Knowledge of the occurrence and etiology of congenital defects is essential to improvements in diagnosis, management, and genetic counseling. Congenital cardiovascular disease refers to structural abnormalities of the heart or intrathoracic great vessels that impact the function of the cardiovascular system. This chapter summarizes current knowledge regarding epidemiology and etiology of congenital cardiovascular disease. Information regarding the etiology of inherited cardiomyopathies and arrhythmias is presented in Chapters 9 and 10, respectively.

Epidemiologic studies seek to measure disease frequency and to establish associations between disease states and a multitude of other variables, such as cardiovascular defects and maternal diabetes. These observational studies establish statistical associations—but not causality—that are useful for (1) developing diagnostic screening studies, (2) defining heritability and recurrence risk, (3) evaluating the contribution of candidate genes identified in high-risk families or experimental models to disease in the general population, (4) characterizing environmental risk factors, (5) developing testable hypotheses regarding etiology and pathogenesis, and (6) planning for effective delivery of health care services.

All epidemiologic studies begin with measures of disease frequency (ie, how often a disease is found). The two most common measures are prevalence and incidence:

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  Prevalence is the proportion of the population at risk affected by disease at a given point in time. Prevalence excludes those who have already died from the disease, those in whom the disease has been cured or has spontaneously resolved, and those with undetected disease. Prevalence answers the question, “How many people have this disease in this place, at this time?”

  
  
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  Incidence is expressed as a rate and is defined as the number of new cases among those at risk within a population over a certain period of time. Incidence answers the question, “How often does this disease occur?” For congenital cardiovascular disease, the total population at risk includes all embryos. However, even with advances in fetal echocardiography, the true incidence of congenital cardiovascular disease is difficult to measure. Cardiovascular defects are associated with spontaneous abortion, elective pregnancy termination, and stillbirth so that many of those embryos are never known to have cardiovascular disease. Congenital cardiovascular disease is estimated to occur in about 15% of fetuses that have been spontaneously aborted and in about 8% of stillborn infants. Based on these estimates, it is likely that the true incidence of congenital cardiovascular disease is much greater than that reported in studies of the incidence of congenital cardiovascular disease at birth. Although incidence at birth is most frequently reported and is probably the most useful concept for the clinician, this figure must be interpreted with caution because the entire population with congenital cardiovascular disease is not considered.

  
  
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  Counting congenital cardiovascular disease cases after birth depends on the accurate detection of persons with various cardiac defects, and the accuracy of detection depends on the method used. No one method is completely accurate. Some studies have relied on data from medical records and birth/death certificates, which are known to be inaccurate. Others have relied on physical examination alone, in which case the training and skill of the examiner will certainly affect the results. More recently, some investigators have included results of echocardiograms, cardiac catheterizations, cardiac surgeries, and autopsies to increase diagnostic accuracy.

Once a case of congenital cardiovascular disease has been identified, the method of naming and classifying the defects will affect the results of epidemiologic studies. Classifying defects based on developmental mechanisms may reveal important pathophysiologic relationships among heterogeneous lesions. Unfortunately, no universally agreed-on nomenclature and classification scheme exists. It is difficult, if not impossible, to compare results from studies that have used different systems. For example, the same infant with pulmonary stenosis, a ventricular septal defect, and a malaligned ventricular septum may be classified as having tetralogy of Fallot or as having double-outlet right ventricle with pulmonary stenosis. This will affect the relative proportion of patients having each of these defects. Currently, international collaborations of clinicians are working to develop consensus-based nomenclature and classification systems and to map defects across different existing systems.

Difficulties in calculating prevalence also result from determining the denominator, or reference, population. Characterizing an entire population at risk for developing congenital cardiovascular disease is quite difficult, so a representative sample or subgroup is often selected. The process of selection must ensure that bias is not introduced. For example, studying only patients seen at a tertiary care center will be biased toward patients with more serious conditions.

Multiple studies have been published reporting the birth incidence of congenital cardiovascular disease. The overall incidence ranges from about 2 to 20 cases per 1000 live births and depends largely on the number of trivial lesions included. In general, the incidence is 3 per 1000 for clinically severe conditions that require surgical or catheter intervention, excluding atrial septal defects and noncritical coarctation. The incidence of less severe defects (atrial septal defect, mild to moderate aortic stenosis/insufficiency, moderate pulmonic stenosis or insufficiency, complicated but not large ventricular septal defects) is another 3 per 1000. The reported incidence increases to a total of 9 to 20 per 1000 when minor conditions, such as small septal defects and mild pulmonic stenosis, are included. Of note, this does not include isolated bicuspid aortic valve, which has an estimated incidence of 9 to 14 per 1000.

Attempts have also been made to define the birth incidence of individual cardiovascular defects. As noted above, these efforts have been hampered by the lack of a uniform naming and classification scheme. The results also are affected by whether patients with chromosomal abnormalities such as trisomy 21 and other important noncardiac defects are included. Multiple studies have shown that the prevalence of ventricular septal defect has increased as a result of detection of tiny defects by color Doppler imaging. Indeed, differences in the relative frequency and prevalence of various defects in more recent studies are driven primarily by inclusion of minor conditions, such as small septal defects and mild valve stenosis, that are detected by echocardiographic examination. A decline noted in the incidence of hypoplastic left heart syndrome may be the result of an increase in therapeutic pregnancy terminations or direct referral of prenatally detected cases to a surgical center outside of the study area. Prevalence data for specific defects from a large study that used the Society of Thoracic Surgeons nomenclature and classification system are shown in Table 15-1.

Genetic Factors

Epidemiologic data indicate that genetic factors play an important role in the pathogenesis of congenital cardiovascular defects. First, several studies have shown that the relative risk for any defect in first-degree relatives is >3. Second, parental consanguinity significantly increases the risk of congenital cardiovascular defects. Third, rare families have been reported that show similar defects in multiple members across two or more generations. Finally, specific congenital cardiovascular defects are associated with specific chromosomal syndromes, such as atrioventricular septal defect in patients with trisomy 21.

The search for genetic alterations contributing to congenital cardiovascular disease either as part of a syndrome or in isolation has progressed rapidly over the past decade. These efforts have been aided by advances in molecular genetic techniques (Table 15-2). Beginning in the 1980s, classical linkage analyses identified congenital cardiovascular defect loci in rare families with multiple affected members; sequence analyses of candidate genes or those identified by positional cloning identified disease-related mutations. Rapidly improving sequencing techniques that allow detection of smaller chromosomal deletions and duplications as well as automated sequencing and mutation detection have accelerated these efforts. Other techniques, such as genomewide association studies and whole-genome and exome sequencing, are also contributing to our knowledge of disease-associated novel genetic abnormalities.

Many of the disease-causing mutations are thought to directly or indirectly impact cardiac developmental genes or related signaling molecules. The list of genetic abnormalities contributing to congenital cardiovascular disease continues to grow quickly. Clinicians are advised to consult the gene tests website (http://www.genetests.org) for updates on currently available testing. Specific chromosomal abnormalities (Table 15-3) and single-gene disorders (Table 15-4) associated with syndromic congenital cardiovascular disease have been described. The specific genetic abnormality has not been identified for other examples of syndromic congenital cardiovascular disease (Table 15-5). Additionally, the genetic etiology of some nonsyndromic defects has also been described (Chapter 1), but this accounts for a small minority of cases.