Introduction
Examination of the frequency of congenital cardiac disease, either as a rate or as a proportion, has important implications for the study of congenital cardiac malformations, as well as their clinical management. However, there is much confusion and misuse regarding terminology and methodology, with important implications for the accuracy, validity, and comparability of findings reported in the published literature. Knowledge of how critically to appraise these reports is important in defining their value when applied to issues of diagnostic likelihood, surveillance and trends, etiologic associations, burden of disease, and requirements for resources. These issues have more recently been impacted by fetal diagnosis and termination, with individual decisions influenced by contemporary estimates of prognosis related to the natural and modified natural history. As more patients survive into adulthood, estimates of the burden of disease, and the requirements for resources, have also achieved greater importance. Therefore the question of “how much congenital cardiac disease?” continues to evolve. Providing the correct answer has important relevance for both the providers of health care and the health care system itself.
Definitions
In considering and discussing the prevalence of congenital heart disease, key terms to be defined include congenital cardiac disease itself, frequency, ratio, proportion, rate, incidence, and prevalence.
Congenital Cardiac Disease
In examining reports of congenitally malformed hearts, it is important to know how the lesions were defined and what conditions were included or excluded. However, the definitions in Table 13.1 do not address all controversy. There is no current consensus as to whether several groups of lesions should be considered to represent congenital cardiac malformations because they do not manifest clinically until later in life. These conditions include genetic conditions, arrhythmic conditions, primary cardiomyopathies, and structural defects that do not have functional importance in many, but not all, circumstances. Considerations regarding the inclusion or exclusion of these lesions are important because these lesions are common and their inclusion might inflate a prevalence estimate. Comparability of previous reports has somewhat suffered from a lack of common nomenclature regarding the description and classification of congenital heart defects. To some extent, there has been important work in consolidating nomenclature toward an internationally accepted standard, which may facilitate future work.
| Term | Definition and Examples |
|---|---|
| Congenital cardiac disease | A gross structural abnormality of the heart or intrathoracic great vessels that is actually or potentially of functional significance. Excludes normal variants without functional consequence (e.g., persistent patency of the left superior caval vein, or abnormal patterns of branching of the systemic arteries). |
| Genetic conditions | Present from conception and may not have manifest cardiovascular consequences until much later in life (e.g., Marfan syndrome, Williams syndrome, and hypertrophic cardiomyopathy). |
| Arrhythmic conditions | Abnormalities at the physiologic or ultrastructural level that result in arrhythmias (e.g., long QT syndrome and ventricular preexcitation). |
| Primary cardiomyopathies | Myocardial structural abnormalities with a genetic or metabolic etiology (e.g., hypertrophic cardiomyopathy and ventricular noncompaction). |
| Structural defects with functional abnormalities only in some cases | Defects that do not have functional significance in many, but not all, circumstances or resolve without becoming clinically manifest (e.g., aortic valve with two leaflets, the prolapsing mitral valve, silent persistent patency of the arterial duct or small septal defects, included patency of the oval foramen). |
Ratios, Rates, and Proportions
Confusion and misuse regarding the terms incidence and prevalence are rooted in misunderstanding regarding what constitutes a ratio, a rate, and a proportion. These definitions are summarized in Table 13.2 .
| Term | Definition, Some Considerations, and Examples |
|---|---|
| Ratio | A relationship between two quantities where the numerator and a denominator are mutually exclusive (e.g., the ratio of males to females with transposed arterial trunks). |
| Proportion | The frequency of a condition or category within the population specified in the denominator independent of time (e.g., the proportion of muscular septal defects among all ventricular septal defects). |
| Rate | The frequency of occurrence of a condition that takes into account the time period over which the numerator was accumulated (e.g., the rate of the occurrence of a thrombotic episode in patients during their first year subsequent to the Fontan operation). |
| Kaplan-Meier estimates | The cumulative frequency of occurrence of a condition that reflects instantaneous changes in rates and risk over time and, unlike rate, does not assume that the condition occurs uniformly over the specified period of time (e.g., freedom from of a thrombotic episode in patients subsequent to the Fontan operation over 10-year period, showing maximal occurrence in first postoperative year). |
| Incidence | The rate of new occurrences of a condition over a specified period of time in a population at risk (e.g., new cases per year of Kawasaki disease per 100,000 children <5 years). |
| Prevalence | The proportion of preexisting and new occurrences of a condition identified in a population at risk, either at a single point in time or over a specified period (e.g., prevalence of congenital heart disease at birth amongst all live born individuals). |
| Denominator | Represents the population of interest or at risk over a defined time period and should be the first consideration when estimating the prevalence. |
| Numerator | Represents the number of cases of congenital heart disease that were identified from a population at risk over a defined period of time. |
| Ascertainment of cases | The completeness of identification of all the cases from the population at risk. This is a key aspect of appraisal of the numerator of prevalence estimates (e.g., active surveillance is better than nonmandatory reporting). |
| Verification of cases | The accuracy of definition or classification of all cases. The method of verification can affect the prevalence (e.g., clinical identification versus autopsy, angiography, and echocardiography). |
| Definition of cases | The specification and use of clear and standard definitions of congenital heart lesions described with accepted nomenclature. It is also important to consider which lesions were included and excluded. |
Incidence and Prevalence
Using the definitions in Table 13.2 , what many mistakenly refer to as the incidence of congenital cardiac disease is in reality the prevalence, consisting of the number of newborns who are subsequently confirmed to have congenitally malformed hearts as observed within a defined population of live born individuals over a specified time. However, incidence and rates are very relevant in the study of prognosis and the natural and modified natural history.
The prevalence at or for a variable period following live birth is important in defining the maximal burden of congenital cardiac disease in the population. The natural and modified natural history specific to certain defects and strategies for their management influence the changing prevalence in the population over time, with the numerator and denominator both decreasing due to deaths, and the numerator perhaps decreasing due to spontaneous resolution of some lesions. The absolute number and characteristics of patients at any given time point are important for defining the burden posed by disease, which is a key determinant in defining the requirements for resources. With the increasing survival of patients into adulthood, and their transition into the system of health care providing for adults, this number has taken on increasing importance, but its accurate estimation is fraught with numerous methodologic challenges.
Denominator
The definition of the denominator is a key piece of information because it characterizes the population to which the estimate of incidence or prevalence may be applied. Knowledge of the population characteristics is also necessary to evaluate similar populations to which the estimate might be extrapolated. The most valid denominators are ones that are enumerated during the time of ascertainment of the cases, which is best achieved by using a prospective cohort study design. However, such an approach is intensive in terms of both time and resources. Most estimates of prevalence use as their denominator the total number of live births occurring over a specified period of time derived from a geographically defined population.
A convenient and readily available denominator that is used frequently is the number of births reported to a governmental or administrative system of registration or vital statistics. If used, information regarding the completeness of ascertainment/reporting of births, usually through audits of the data, should be sought. Some registries will include stillbirths and fetal deaths, and this information should be clearly indicated. Registries of births usually collect additional information, specifically demographics of the birth parents, but may also include data regarding clinical diagnoses and characteristics present or evident at birth. Some estimates of prevalence will additionally rely on this information for ascertainment of cases. If so, then the validity and reliability of that data need to be carefully scrutinized.
Numerator
To evaluate the numerator of a prevalence estimate, one must know how the cases were identified and verified from the data source, what types of lesions were included and excluded, and what nomenclature and classification scheme was used.
Ascertainment of Cases
A comprehensive and active prospective surveillance of all sources of cases is likely to yield the most complete ascertainment because case ascertainment is a specific and planned endeavor. Most studies of this nature rely on clinical presentation or evaluation of a living subject as the initial entry point. The duration of follow-up for case ascertainment must be sufficiently long that all cases are identified, especially because some important congenital heart disease may not manifest very early in life.
Verification of Cases
Given the preceding discussion that most prevalence studies rely on a clinical diagnosis for the majority of case identification, verification or confirmation of the diagnosis is important. Earlier studies have included cases verified by autopsy, surgery, or cardiac catheterization, which may have limited ascertainment but assured verification. These prevalence estimates have been somewhat low and skewed toward more serious congenital heart lesions. Echocardiography has become the standard for the initial verification of cases and has proven to have a high sensitivity and specificity.
Sources of Data
Data sources regarding cases vary widely in the degree to which ascertainment was passive or active and the degree to which they accurately relate to a defined denominator. Knowledge of the details and limitations of these data sources is important for critical appraisal. The most complete data source would entail the active screening of a defined population-based cohort. A sensitive and accurate method of identification would be universally applied to all subjects included in the denominator. Clinical assessment by pediatric cardiologists has been shown to have sufficient though not perfect sensitivity and specificity for clinical detection, whereas assessments by other types of providers have fared less well. Echocardiography could then be applied more selectively for clinically suspected cases, to provide verification and specification.
Definition of Cases
Regardless of the data source used for case ascertainment, it must be clearly defined which specific lesions were included and excluded from the numerator. This predominately applies to lesions of minor or no functional consequence but which are very common, as discussed previously. The inclusion or exclusion of these types of lesions can have an important impact on inflating the prevalence estimate. In addition, the time period after live birth during which cases could be identified should be specified and reported. It should be clearly stated whether cases identified as still births and cases diagnosed by fetal assessment but either spontaneously or electively aborted are included or excluded.
Relevance
Estimates of incidence and prevalence, and the study of factors influencing them, have relevance to many aspects of congenital cardiac disease and its management. This is summarized in Fig. 13.1 .
Etiologic Associations
Accepting the caveats discussed earlier, knowledge of factors that are associated with variations in the prevalence of specific lesions, or groups of lesions, may suggest etiologic influences. These factors might then be used to target prenatal screening and counseling, or they might be amenable to intervention, resulting in the prevention of congenital cardiac disease.
Surveillance and Trends Over Time
Related somewhat to etiology, there is an ongoing interest in discovering trends in the prevalence of congenital cardiac disease. Ongoing surveillance is necessary to detect acute changes in prevalence that may be attributable to a specific etiology, such as occurred with the epidemic of birth defects associated with the use of thalidomide during pregnancy.
Likelihood of Diagnosis
Knowledge of the relative frequency of specific lesions can aid somewhat in formulating differential diagnoses and informing an index of suspicion.
Burden of Disease and Requirements for Resources
Disease involving the cardiovascular system continues to be the greatest contributor to infant mortality related to congenital malformations. However, trends have shown significant decreases in mortality and an increasing age at which death might occur. These factors increase the point prevalence of congenital cardiac disease at advancing ages and have created a growing population of adults with congenitally malformed hearts. Indeed, the population of adults living with congenital heart disease has likely exceeded that for children.
Critical Appraisal
Most studies that report estimates of prevalence are specifically designed to do so and have it as the primary aim of the study. Before accepting the results of these studies, it is important critically to appraise the methods and reporting, to determine if the findings are valid, reliable, and relevant. Critical appraisal is also required when one wishes to compare estimates arising from different studies, such as comparisons of trends over time or across different populations. Consideration must be given to all of the aspects by which the denominator and numerator are defined and derived and to the adequacy of reporting of the associated methods and results. In Box 13.1 , questions for which the answers should be evident when critically appraising a report regarding prevalence are noted.
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What was the stated purpose or aim of the study?
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How accurate and valid was the estimate reported?
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How accurate and valid was the definition and completeness of the numerator?
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What forms of congenital heart disease were included or excluded?
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What nomenclature and system of classification was used to describe and group cases?
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What were the methods by which cases were ascertained and reported?
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What was the overall design of the study and data collection?
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How were cases detected and reported from the population studied?
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What factors, particularly relating to the system for health care, may have influenced the ascertainment of cases? Specifically, did everyone in the population studied have equal access to health care and the referral center, and was screening and verification influenced by differences in quality and availability of expertise or technology?
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How were diagnoses confirmed or verified?
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How long was the follow-up, and was it sufficiently long to capture cases with later clinical manifestation?
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If a universal screening was applied, was it applied equally to the entire population at an early enough time point, was it sufficiently sensitive and specific, and was an assessment of verification performed?
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How accurate and valid was the definition and completeness of the denominator?
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What was the definition of the population studied?
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What were the sources of data used to derive the denominator, and were they valid and reliable?
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How accurately and completely does the population studied reflect the target population or population at large?
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Are the cases completed derived from the population studied as defined in the denominator? Were the cases and population characterized as part of the same study with the same methodology, as in a cohort study?
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How reliable is the estimate of prevalence estimate? Are confidence intervals provided?
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How does the estimate from the study compare with those reported from other studies with comparable methodology?
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Is the estimate applicable to your own clinical population? Is the population studied similar to your own clinical population in terms of setting, time, geography, and demographic characteristics? Is the estimate of prevalence relevant to your own clinical or research question?
Factors Influencing Estimates of Prevalence
Ideally, factors that might have a true causal relationship to the development of congenital cardiac disease and hence influence the true incidence should be identified. Identification of such factors may allow for the prevention of congenital cardiac disease or provide new knowledge as to etiology and development. The identification of these associations comes mainly from observational studies.
Environmental Factors
The most widely held belief is that congenital cardiac disease is the product of an interaction between genetic and environmental factors. However, evidence has yet to progress sufficiently far to prove this notion, although advances in the understanding of genetic underpinnings continue to increase. For example, recent studies have suggested the presence of an interaction between maternal genes and maternal exposures to aromatic hydrocarbons and congenital heart disease. Numerous environmental factors have been linked to such development, independent of any already known genetic influence or predisposition.
A scientific statement from the American Heart Association reviewed studies of prevalence and summarized studies of environmental factors. In Table 13.3 , positive associations for maternal illnesses and maternal exposures are highlighted.
| Odds Ratio | |
|---|---|
| MATERNAL ILLNESS | |
| Phenylketonuria | >6 |
| Pregestational diabetes | 3.1–18 |
| Febrile illness | 1.8–2.9 |
| Influenza | 2.1 |
| Maternal rubella | b |
| Epilepsy | b |
| Prepregnancy overweight/obesity | 1.13–1.40 |
| MATERNAL THERAPEUTIC DRUG EXPOSURE | |
| Anticonvulsants | 4.2 |
| Ibuprofen | 1.86 |
| Sulfasalazine | 3.4 |
| Thalidomide | b |
| Trimethoprim-sulfonamide , c | 2.1–4.8 |
| Vitamin A congeners/retinoids , c | b |
a Exposures associated with definite or possible risk of offspring with any congenital cardiovascular defect.
Maternal exposure to organic solvents has frequently and consistently been reported to be associated with relatively high odds ratios for the development of specific congenital cardiac malformations. In contrast to maternal illnesses and use of medications, it is feasible to avoid exposure to organic solvents, and prevention strategies might be directed at reducing maternal exposures to these materials.
Other maternal exposures, including pesticides, air pollutants, and lead, have been reported to have an association with congenital heart defects. The Baltimore-Washington Infant Study was a large population-based surveillance with careful verification of maternal exposures. The attributable fraction, which is the proportion of cases of specific heart defect that might be attributable to specific exposure, is summarized in Table 13.4 . Note that some of the significant exposures were paternal rather than maternal.
| Malformation and Potential Risk Factors | P < .01 | Relative Risk | |
|---|---|---|---|
| AF (%) | 95% CI | ||
| Transposition with intact ventricular septum ( n = 106) | 12.1 | 8.5–15.8 | |
| Influenza | 7.0 | 3.6–10.3 | 2.2 |
| Miscellaneous solvents | 4.8 | 3.0–6.6 | 3.2 |
| Tetralogy of Fallot ( n = 204) | 6.5 | 4.8–8.3 | |
| Paternal anesthesia | 3.9 | 2.4–5.5 | 2.5 |
| Clomiphene | 2.4 | 1.5–3.4 | 3.0 |
| Atrioventricular septal defect with Down syndrome ( n = 190) | 4.6 | 2.7–6.5 | |
| Ibuprofen | 4.6 | 2.7–6.5 | 2.4 |
| Hypoplastic left heart syndrome ( n = 138) | 8.6 | 6.9–10.3 | |
| Solvent/degreasing agent | 4.6 | 3.2–6.0 | 3.4 |
| Family history of congenital heart disease | 4.0 | 3.1–4.9 | 4.8 |
| Coarctation of the aorta ( n = 120) | 9.4 | 8.1–10.8 | |
| Family history of congenital heart disease | 4.6 | 3.5–5.7 | 4.6 |
| Macrodantin | 2.3 | 1.8–2.8 | 6.7 |
| Clomiphene | 2.0 | 1.4–2.7 | 4.5 |
| Isolated/simple perimembranous VSD ( n = 459) | 7.9 | 4.2–11.6 | |
| Paternal use of marijuana | 6.0 | 2.2–9.7 | 1.4 |
| Maternal use of cocaine | 1.7 | 0.9–2.5 | 2.4 |
| Multiple/multiplex perimembranous VSD ( n = 181) | 8.3 | 6.0–10.5 | |
| Paternal use of cocaine | 4.8 | 2.6–6.9 | 2.3 |
| Diabetes mellitus | 2.1 | 1.4–2.8 | 3.9 |
| Metronidazole | 1.4 | 1.1–1.7 | 7.6 |
| Atrial septal defect ( n = 187) | 14.1 | 11.3–17.0 | |
| Gestational diabetes mellitus | 4.4 | 2.5–6.2 | 2.4 |
| Paternal use of cocaine | 3.7 | 1.9–5.4 | 2.3 |
| Family history of congenital heart disease | 3.4 | 2.4–4.3 | 3.9 |
| Corticosteroids | 2.6 | 1.9–3.2 | 4.8 |
Genetic Factors
The prevalence of congenital cardiac disease is increased in children with specific chromosomal abnormalities and syndromes, and the knowledge of these associations is expanding. These genetic factors are further explored in other chapters. A high prevalence of congenital cardiac disease has been observed among children with trisomy 21 (Down syndrome), trisomy 18 (Edwards syndrome), trisomy 13 (Patau syndrome), and monosomy XO (Turner syndrome).
With the average maternal age increasing, the prevalence of infants with chromosomal abnormalities is likely to rise, in particular the number of infants with trisomy 21. This is associated with congenital cardiac disease in 40% to 50% of pregnancies. After the age of 30 years, a mother’s risk of having a child with trisomy 21 increases exponentially, such that by the time she is 35 years, the risk is 1 in 365 pregnancies.
The deletion of the 22q11 gene has been implicated as an important contributor to the development of congenital cardiac disease. Studies have estimated the prevalence of the deletion to be approximately 1.5 cases in each 10,000 live births. It has been suggested that more than 1% of all congenitally malformed hearts are associated with this deletion, accounting for half of the cases with interrupted aortic arch, 20% of those with common arterial trunk, and approximately 16% of those with tetralogy of Fallot.
The risk of recurrence is also higher in families and mothers with nonsyndromic congenital heart disease, as summarized in Table 13.5 . The prevalence of a congenital heart defect in at least one twin of a monochorionic pair is estimated at almost 10%, with the prevalence in the second twin increasing to more than 25% if the first twin is affected. Furthermore, assisted reproduction techniques may result in a modest increase in the risk of congenital heart disease, with a recent meta-analysis showing an odds ratio of 1.3 compared with fetuses conceived spontaneously.
| Congenital Heart Defect | Mode of Inheritance | Recurrence Risk (%) | Genes | References |
|---|---|---|---|---|
| Atrioventricular canal defect | Multifactorial | 3–4 | – | |
| Autosomal dominant | 50 | p93 | ||
| CRELDI | ||||
| GATA4 | ||||
| PTPN11 | ||||
| Tetralogy of Fallot | Multifactorial | 2.5–3 | — | |
| Autosomal dominant | 50 | NKX2.5 | ||
| Autosomal recessive | 25 | Jagged 1 | ||
| Three-gene model | 2.5–3 | FOG2 | ||
| — | ||||
| — | ||||
| Transposition of the great arteries | Multifactorial Autosomal dominant | 1–1.8 50 | – CFC1 | |
| Congenitally corrected transposition of the great arteries | Multifactorial | 5.8 | – | |
| Left-sided obstructions | Multifactorial | 3 | – | |
| Autosomal dominant | 50 | NOTCH1 | ||
| Autosomal recessive | 25 | NKX2.5 | ||
| — | ||||
| Atrial septal defect | Multifactorial | 3 | – | |
| Autosomal dominant | 50 | NKX2.5 | ||
| GATA4 | ||||
| MHC6 |
Systemic Factors
Systemic factors are those that result from changes to the systems providing health care and include improved prenatal diagnosis and survival into adulthood. Prenatal diagnosis allows for selective termination and fetal interventions, which may alter the prevalence at live birth. Improvements in management of most congenital cardiac lesions have led to improved survival into adulthood. This has resulted in dramatic changes in the point prevalence of congenital cardiac disease, its spectrum, and its demographics.
Reported Prevalence of Congenital Heart Disease
It is unlikely that any single study will give the definitive estimate of the prevalence of congenital heart defects because such studies differ, sometimes widely, in methodology, quality, population, and period of time studied. One of the first reports was from a cardiac substudy of the Collaborative Study of Cerebral Palsy, Mental Retardation, and Other Neurological and Sensory Disorders of Infancy and Childhood, published in 1971. This study prospectively enrolled pregnant mothers at 12 participating large institutions within the United States and then repeatedly assessed the infants up to the age of 7 years. The study included still births. Hospital and outpatient records, and autopsy reports, were reviewed for diagnoses of congenital heart disease. From 56,109 births, 457 cases were identified, with 178 diagnosed at autopsy, 36 from surgical findings, 42 from cardiac catheterization, and 201 from clinical evaluation only. This gave an estimate of prevalence of 8.1 per 1000 births. The prevalence among live births only was 7.7 but among still births only was 27.5. For those live born, the prevalence among those who died earlier than 28 days after birth was 73.2 per 1000 deaths and among those who died between 28 days and 1 year was 112.6 per 1000 deaths. Ventricular septal defect was the most frequent diagnosis, occurring in 133, or 30%, of the 457 cases. Table 13.6 summarizes findings from some of the large studies that have evaluated the prevalence of congenital cardiac disease.
