Accurate Prenatal Diagnosis of Coarctation of the Aorta by Three-step Echocardiographic Diagnostic Model

doi:10.21203/rs.3.rs-2006908/v1

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Accurate Prenatal Diagnosis of Coarctation of the Aorta by Three-step Echocardiographic Diagnostic Model

https://doi.org/10.21203/rs.3.rs-2006908/v1

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published 27 Aug, 2024

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Background Coarctation of the aorta (CoA) is the most common undiagnosed congenital heart defect during prenatal screening. High false positive and false negative rates seriously affect prenatal consultation and postnatal management. The objective of the study was to assess the utility of various measurements to predict prenatal CoA and to derive a diagnostic algorithm.

Methods One hundred and fifty-four fetuses with suspected CoA who presented at Fuwai Hospital between December 2017 and August 2021 were enrolled and divided into confirmed CoA cases (47) and false-positive cases (107), according to their postnatal outcomes. Fetal echocardiographic measurements included the cardiac chambers sizes, valve annular diameters, and ascending aorta and pulmonary artery dimensions. The corresponding gestational age-related Z-scores were collected. The diameter of the transverse aortic arch and the aortic isthmus were measured. The TAO-DAO angle between the transverse aortic arch and isthmus was also measured. The receiver operating characteristic curve determined the predictive capability of each diagnostic parameter, and the kappa test determined the diagnostic accuracy of the proposed model.

Results Confirmed CoA cases had thinner transverse arches (1.92 ± 0.32 mm vs. 3.06 ± 0.67 mm, P = 0.0001), lower Z-scores of the isthmus (-8.97 ± 1.45 vs. -5.65 ± 1.60, P = 0.0001), smaller TAO-DAO angles (105.54 ± 11.51° vs. 125.29 ± 8.97°, P = 0.0001) and larger distance between the left subclavian artery and left common carotid artery (4.45 ± 1.75 mm vs. 2.74 ± 1.07 mm, P = 0.0001) than the false-positive cases. The area under the curve was 0.947 (95% CI 0.91–0.98) for the TAO-DAO angle, 0.942 (95% CI 0.91–0.98) for the transverse arch diameter, and 0.937 (95% CI 0.90–0.98) for the Z-score of the isthmus. Three important echocardiographic indices were combined to derive a three-step echocardiographic diagnostic model. The kappa test showed that the model’s diagnostic accuracy was consistent with postnatal outcomes (kappa value 0.936, P = 0.0001).

Conclusions The three step approach included the three most useful measurements and the five additional indices with appropriate cut-off values. The algorithm optimizes the diagnosis of fetal CoA and is clinically feasible.

Trial registration: retrospectively registered.

Aortic arch

TAO-DAO angle

Coarctation of the aorta

Fetal echocardiography

Coarctation of the aorta (CoA) is the most common undiagnosed congenital heart defect during prenatal screening, with a true positive detection rate of < 50% [1, 2]. Accurate prenatal diagnosis allows for planning of the delivery in a center with a pediatric cardiology service, maintaining arterial duct patency by starting prostaglandin infusion immediately after birth, and performing surgery timeously, thus reducing mortality and morbidity. High false positive and false negative rates seriously affect prenatal consultation and postnatal management, causing unnecessary parental anxiety and hospitalization costs. The main limitations to the prenatal diagnosis of CoA are the low specificity of the classic echocardiographic signs (ventricular disproportion, great vessel asymmetry, shelf of the aortic isthmus) and the hard-to-predict arch remodeling after the closure of the patent ductus arteriosus (PDA) [3, 4]. Even though some authors have studied the Z-scores of cardiovascular dimensions to identify fetal CoA [5, 6], it cannot be reliably diagnosed using a single parameter, and clinicians should maintain a high index of suspicion when multiple parameters are outside of the expected ranges.

The objective of this retrospective study was to summarize the diagnostic performance of various echocardiographic measurements for detecting fetal CoA and to derive an optimal diagnostic algorithm.

Fetuses presenting with suspected CoA based on right ventricular dominance and a small diameter of the aortic arch or isthmus between December 2017 and August 2021 were included in the study. They underwent fetal echocardiography at Fuwai Hospital and Branch Hospital. The exclusion criteria were prenatally suspected hypoplastic left heart syndrome, complex congenital heart defect (CHD), and insufficient technical quality including suboptimal imaging. The study was approved by the institutional review board of Fuwai Hospital.

The participants were divided into confirmed or false-positive cases according to the postnatal echocardiography or cardiac computed tomography (CT) results. Pregnant women and their families were informed about the limitations of fetal echocardiography before the examination and signed an informed consent form for the performance of the exam. And the consent forms to collect data for research were obtained during follow up after birth. Echocardiography was performed by two experienced doctors (H. M. and L.Z.L.), and all measurements were performed by an experienced fetal echocardiographer (H.M).

Fetal echocardiography was performed on a GE Voluson E10 ultrasound machine (GE Medical Systems, Austria). Measurements were taken according to published standards and included the right ventricular (RV) end diastolic dimension (RVEDD), left ventricular (LV) end diastolic dimension (LVEDD), LV end diastolic area (LVEDA), RV end diastolic area (RVEDA), mitral valve (MV) and tricuspid valve (TV) annular diameters in the 4-chamber view, aortic valve (AV) annular diameter and ascending aorta diameter in the LV outflow view, pulmonary valve (PV) annular diameter and main pulmonary artery diameter in the RV outflow view, aortic artery (AO) and pulmonary artery (PA) diameters in the three vessels and trachea view (3VT).

The transverse aortic arch, isthmus, and descending aorta should be clearly shown in the long-axis view of the aortic arch. The diameter of the left subclavian artery (LSA), distance between the LSA and left common carotid artery (LCCA), distance between the right innominate artery (RIA) and LCCA, and diameter of the distal transverse aortic arch (segment of the aortic arch between the LCCA and LSA) were measured. The aortic isthmus should either be measured proximal to the insertion of the PDA in the sagittal and coronary views or may be measured proximal to the orifice of the LSA in the long axis view.

The TAO-DAO angle was defined between the transverse aortic arch and isthmus in the long axis or sagittal view. It was measured by two straight lines, where one line was drawn proximal (from the take-off of the second head vessel) to distal (to the end of the third head vessel) along the internal boundary of the transverse arch, and the second line was drawn proximal (just prior to the isthmus) to distal (to the end of the isthmus) along the internal boundary of the isthmus (Fig. 1) [3, 7].

The Z-scores of the valvular annular diameters and the dimensions of the aorta were calculated in relation to the gestational age [8]. The RVEDD-to-LVEDD ratio, RVEDA-to-LVEDA ratio, MV-to-TV ratio, isthmus-to-LSA ratio, AO-to-PA ratio, and the ratio of the distances (the distance between the LSA and LCCA to the distance between the RIA and LCCA) were calculated. The flow directions across the atrial septum and across the isthmus were observed. Abnormal blood flow across the isthmus were included a retrograde or delayed passage.

After birth, all participants were followed up using echocardiography, and postnatal outcomes were obtained through medical records and parental telephonic follow-up. The diagnostic criteria of CoA in children were: 1) the diameters of the proximal and distal transverse aortic arch and aortic isthmus being less than 60%, 50%, and 40%, respectively, of the distal ascending AO; 2) the diameter of the transverse aortic arch being less than 50% of the descending AO at the diaphragm; 3) the diameter of the transverse aortic arch being less than one plus the neonatal weight; and 4) the peak coarctation velocity being ≥ 2.5 m/s (> 2.0 m/s for neonates). If CoA was not confirmed in the early neonatal period, all newborns underwent cardiologic and echocardiographic follow-ups at 3, 6, and 12 months of age. Cardiac CT was performed to confirm the diagnosis before surgery.

The continuous data are expressed as mean ± SD, and categorical data are expressed as frequency and percentage. Continuous variables were analyzed using the t-test, and categorical variables were analyzed using the chi-square test. The receiver operating characteristic (ROC) curve determined the predictive capability of each diagnostic parameter. The cut-off points with the best balance between specificity and sensitivity, and maximum sensitivity and specificity were established. The kappa test measured the disagreement and agreement between the observers or indices.

One hundred and fifty-four fetuses with suspected CoA were enrolled in the study. Postnatal echocardiography or cardiac CT confirmed the diagnosis of CoA in 47 cases, and that of normal aortic arches in 107 false-positive cases. The mean maternal age was 30.0 ± 4.5 years (range, 21–43 years), and the mean gestational age at diagnosis was 28.1 ± 4.1 weeks (range, 20–39 weeks). Fifty four fetuses (35.1%) had ventricular septal defects (VSD), and nineteen (12.3%) had persistent left superior venae cavae (PLSVC). The flow direction across the atrial septum was right-to-left in all fetus,. Fourteen fetus with limited atrial shunt (< 3mm) among 107 false-positive cases, while five fetus among 47 confirmed cases (P > 0.05). And the characteristic of the flow across the isthmus was different between the two groups (P = 0.0001).

All of the fetuses were born alive, and twenty-nine children underwent cardiac surgeries. Figure 2 shows the outcomes for the entire group. A number of echocardiographic indices in the fetuses with confirmed CoA differed significantly, while the ventricular size ratios, MV-to-TV ratio, and AO-to-PA ratio were no different from that of those with normal arches postnatally. Confirmed CoA was positively associated with concomitant VSD and PLSVC (Table 1).

The ROC curve determined that a TAO-DAO angle ≤ 115.75°, a transverse arch diameter ≤ 2.31 mm, and a Z-score of the isthmus ≤ -7.5 were the strongest indicators of fetal CoA. The area under the curve (AUC) was 0.947 (95% CI 0.91–0.98) for the TAO-DAO angle, 0.942 (95% CI 0.91–0.98) for the transverse arch diameter, and 0.937 (95% CI 0.90–0.98) for the Z-score of the isthmus (Fig. 3). The following indices showed a strong specificity for the diagnosis of fetal CoA: a Z-score of the transverse arch of ≤ -5.29, diameter of the isthmus of ≤ 1.64 mm, distance from the LSA to LCCA of ≥ 3.5 mm, and ratio of the distances of ≥ 1.81 (Table 2).

When all of the first-three measurements (the TAO-DAO angle, a transverse arch diameter, and a Z-score of the isthmus ) were abnormal, the diagnosis of fetal CoA was supported in 34 cases (72.3%, 34/47), and conversely, when all of these indices were within the normal range, a postnatal normal arch was predicted in 81 cases (75.7%, 81/107). So the five addiitonal measurements were utilized in the assessment to make the algorithm. According to their diagnostic performance, the indices were incorporated into a diagnostic flow chart (Fig. 4) that forms the basis of our proposed three-step echocardiographic diagnostic model for fetal CoA. The kappa test showed that the diagnostic model’s evaluation of the aortic arch was consistent with the postnatal outcome of the aortic arch (kappa value 0.936, P = 0.0001), whereas the accurate diagnosis rate from the two experienced doctors (H.M; L.Z.L.) was approximately 77%.

Four neonatal deaths occurred among the 154 cases due to duodenal atresia (1.3%, 2/154), cerebral anomalies (0.65%, 1/154), and premature birth (0.65%, 1/154). Among the 47 children with postnatally confirmed CoA, 22 children underwent arch correction surgeries, including 15 in the neonatal period and 7 in childhood. Among the 107 children with a normal arch postnatally, six underwent VSD repairs, and one underwent ductus arteriosus ligation. No postoperative deaths occurred. Their echocardiographic and clinical follow-up findings, growth, and development were normal.

Fetal prediction of postnatal CoA continues to be a challenge. Although several echocardiographic indices are used to diagnose fetal CoA, no single parameter has good diagnostic accuracy [9, 10]. In this retrospective study, we validated that postnatal CoA can be predicted with a high degree of accuracy using a three-step echocardiographic diagnostic model.

Step One

Previous studies demonstrated that a tortuous and rigid aortic arch is the most intuitive sign of CoA diagnosis in children. Some researchers have used the TAO-DAO angle to digitally evaluate the arch contour rather than relying on the operator’s subjective evaluation. Drs. Arya [3] and Freeman [11] defined one angle between the ascending and descending aorta (≤ 20.31°) and another angle between the transverse and descending aorta (≥ 96.15°) to detect fetal CoA. These two measurements could not be obtained if the aortic arch was too tortuous or if no standard view of the entire aortic arch was present. So they suggested combining the distance between the LCCA-to-LSA and Z-score of the ascending aorta to decrease the rate of misdiagnosis.

Coarctation occurs mostly at the isthmus, so a change in the angle due to a tortuous or rigid lumen is most likely to occur at this point, which may explain why the TAO-DAO angle between the transverse arch and isthmus in our study was found to be the best index to judge the shape of the arch, as it had the largest AUC (0.95) and the best sensitivity and specificity (both 92%). Difficulty in clearly displaying the entire arch contour in one view may lead to incorrect measurements, which may explain why we found that some fetuses with confirmed CoA had a normal TAO-DAO angle or that a fetus with a postnatal normal arch had an abnormal TAO-DAO angle. We appointed the TAO-DAO angle as the most important index in the diagnostic model but still utilized the subsequent two steps to minimize errors in diagnosis.

Step Two

The diameter of the transverse arch was measured, and the Z-score of the isthmus was calculated. In agreement with published data [9, 12], we found that the presence of a hypoplastic aortic arch had a good diagnostic performance in detecting CoA. Considering that a 0.5 mm difference in the isthmus diameter may result in a Z-score of − 2 instead of − 1, we proposed that the Z-score of the isthmus, instead of the absolute data, should be used to increase the diagnostic sensitivity to 92.5%, while concurrently using the transverse arch diameter to improve the specificity to 89.4%. The two indices used together would balance any false negative and false positive rates. Gómez-Montes [7] proposed the cut-off value of the Z-score of the isthmus to be ≤ -2 when measured in 3VT view, which is larger than our data. In our study, the measurement of the isthmus had to be taken at the insertion of the PDA in the sagittal and coronary views or proximal to the orifice of the LSA in the long axis view, and the cut-off value was ≤ -7.5. We hold that a strict protocol is more suitable for clear display and standard measurements, facilitating diagnostic accuracy.

The first three indices used in steps 1 and 2, representing the arch contour and dimension, could differentiate the cases of true narrowing from those of suspected CoA most of the time. When all of these indices were abnormal, the diagnosis of fetal CoA was supported, and conversely, when all of these indices were within the normal range, a postnatal normal arch was predicted.

Step Three

When the two-step measurements were completed, the diagosis of CoA was still undetermined in about 25% fetus. So the following five indices should be added to improve the diagnostic accuracy further.

The distance from the LCCA to the LSA is always increased in patients with CoA, which is theorized to be secondary to a stretch in the contour of the transverse arch [13]. Therefore, we measured the distances and calculated the ratio. Since the distance from the LCCA to the LSA and the ratio of the distances had a high specificity of 86%, they could reduce the false positive rate and provide an indirect evaluation of the arch contour.
The aortic arch was further assessed using the Z-score of the transverse arch and the diameter of the isthmus [14]. The two indices compensated for the contradictory judgment in step 2. A reduced Z-score of the transverse arch would strongly support the diagnosis of fetal CoA. If isthmus stenosis is associated with transverse arch narrowing or dysplasia, arch repair surgery should be considered in neonates.
Prior studies have indicated that the diameter of the isthmus should be smaller than that of the LSA in fetal CoA [15]. Therefore, the isthmus-to-LSA ratio is considered an important clue to the diagnosis of fetal CoA, which was confirmed in this study. However, the isthmus-to-LSA ratio had a lowest specificity (41%). Therefore, the isthmus-to-LSA ratio may suggest CoA, but it is not specific enough to independently diagnose CoA. The diagnosis must be made in conjunction with more specific indices.

Dr. Dodge-Khatami [13] first defined the carotid-subclavian artery index as the ratio of the isthmus diameter to the distance between the LCCA and LSA. They found that this parameter had high sensitivity and specificity for detecting fetal CoA [16]. In this study, the isthmus diameter and the distance between the LCCA and LSA were also assessed in this step separately.

We found that the arterial duct often appears as a tortuous aneurysm in CoA, especially in the third trimester. The tortuous arterial duct is often mistaken for the aortic arch, resulting in both a missed diagnosis and misdiagnosis. Therefore, a key point of prenatal echocardiography is to clearly show the isthmus where the LSA originates or the arterial duct inserts. In future research, three-dimensional printing may be used to visualize these structures directly, especially when it is difficult to obtain a clear view of the arch due to operator skills and the overlap of the aortic and ductal arches. An ideal next step would be to create a prospective multicenter registry of suspected CoA fetuses to validate this model.

Limitation

The proposed algorithm has not been tested in more patients. In the future, the algorithm based on our retrospective study requires to be shown the actual sensitivity and specificity of the fetal CoA diagnosis.

In conclusion, the three-step echocardiographic diagnostic model starts with a measurement of the aortic TAO-DAO angle, followed by measurements of the transverse arch and isthmus, and finally incorporates additional indices to maximize the sensitivity and specificity of the CoA diagnosis. The algorithm is clinically feasible.

CoA

Coarctation of the aorta

PDA

Patent ductus arteriosus

CHD

Congenital heart defect

Computed tomography

Right ventricular

RVEDD

Right ventricular end diastolic dimension

RVEDA

Right ventricular end diastolic area

Left ventricular

LVEDD

Left ventricular end diastolic dimension

LVEDA

Left ventricular end diastolic area

Mitral valve

Tricuspid valve

Aortic valve

Pulmonary valve

Aortic artery

Pulmonary artery

3VT

Three vessels and trachea view

LSA

Left subclavian artery

LCCA

Left common carotid artery

RIA

Right innominate artery

ROC

Receiver operating characteristic

AUC

Area under the curve

Confidence interval

VSD

Ventricular septal defects

PLSVC

Persistent left superior venae cavae.

Acknowledgements

Not applicable.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Authors’ contributions

HM designed the study, performed the echocardiographic examinations, collected and analyzed the data, and drafted the manuscript. Z-L L performed echocardiographic examinations. YS and Q-QL followed up the patients. M-Z L and Y-M G collected the clinical data. All authors read and approved the final manuscript.

Funding

Yunnan Provincial Cardiovascular Disease Clinical Medical Center Project (No. FZX2019-06-01 2022YFKY085)

Declarations

Ethics approval and consent to participate

The study was approved by the institutional review board of Fuwai Hospital (November 5, 2020, Ethics approval number: 2020-063) and performed in accordance with the Declaration of Helsinki. All parents enrolled in our study had signed a consent form. Details related to subjects’ identity were omitted.

Consent for publication

Subjects signed informed consents regarding publishing their data.

Competing interests

The authors declare no competing interests.

Author details

^1.Department of Echocardiography, Fuwai Hospital National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, China

^2.Department of Echocardiography, Fuwai Yunnan Cardiovascular Hospital Kunming, China

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Tables 1 and 2 are available in the Supplementary Files section.

No competing interests reported.

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Accurate Prenatal Diagnosis of Coarctation of the Aorta by Three-step Echocardiographic Diagnostic Model

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