Abstract
Background
Congenital heart disease (CHD) is a major cause of morbidity and mortality in patients with Down syndrome.
Objectives
The objective of this study is to identify the prevalence of abnormal aortic arch dimensions in patients with Down syndrome.
Methods
This was a retrospective chart review of patients with Down syndrome who were born at Jackson Health System over a 14-year period. The initial neonatal echocardiograms were reviewed for presence of CHD along with the dimensions of aortic annulus, distal transverse arch, and aortic isthmus, and then compared with age and sex matched cohorts.
Results
A total of 138 patients were included in this study. The overall prevalence of congenital heart disease in our cohort was 70.7 % ( n = 97). Among those identified, the most common CHDs were ventricular septal defect (VSD) (23.2 %), atrial septal defect (ASD) (24.6 %), and atrioventricular septal defect (AVSD) (34.8 %) Fourteen patients (10.1 %) had aortic isthmus hypoplasia and 9 (6.5 %) had hypoplasia of the distal transverse arch.
Conclusion
Mild aortic arch hypoplasia without coarctation is found in 13.8 % of patients with Down syndrome. Specific nomograms may be necessary for measuring aortic arch dimensions in patients with Trisomy 21.
Highlights
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Mild aortic arch hypoplasia without coarctation is frequently seen in patients with Trisomy 21.
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Presence of a co-existing congenital heart disease increases the risk of aortic arch hypoplasia in this sub-group.
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Traditional references for aortic arch dimensions may over-estimate the incidence of coarctation.
1
Introduction
Down syndrome, with an incidence of 1 in 700 live births, is the most common chromosomal abnormality [ ]. Over the last few decades, there has been a steady rise in the number of infants born with Down syndrome, with an estimated 30 % increase between 1979 and 2003 [ ]. In patients with Down syndrome, morbidity and mortality are strongly correlated to the presence of congenital heart disease (CHD). CHD is known to occur in approximately 50 % of the infants born with Down syndrome. Presence of CHD has been shown to significantly increase mortality in infancy by nearly 5-fold, and it continues to be the most significant predictor of mortality through age 20 [ ].
Among the various CHDs, atrioventricular septal defect (AVSD), ventricular septal defect (VSD), and atrial septal defect (ASD) are the most common forms in patients with Down syndrome [ ]. Coarctation of the aorta and clinically significant aortic arch abnormalities is comparatively less common and seen in 1 % to 4.8 % of patients with Down syndrome [ ]. A recent study by Bergstrom et al. conducted among 2588 singleton live-born infants with Down syndrome describes the prevalence of aortic arch anomalies at 3.5 % [ ]. In contrast to the low prevalence of clinically significant aortic arch anomalies in postnatal life, patients with Down syndrome have an increased prevalence of narrowing of the aortic arch in fetal life [ ]. Interestingly, the degree of narrowing of the aortic isthmus has been shown to be associated with higher nuchal translucency thickness [ ]. The pathophysiological basis of aortic arch anomalies in Down syndrome is poorly understood.
There is limited data available on aortic arch dimensions in neonates with Down syndrome. The clinical significance of aortic arch anomalies and their relationship with the presence of other significant CHD in patients with Down syndrome is also unclear. We have observed anecdotally that infants with Down syndrome appear to have a higher likelihood of smaller aortic arch dimensions. Given the lower overall prevalence of coarctation of the aorta in this population, it is often challenging for cardiologists to determine the clinical relevance of smaller aortic dimensions and more importantly to predict the group of patients who will be prostaglandin dependent. We hypothesize that patients with Down syndrome have a higher likelihood of having smaller aortic arch dimensions when measured by standard Boston Children’s Hospital nomograms, in absence of hemodynamically significant aortic coarctation. Therefore, the primary aim of this study is to describe the prevalence of significant narrowing of the aortic arch (Z score of <−2.0) in patients with Down syndrome. The secondary aim is to identify any relationship of arch hypoplasia with other CHD.
2
Materials and methods
2.1
Study population
This was a retrospective chart review of patients with Down syndrome who were born in the Jackson Health System, affiliated with the University of Miami, Miller School of Medicine in Miami, Florida, between January 2005 and December 2018. This review was approved by the Institutional Review Board of Human Subjects Research at the University of Miami and Holtz Children’s Hospital. Patients with genetically confirmed Down syndrome were included in this study. Those with established coarctation of the aorta or interrupted aortic arch requiring surgery were excluded from our study.
2.2
Data collection
Basic demographic data collected include gender, race, gestational age at birth, birth weight, and length, along with maternal age. Maternal charts were also reviewed to identify any fetal cardiac diagnosis. The cardiac diagnosis for the infant was reviewed from the initial transthoracic echocardiogram after birth. Any surgical or percutaneous cardiac intervention performed in this group prior to 1 year of age and overall infant mortality were also reviewed.
Linear measurements of the aortic isthmus were obtained in the suprasternal long axis view of the aortic arch, immediately distal to the origin of the left subclavian artery at its greatest width during the cardiac cycle, usually at mid to end systole. If a patent ductus arteriosus was present, the aortic isthmus was measured just before the entry of the ductus arteriosus. The aortic annulus diameter was measured as the distance between the insertions of the two aortic valve leaflets seen in the parasternal long axis view. The distal transverse arch was measured midway between the origins of the left carotid and the left subclavian arteries in the suprasternal long axis view [ ]. Aortic arch hypoplasia was defined in our study as Z score of the distal aortic arch and/or aortic isthmus of <−2.0. In addition, a cohort of 15 consecutive patients whose original echocardiograms were not read by SS was selected. Aortic isthmus of these patients was independently measured by SS to assess for interobserver reliability.
2.3
Statistical analysis
Continuous variables were represented in the form of mean and standard deviation. Categorical variables were presented in the form of frequency distribution tables and percentages. The aortic annulus size, distal transverse arch, and the isthmus were measured in cm and were normalized to body surface area using Z scores extrapolated from Boston Children’s Hospital nomograms [ ]. The number of patients with aortic annulus, aortic isthmus, and distal transverse arch Z score <−2.0 was calculated. The total number of patients with abnormal aortic dimensions combining all three parameters was also calculated. Cross tabulation was performed to analyze the relationship between aortic dimensions and specific congenital heart disease. Pearson Chi square analysis was used as the test of significance and p < 0.05 was considered as statistically significant. Interobserver reliability was assessed using inter-class correlation coefficient (ICC), and a two-way mixed model was used for analysis. ICC below 0.5 indicates poor reliability, between 0.5 and 0.75 moderate reliability, between 0.75 and 0.9 good reliability, and any value above 0.9 indicates excellent reliability. SPSS v28.0 (IBM Corp, Armonk, NY) was used for statistical analysis.
3
Results
3.1
Demographics
A total of 140 patients with Down syndrome were born during the study period. During the 14 years of this study, 86,280 live births were documented in our institution. This constituted an incidence rate of 16.22 Down syndrome patients per 10,000 live births (1 in 616 live births). Two patients were excluded from our study as one of them had significant coarctation of the aorta, and the other had interrupted aortic arch, both requiring neonatal surgical intervention. Our study thus encompasses 138 consecutive patients with Down syndrome. The maternal age of the infants born with Down syndrome was 33.2 ± 5.7 (mean ± SD) years, with 61 (44.2 %) mothers whose age was >35 years. Among these infants, 68 were females (49.3 %). The study population included 13.8 % African Americans, 14.5 % Caucasians, and 31.1 % with mixed or unknown racial origin. 40.6 % of patients were of Hispanic ethnicity. The mean gestational age at birth was 37.5 ± 2.7 weeks. There were 29 patients (21 %) with gestational age < 37 weeks. The mean birthweight of the cohort was 2927.9 ± 783.3 g. Birth weight was <2500 g in 32 (23.2 %) patients. The length and body surface area of the newborns in this cohort were 47.6 cm ± 6.9 cm. and 0.19 ± 0.036 m 2 , respectively.
3.2
Prevalence of CHD
The overall prevalence of CHD in our cohort was 70.7 % ( n = 99). This included 34 with hemodynamically significant ASD (24.6 %), 32 with VSD (23.2 %), 48 with AVSD (34.8 %), and 25 with significant patent ductus arteriosus (18.1 %) ( Fig. 1 ). Only ASDs that needed catheter based or surgical intervention or persisted at an echocardiogram at or after 1 year of age and measuring >10 mm were classified as hemodynamically significant ASDs. Four patients with ASDs diagnosed at the newborn stage were lost to follow-up by this time, and might cause minor flaw in the results. The other less common CHDs included 4 with isolated cleft mitral valve (2.9 %), 5 with tetralogy of Fallot (3.6 %), and 2 with isolated bicuspid aortic valve without stenosis or insufficiency (1.4 %) ( Fig. 1 ). We defined significant PDA as those which subsequently required device (56 %, n = 14) or surgical closure (44 %, n = 11). Overall, at the time of the initial echocardiogram, 77.5 % ( n = 107) had PDA. Of these, 25 persisted to a clinically significant degree on follow up needing intervention. Prenatal diagnosis of CHD was available in 62 % of the cohort. At 1-year follow up, mortality was 4.3 % ( n = 6). Of these, 2 (1.4 %) were cardiac-related mortality.
3.2.1
Aortic arch dimensions
Aortic annulus size was available in 134 patients with the annulus diameter of 0.77 ± 0.13 cm. The Z score ranged from −2.28 to +2.68. There was 1 patient with a Z score of <−2 among the 134 patients (0.7 %). The distal transverse arch diameter was available in 138 patients. The mean diameter was 0.45 ± 0.12 cm. The Z score ranged from −2.74 to 4.36. There were 9 patients (6.5 %) with a Z score of less than −2. The aortic isthmus dimensions were available in 134 patients with mean diameter of 0.59 ± 0.49 cm. The Z score ranged from −3.09 to 1.80. There were 14 patients (10.1 %) with a Z score of <−2. Overall, there were 19 patients (13.8 %) who had aortic arch hypoplasia (hypoplasia of the distal arch and/or the isthmus) ( Table 1 ). The cohort of 15 consecutive patients whose aortic isthmus was independently measured by SS demonstrated excellent interobserver reliability with an ICC of 0.94.
