A combination of physical examination and ECG detects the majority of hemodynamically significant heart defects in neonates with Down syndrome

INTRODUCTION

Congenital heart defects (CHD) occur in 40–50% of children with Down syndrome [Rowe and Uchida, 1961; Stoll et al., 1990; Khoury and Erickson, 1992; Freeman et al., 1998], with atrioventricular (AV) canal (complete or partial) being the most common (38–60%). Other types of CHD include ventricular septal defects (VSDs), usually membranous (30%); secundum atrial septal defect (ASD) (10–20%); tetralogy of Fallot (TOF) (4–10%); and patent ductus arteriosus (PDA) (3–7%) [Rowe and Uchida, 1961; Ferencz et al., 1989; Khoury and Erickson, 1992; Pradat, 1992; Wells et al., 1994; Freeman et al., 1998]. Patients with complete AV canals do not have spontaneous resolution of the CHD and are operatively corrected usually in the first 6 months of life [Hanley et al., 1993]. Ninety-five percent of large VSDs (some membranous, all inlet or conoventricular) are operated on. Moderate VSDs are generally repaired at age 1 year if there is associated failure to thrive or recurrent lower respiratory infections. If a moderate VSD appears to be getting smaller, one can wait several years (up to age 5 years) to provide an opportunity to avoid surgery. ASDs that need surgery are typically operated on after 2 years of age. Surgical correction of the hemodynamically significant defects (complete AV canal, large and moderate VSD, TOF, ASD, and PDA that do not resolve by 1 year of age) decreases the mortality rate and enhances quality of life in these children [Baciewicz et al., 1989; Malec et al., 1999; Schaffer et al., 1999: Hartyanszky et al., 2000].

Echocardiography provides definitive imaging in most newborns with a CHD, including those with Down syndrome. The American Academy of Pediatrics (AAP) recommends that all newborns with Down syndrome undergo echocardiography [AAP, 1994]. The reasons for universal performance of echocardiography in these neonates are as follows. 1) Physical examination (PE) alone can miss 40–50% of CHD in neonates with Down syndrome [Tubman et al., 1991]. The newborn may be asymptomatic and clinical signs such as murmurs may not be evident, due to high pulmonary vascular resistance. 2) Chest radiography may not show changes suggestive of CHD in the newborn period [Tubman et al., 1991]. 3) A delay in diagnosis of an AV canal has an adverse impact upon prognosis, due to a high risk of irreversible pulmonary hypertension [Cooney and Thurlbeck, 1982; Clapp et al., 1990]. Surgical repair prior to 6 months of age minimizes this risk [Hanley et al., 1993; Malec et al., 1999]. 4) Definitive information regarding the presence or absence of CHD that is provided by echocardiography has important psychological implications for family members.

Conversely, with the advent of echocardiography, the ascertainment of CHD in neonates with Down syndrome is much better, with the incidence approaching 50% [Khoury and Erickson, 1992]. However, transient defects, such as a PDA and patent foramen ovale that may otherwise go undetected, are ascertained by neonatal echocardiography [Khoury and Erickson, 1992], necessitating a follow-up echocardiogram.

Although echocardiography remains the most sensitive method to diagnose CHD in Down syndrome, there is a need for an alternative method in situations where access to a pediatric cardiologist may be limited (geographically remote areas) and when financial constraints make echocardiography difficult. This alternative method can be used as a temporary measure to detect CHD when echocardiography is not immediately accessible. Surprisingly few studies have been performed to evaluate such an alternative approach [Tubman et al., 1991; Bhatia et al., 1992; Narchi, 1999]. These studies concluded that physical exam alone is insufficient in detection of CHD and the addition of an electrocardiogram (ECG) does not increase the sensitivity significantly, thus strengthening the view that echocardiography remains the best method to diagnose CHD in Down syndrome. However, it is evident from these studies that the positive predictive value of ECG was high (80–100% when data available). To further study the sensitivity and specificity of PE and ECG, we reviewed the cardiac evaluations of neonates with Down syndrome.

MATERIALS AND METHODS

Our medical center is the tertiary referral center for the central and northwestern parts of North Carolina, serving a population of 2 million. The majority of children with Down syndrome are seen at our medical center, most often in both the Genetics and Cardiology Clinics. All neonates (< 30 days of age) have a Doppler echocardiogram (performed or interpreted by a pediatric cardiologist) as part of their routine care. We performed a retrospective chart review on all patients seen with Down syndrome, from 1991 onward.

Those included in the study were less than a month (30 days) of age at the time of initial examination, with a confirmed diagnosis of Down syndrome by karyotype, with the cardiac examination performed by one of two clinical geneticists or one of four cardiologists. The physical examination had to have been performed prior to the ECG and the echocardiogram. Excluded were infants over 1 month (30 days) at the time of initial examination, those with insufficient information in the medical record, neonates with a prenatal echocardiogram, or those with an echocardiogram that was performed prior to PE and/or ECG. Also excluded were those whose cardiac examination had been performed by individuals other than those listed above.

A total of 287 charts were reviewed. With the above exclusions, 49 were deemed suitable for inclusion. The time between the PE and ECG and echocardiogram varied from the same day to a week later. The presence of at least one of the following physical examination findings was considered significant: an abnormal heart sound, a significant murmur, cyanosis, and findings suggestive of congestive heart failure. The data were analyzed to determine sensitivity, specificity, and positive predictive value.

RESULTS

Using echocardiography, a CHD was detected in 33 of the 49 cases (67%). There were eight patients with complete AV canal defects (24%), six with VSD (18%), three with secundum ASD (9%), three with PDA (9%), six with VSD and secundum ASD (18%), and seven with other combinations of CHD (22%), including two patients with coarctation of the aorta and an AV canal. Of these 33 patients, 20 had abnormal findings on PE: thus, the sensitivity of PE was 61%. The specificity of PE was 81% (three patients with false positive PE findings in the 16/33 with no CHD). Thirteen of the 33 had normal findings on PE (39%): 3/13 had minor (hemodynamically insignificant) CHD that would not require surgical intervention (Table I). The others (10/13) had hemodynamically significant CHD that would require close monitoring and probable surgery (Table II).

We then analyzed the ECG findings in the 13 patients that would have been missed on PE alone. In the patients with minor CHD (3/13) (Table I) the ECG was normal, and on follow-up echocardiogram, the lesions had resolved spontaneously. In those with hemodynamically significant CHD (10/13) (Table II), an ECG was available in six patients and was abnormal in all six (deviation of the axis and/or ventricular hypertrophy). In the other four cases no ECG was available, and thus for statistical purposes, we assumed that the ECG was normal (Table II). In CHD patients with an abnormal PE (20/33), the ECG was abnormal as well. In those who did not have CHD (16/49), the ECG was normal in all 15 patients where it was available. There was no case in which the ECG was falsely abnormal. The specificity of ECG was 100% (no false positives) and the positive predictive value was 1.0.

When PE was combined with ECG, the sensitivity rose to 78% (26/33) (calculated with the assumption that in the four cases in which it was not available the ECG may not have shown abnormalities). Had the ECG been available in those four cases, we speculate that the sensitivity would have been higher.

DISCUSSION

Early diagnosis of CHD in Down syndrome is important to prevent irreversible pulmonary hypertension in those with AV canal defects [Clapp et al., 1990; Hanley et al., 1993]. Additionally, the high frequency of CHD and the lack of symptoms and signs in the first few weeks of life have made echocardiography universal in neonates with Down syndrome. While this still remains the best approach, we set out to identify an alternative method for clinicians and families who may not have ready access to echocardiography.

Tubman et al. [1991] in a prospective study of 81 newborns with Down syndrome reported a sensitivity of 53% when PE alone was used to detect CHD. The specificity of PE was fairly high at 94%, indicating that the presence of abnormal findings on PE most often points to a CHD. A combination of PE, ECG, and chest radiography was analyzed and the combined sensitivity increased to 71%. The sensitivity of ECG alone was low at 41%, but the specificity was high, i.e., 100%. Of the lesions missed by the combined approach of PE, ECG, and radiography, two were AV canal defects. The others included a VSD, secundum ASD, and PDA. It is notable that two AV canal defects, the lesion that needs to be corrected prior to 6 months, were indeed missed by this approach, although the authors do not specify whether the AV canal defects were complete or partial. The limitation of this study was that there was a lag time period of up to a month between the PE in the newborn period (at birth or soon after) and the performance of the ECG, chest radiograph, and echocardiogram. This potentially could confound the correlation between the PE findings and other investigations. Bhatia et al. [1992] on a prospective analysis of 50 children with Down syndrome between the ages of 6 days and 2 years found that PE, ECG, and chest radiography in combination enabled detection of CHD in 86.4% of the patients. The defects missed by this approach were a closing VSD, a cleft mitral valve leaflet, and a bicuspid aortic valve. All complete AV canals were detected by the combined approach. However, it is worth noting that not all patients in this study were neonates. Older children are more likely to have signs and symptoms of CHD on PE. Rosenberg et al. [1994] in a study involving older children with Down syndrome (over 6 weeks of age) reported that a combination of PE and ECG detected all lesions that needed surgery: missed lesions were a PDA, a small ASD, and a cleft mitral valve. Again, it seems that in older children these findings would be expected. The latest study by Narchi [1999] was carried out in 37 neonates less than 48 hours of age with Down syndrome. The ECG was abnormal in all the neonates that had a complete AV canal (sensitivity, 100%; specificity, 100%; positive and negative predictive values of 100%) and normal in all those without CHD. Defects that were missed were one VSD, two TOF defects, and four secundum ASDs. The shortcoming of this study is that they do not correlate PE findings with the ECG or the echocardiogram. In addition, an echocardiogram was performed much later (6–12 months of age) in those that had a normal ECG in the first 48 hours of life. We speculate that in these infants another ECG at the time of echocardiography may have shown abnormalities. With the limitations as noted above, the previous studies demonstrate that ECG detects most cases of complete AV canal in Down syndrome, but may miss other lesions that may require surgery.

The most common ECG finding in a complete AV canal is a superior axis with S waves in leads I, II, III, and AVF. This finding is typically seen at birth and does not change subsequently, although other findings, such as ventricular hypertrophy, may develop with time. The mechanism responsible for the superior axis is the congenital displacement of the conduction pathways in the ventricles, and thus the superior axis is seen in at least 97% of complete AV canals at birth [Durrer et al., 1966; Feldt et al., 1970; Boineau et al., 1973; Goodman et al., 1974; Borkon et al., 1975; Feldt and Titus, 1976; Perloff et al., 1979]. Thus, it would appear that the absence of a superior axis in a newborn with Down syndrome would greatly reduce the likelihood of a complete AV canal.

Our study focused on the utility of PE and ECG in the detection of CHD in neonates with Down syndrome. Our results are not indicative of the actual incidence or pattern of CHD in Down syndrome, since this is a retrospective study that excluded a number of children with and without CHD, resulting in ascertainment bias. As previous studies have shown, we found that PE alone was of limited value, with a sensitivity of 61%. When ECG was added, the sensitivity increased to 78%, although we speculate that it would have been higher had we had ECG data for the four patients with significant CHD that had normal PE findings. It is notable that the ECG was very specific (100%), with no false positives. In all the AV canal defects where an ECG was available, a superior axis was evident. We would expect that major defects missed initially would likely be diagnosed by subsequent PE and ECG. The three patients with CHD missed by both ECG and PE had minor defects that would not require surgical intervention, with subsequent resolution on a follow-up echocardiogram. However, these children would have required bacterial endocarditis prophylaxis if they had undergone dental/urogenital/gastrointestinal surgery prior to the spontaneous resolution.

The combination of PE and ECG may be a useful alternative to echocardiography when the latter is not readily available, in geographically remote areas or when there are financial restrictions (such as an inability to afford the test) to obtaining an echocardiogram. These constraints may be especially relevant in the developing world. Most complete AV canals (the most frequent and the ones that should be detected early) would be diagnosable by this approach. Immediately life-threatening lesions, such as coarctation of the aorta (1%) and transposition of the great arteries that present with signs and symptoms early in neonatal life, are uncommon in Down syndrome [Marino, 1993; Freeman et al., 1998], but there is a small risk that these could be missed by this approach. Neonates who have a normal PE and ECG should be brought back for follow-up in 3–4 weeks. It is rational to think that neonates with hemodynamically significant defects such as VSD or a complete AV canal that may have been missed would show symptoms/signs and may have developed ECG abnormalities in the interim. If chamber enlargement is detected, an echocardiogram could be arranged. This approach can also be used as an interim measure prior to discharging a neonate with Down syndrome from the nursery. An echocardiogram could be arranged for at a later date as an outpatient. Parental education regarding signs and symptoms that would warrant seeing their physician would be essential. The disadvantage would be parental and physician anxiety, since the PE and ECG are not definitive in excluding CHD.

Based on our results, we conclude the following. 1) PE alone is insufficient in the diagnosis of CHD in neonates with Down syndrome. 2) The use of ECG as an adjunct to PE will detect the majority of AV canal defects in the newborn period. The two in combination will increase the detection rate of other hemodynamically significant CHD. This approach would be cost effective in circumstances of financial constraint. 3) A subsequent ECG may detect hemodynamically significant heart defects missed earlier. 4) Lesions that are minor but may require bacterial prophylaxis will be missed by this approach. We advocate this alternative approach as a temporary measure, when echocardiography is not readily available. Further prospective studies that would determine the sensitivity and specificity of this approach would help in clarifying this issue.