Background
Diagnosing coarctation of the aorta (CoA) in the presence of a patent ductus arteriosus (PDA) may require observation until PDA closure. The aim of this study was to create a model incorporating previously published indices to estimate the probability of neonatal CoA in the presence of a PDA.
Methods
A retrospective “investigation” cohort of 80 neonates was divided into two groups: (1) neonates with PDA and suspicion for CoA requiring observation to confirm the presence or absence of CoA and (2) neonates with PDA and confirmed diagnosis of either CoA or unobstructed aortic arch. Multivariate logistic regression was used to create the coarctation probability model (CPM), which was used to calculate a neonate’s probability of CoA. The CPM was validated internally using bootstrapping and subsequently validated prospectively using a “validation” cohort of 74 neonates with PDA.
Results
The CPM had an area under the receiver operating characteristic curve of 0.96 and demonstrated good clinical significance in the risk stratification of neonates with PDA and CoA. No neonate with a CPM probability of <15% had CoA after PDA closure. Neonates with CPM probability < 15% were classified at low risk, between 15% and 60% at moderate risk, and >60% at high risk for CoA.
Conclusions
On the basis of these results, the authors recommend measurement of the CPM in all neonates with PDA. Those with CPM probability < 15% no longer require observation, which could decrease observation in as many as half of neonates with unobstructed aortic arches; those with CPM probabilities between 15% and 60% require follow-up imaging, while those with CPM probabilities > 60% should be observed as inpatients until PDA closure.
Coarctation of the aorta (CoA) is a common congenital heart defect characterized by aortic arch obstruction, typically at the insertion point of the ductus arteriosus. Failure to diagnose CoA promptly can lead to heart failure, shock, and death. Echocardiography is the primary imaging modality used to diagnose CoA. Although the diagnosis is more difficult in neonates with patent ductus arteriosus (PDA), findings such as an elevated descending aortic velocity, a posterior shelf, or a markedly hypoplastic transverse arch can still help make the diagnosis. Once the diagnosis is reached in a neonate, prostaglandin E 1 (PGE) can be administered to reopen or enlarge the PDA and alleviate the obstruction before surgical repair.
Because a PDA can normalize the descending aortic Doppler velocity and aortic arch diameters, a subset of neonates with CoA and PDA have more subtle findings that are unmasked only after PDA closure. Although these findings are subtle, the resultant aortic arch obstruction is no less critical. These neonates require close observation in the neonatal intensive care unit (NICU) without PGE to determine whether they have CoA. For the purposes of this study, we term this subset of neonates “equivocal.” Neonates in the equivocal category who ultimately have CoA but are discharged home before PDA closure may present in shock or even die at home. Those equivocal neonates who do not develop CoA can require extended stays in the NICU that increase health care costs and familial stress.
Several echocardiographic indices have been developed to help diagnose CoA. These include the carotid artery–to–distal transverse arch (CA/DT) index, the carotid artery–to–subclavian artery (CSA) index, and the isthmus–to–descending aorta (I/D) index. The CA/DT index is the diameter of the common carotid artery (left common carotid artery in a left arch and right common carotid artery in a right arch) divided by the diameter of the distal transverse arch ( Figure 1 A). The CSA index is defined as the distal transverse arch diameter divided by the distance from the common carotid artery (left common carotid artery in a left arch and right common carotid artery in a right arch) to the subclavian artery (left subclavian artery in a left arch and right subclavian artery in a right arch) ( Figure 1 B). The I/D index is defined as the diameter of the aortic isthmus divided by the diameter of the descending aorta ( Figure 1 C). Although these indices have demonstrated some success in diagnosing CoA in children of varying ages, none of these indices has been validated in a population of equivocal infants requiring observation without PGE.
The goal of this study was to create a noninvasive measure to help diagnose or rule out CoA in equivocal neonates requiring observation without PGE. A logistic regression model, termed the coarctation probability model (CPM), was created by incorporating the CA/DT, CSA, and I/D indices into a more comprehensive tool for diagnosis of neonatal CoA. The CPM was created using a retrospective cohort of neonates with PDA (investigation cohort) and then validated using a prospective cohort of neonates with PDA (validation cohort).
Methods
Overview
This study was approved by the Vanderbilt University Medical Center Institutional Review Board. All neonates included in the study were evaluated at Vanderbilt from 2005 to 2011. The investigation cohort was retrospectively analyzed (May 2005 to March 2010) to develop the logistic regression model, or CPM; the CPM was externally validated using the prospective validation cohort (May 2011 to November 2011).
Investigation Cohort
The investigation cohort was identified by searching the echocardiographic database and consisted of 80 neonates (<1 month of age) with PDA. On the basis of review of medical records, neonates with gestational age < 34 weeks, major extracardiac abnormalities, and complex congenital heart disease were excluded. This cohort was divided into two groups ( Figure 2 A): equivocal and control.
The equivocal group consisted of neonates with echocardiographic features suggestive of CoA observed in the NICU without PGE. These neonates were observed during closure of the ductus arteriosus until they could be classified as either having CoA or unobstructed aortic arch.
The control group consisted of neonates with a PDA, classified as having either CoA or unobstructed aortic arch on initial echocardiogram. Neonates in the control group did not require observation during closure of the ductus arteriosus.
CoA was defined as an aortic arch obstruction requiring surgical intervention. Diagnosis of CoA in the investigation cohort was based on clinical assessment, including presentation with shock, abnormal femoral pulses, abnormal four-extremity blood pressures, significant arch hypoplasia by two-dimensional echocardiography, and/or increased descending aortic velocity by pulsed-wave Doppler. All had operative confirmation of significant arch hypoplasia. All had retrospective, blinded review of echocardiographic images by experienced investigators (J.H.S. and D.A.P.) confirming CoA.
An unobstructed aortic arch was defined as no clinical or echocardiographic evidence of CoA after complete closure of the ductus arteriosus. All neonates in the equivocal and control groups who were classified as having unobstructed aortic arches underwent follow-up echocardiography confirming this diagnosis after closure of the ductus arteriosus.
Neonates with inadequate echocardiographic image quality were removed from the study. Of the 88 neonates who met the inclusion criteria, eight were removed because of inadequate image quality, leaving a total of 80 neonates in the investigation cohort ( Figure 2 A).
Data Collection
Four echocardiographers, blinded to clinical outcomes, reviewed the deidentified echocardiographic images from the investigation cohort. Images consisted exclusively of two-dimensional and color Doppler views of the aortic arch obtained from the suprasternal notch. From these images, the measurements labeled in Figure 1 were performed. In addition, the echocardiographers qualitatively estimated the presence or absence of CoA in each neonate solely on the basis of two-dimensional and color Doppler imaging.
Statistical Analysis
Descriptive statistics are presented as median (interquartile range) or percentage (number) as appropriate. Continuous variables were compared using Wilcoxon’s test and dichotomous variables using Pearson’s test. Agreement on arch measurements among the four echocardiographers was assessed with intraclass correlation coefficients.
We fit a logistic regression model, or CPM, to estimate the probability of CoA, incorporating the CA/DT, CSA, and I/D indices. These indices include five aortic arch measurements: carotid artery diameter, distal transverse arch diameter, distance from the left common carotid artery to the left subclavian artery, isthmus diameter, and descending aortic diameter ( Figure 1 ). The nonlinear terms of the three indices were tested as a group and were removed if the result was nonsignificant. The CPM was internally validated and calibrated using the bootstrapping technique. Descriptive statistics were used to compare CPM results with the qualitative analysis by echocardiographers. All analyses were done using the statistical programming language R version 2.14.1 (R Development Core Team, Vienna, Austria). The level of statistical significance was set at P < .05. Study data were collected and managed using Research Electronic Data Capture electronic data capture tools hosted at Vanderbilt.
Validation Cohort
The validation cohort consisted of prospectively collected aortic arch measurements used to validate the CPM ( Figure 2 B). Neonates with PDA who underwent echocardiography between May and November 2011 were included in this cohort. Neonates with hypoplastic left heart syndrome were excluded because retrograde flow in the aortic arch might lead to anatomic differences that invalidate the CPM. Echocardiographers in our institution were trained to perform aortic arch measurements for the three indices described in Figure 1 . These trained echocardiographers prospectively performed offline measurements in neonates with PDA over a 6-month period (May 2011 to November 2011). During that time period, 146 neonates met the inclusion criteria; a full set of arch measurements was performed in 74 neonates. In these neonates, the CPM was not used for clinical decision making. At the conclusion of the 6-month period, investigators collected demographic data and measurements for all neonates in the validation cohort. Neonates with CoA in the validation cohort were diagnosed on the basis of clinical assessment, and this diagnosis was confirmed by the surgeon at operative repair.
Results
Investigation Cohort
Demographics
Of the 80 neonates in the investigation cohort, there were 22 neonates in the equivocal group observed off PGE because of concerns for possible CoA and 58 control group neonates identified by the investigators as definitively having CoA or unobstructed aortic arches. Within the equivocal group, nine neonates had CoA and 13 had unobstructed aortic arches; in the control group, 33 neonates had CoA and 25 had unobstructed aortic arches. There were no significant differences in weight, gestational age, or race between the equivocal and control groups or between neonates with and without CoA ( Tables 1 and 2 ). Comparison of neonates with CoA in the equivocal and control groups demonstrated that neonates in the equivocal group had more preoperative echocardiograms (median, 5.1 vs 2.3; P < .001), longer times between initial echocardiography and surgery (median, 7.4 vs 3.8 days; P = .017), and longer preoperative hospital stays (median, 7.4 vs 4.1 days, P = .023). Associated congenital heart disease in these neonates is categorized in Tables 3 and 4 . In addition, 11 neonates had aortic arch branching abnormalities (13.8%): eight had brachiocephalic trunks (10%) and three had aberrant right subclavian arteries (2.5%). Fifteen neonates (18.8%) had prenatal concern for CoA. Of the 15 neonates with prenatal concern for CoA, nine (60%) were found to have CoA postnatally.
| Variable | No coarctation ( n = 38) | Coarctation ( n = 42) | P |
|---|---|---|---|
| Age at time of echocardiography (d) | 2.1 ± 3.8 | 7.6 ± 23.3 | .018 |
| Gender | .85 | ||
| Male | 53% | 55% | |
| Race | |||
| Caucasian | 67% | 84% | .32 |
| African American | 20% | 11% | |
| Hispanic | 10% | 5% | |
| Asian | 3% | 0% | |
| Height (cm) | 50.3 ± 4.2 | 49.8 ± 3.5 | .74 |
| Weight (kg) | 3.19 ± 0.66 | 3.07 ± 0.68 | .55 |
| Body surface area (m 2 ) | 0.202 ± 0.029 | 0.196 ± 0.027 | .50 |
| Body mass index (kg/m 2 ) | 12.5 ± 1.6 | 12.3 ± 1.8 | .66 |
| Gestational age (wk) | 37.9 ± 1.7 | 37.9 ± 1.8 | .73 |
| Variable | Equivocal ( n = 22) | Control ( n = 58) | P |
|---|---|---|---|
| Age at time of echocardiography (d) | 0.91 ± 1.38 | 6.52 ± 20.00 | .002 |
| Gender | .16 | ||
| Male | 41% | 59% | |
| Race | |||
| Caucasian | 74% | 78% | .85 |
| African American | 16% | 14% | |
| Hispanic | 11% | 6% | |
| Asian | 0% | 2% | |
| Height (cm) | 50.6 ± 3.6 | 49.9 ± 3.9 | .85 |
| Weight (kg) | 3.23 ± 0.65 | 3.09 ± 0.68 | .74 |
| Body surface area (m 2 ) | 0.204 ± 0.027 | 0.197 ± 0.028 | .66 |
| Body mass index (kg/m 2 ) | 12.5 ± 1.8 | 12.3 ± 1.7 | .68 |
| Gestational age (wk) | 38.6 ± 1.3 | 37.7 ± 1.8 | .066 |
| Variable | No coarctation ( n = 38) | Coarctation ( n = 42) | Total ( n = 80) |
|---|---|---|---|
| Congenital heart disease | 1 (2.6%) | 38 (90.5%) | 39 (48.8%) |
| Bicuspid aortic valve | 0 | 26 (61.9%) | 26 (32.5%) |
| Ventricular septal defect | 1 (2.6%) | 21 (50%) | 22 (27.5%) |
| Left superior vena cava | 0 | 6 (14.3%) | 6 (7.5%) |
| Aortic stenosis | 0 | 5 (11.9%) | 5 (6.3%) |
| Partial anomalous pulmonary venous return | 1 (2.6%) | 0 | 1 (1.3%) |
| Variable | Equivocal group ( n = 22) | Control group ( n = 58) | Total ( n = 80) |
|---|---|---|---|
| Congenital heart disease | 8 (36.4%) | 31 (53.4%) | 41 (51.2%) |
| Bicuspid aortic valve | 5 (22.7%) | 21 (36.2%) | 26 (32.9%) |
| Ventricular septal defect | 2 (9.1%) | 20 (34.5%) | 22 (27.5%) |
| Left superior vena cava | 0 | 5 (8.6%) | 5 (6.3%) |
| Aortic stenosis | 1 (4.5%) | 4 (6.9%) | 5 (6.3%) |
| Partial anomalous pulmonary venous return | 1 (4.5%) | 0 | 1 (1.3%) |
Individual Indices and Modeling
In the control group of neonates with definitive diagnoses of CoA or unobstructed arches, the CSA, I/D, and CA/DT indices were each statistically significant in predicting CoA ( P < .001). In the equivocal group of neonates who required observation in the NICU without PGE, the CSA and CA/DT indices were statistically significant in predicting CoA ( P = .006), whereas the I/D index did not reach statistical significance ( P = .209). However, despite this statistical significance, the CSA, I/D, and CA/DT indices exhibited significant overlap in both groups ( Figure 3 ), demonstrating poor clinical utility in discriminating between CoA and unobstructed aortic arch.
Using the investigation cohort, a multivariate logistic regression model, or CPM, was developed to estimate the probability of CoA. We selected the CA/DT, I/D, and CSA (DT/CA_SC) indices to be included in the model on the basis of clinical relevance; the odds ratios and 95% confidence intervals for each of the three predictors’ influence on the risk for CoA are presented in Table 5 . Among the three predictors, the CA/DT and I/D indices met statistical significance at an α level of 0.05. Higher CA/DT and lower I/D indices were associated with increased risk for CoA.
| Predictor ∗ | Odds ratio | 95% confidence interval | P |
|---|---|---|---|
| CA/DT index (0.1) | 3.48 | (1.57–7.74) | .002 |
| I/D index (0.1) | 0.38 | (0.15–0.97) | .042 |
| CSA (DT/CA_SC) index (0.1) | 0.94 | (0.86–1.03) | .193 |
∗ Odds ratios assess the effect of 0.1-unit changes in the CA/DT, I/D, and CSA (DT/CA_SC) indices on the odds of CoA.
We used bootstrapping to internally validate and calibrate the model. Figure 4 A depicts the model’s calibration curve, which plots the predicted versus observed values. The plot demonstrated minimal overfitting and good calibration. The CPM had a concordance statistic of 0.96 (95% confidence interval, 0.88–0.99; Figure 4 B). The equation for the model is probability = (1 + exp{−[−2.02 + (12.5)(CA/DT) − (9.8)(I/D) − (0.601)(DT/CA_SC)]}) −1 , where CA is carotid artery diameter, DT is distal transverse arch diameter, I is isthmus diameter, D is descending aortic diameter, and CA_SC is the distance from the left carotid artery to the left subclavian artery. Inserting each individual measurement into the CPM equation provides a probability (as a percentage) of that patient’s having CoA. Table 6 lists multiple cut points and the associated sensitivity and specificity. The CPM reliably differentiated between CoA and unobstructed aortic arch in the equivocal and control groups ( Figure 5 A).
