outflow tracts is seen, and the fetal scan can beistaken for normal. The difficulty in diagnosing IAA in
he fetus is illustrated by the facts that IAA was missedy fetal echocardiography in 3 cases and “overcalled” infetuses with COA and that in 1/2 of the prenatally
dentified cases, the fetal echocardiography report eitheredged whether the diagnosis was IAA or COA or did notpecify the type of IAA. The difficulty in identifying IAAn prenatal echocardiograms is due in part to the poten-ial for the ductus arteriosus to resemble the aortic archnd for the left subclavian artery arising from the prox-mal descending aorta, just distal to the ductal arch, to beistaken for head and neck vessels arising from the
ortic arch (Figure 2).Other than the aortopulmonary size discrepancy, ana-
omic patterns and relationships can aid in the prenataliagnosis of IAA. For example, a common feature of IAAs that the ascending aorta travels straight up craniallynd does not begin to curve at the first brachiocephalicessel (Figure 2). The ultrasonographer might notice a Yppearance (Figure 2), with the ascending aorta branch-ng into the first 2 brachiocephalic branches (innominater right common carotid and left common carotid). Inome cases, particularly fetuses with a chromosome2q11 deletion, arch imaging can be further compro-ised by the lack of a thymus gland, which often con-
rasts with the arch.A size discrepancy between the left ventricle and right
entricle on prenatal echocardiogram is a commonly recog-ized feature of LV outflow tract or arch obstruction16–18
ut was absent in fetuses with IAA. This important differ-nce is almost certainly owing to the presence of a VSD inost patients with IAA. In the presence of a VSD, the netow through the left ventricle is unimpeded, thereby allow-
ng normal LV loading and growth. In contrast, when theV outflow tract or aortic arch obstruction occurs in asso-iation with an intact ventricular septum, LV loading androwth are more likely to be affected, and LV size to bebnormal (either dilated or small). Accordingly, the combi-ation of a low aortopulmonary diameter ratio and absencef a ventricular size discrepancy should be considered a clueo the presence of arch obstruction in combination with aSD. Slodki et al19 recently showed that mediastinal great
rterial diameter ratios might also be useful in the diagnosis
f fetal COA.
This was a retrospective study that included patientsvaluated during a 21-year period in which the prenataletection rates and ultrasound technology changed con-iderably. The intra- and interobserver variability fornatomic measurements was not performed for theresent study, and it has been shown that importantntraobserver variability might exist in fetal 2-dimen-ional and Doppler measurements.20 Genetic testing wasot performed in all patients; thus, the frequency ofhromosomal and other syndromes may not be com-letely accurate. The anatomic diagnoses were not con-rmed in the terminated pregnancies; thus, diagnosticccuracy could not be assessed in �20% of prenatallyiagnosed cases of IAA. The apparently greater earlyortality in the prenatal diagnosis group might reflect
scertainment bias if the newborns with IAA in oureographic catchment died before or without transfer tour center. For the same reason, our estimates of therequency of prenatal diagnosis might have overesti-ated. Although some of our patients were found to have
evere COA after birth, our study was not intended tonvestigate the differentiation of IAA from COA in theetus.
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