**2. Epidemiology of congenital heart diseases**

#### **2.1 Incidence rate**

The incidence of CHD refers to the number of newly identified cases, children or adult, depending on the degree of defective development of the individuals' heart, per unit of time or population. Incidence demonstrates the rate of disease. The incidence of congenital heart defect is difficult to precisely determine, partly because of difficulties in definition. However, not all cases of congenital heart disease are diagnosed in infancy. Incidence rates based on diagnoses in pregnant women and the first 12 months of the baby's life will, therefore, be an underestimate of true incidence. Accurate assessment of incidence of CHD is important in determining the etiology of CHD, and in comparisons between populations over time, which might reflect population genetics or environment factors to a region or country. The incidence of CHD ranges from 4 to 85.9 per 1,000 pregnancies. Many congenital heart defects have been detected in stillbirths, particularly by an early loss in gestation due to chromosome anomalies. According to Hoffman (1978), the incidence of CHD among stillbirths is 79 per 1,000, whereas Mitchell (1972) reported an incidence of CHD in stillbirths and neonatal death (death after birth and before 28 days of age) to be 27.5 per 1,000 and 73.2 per 1,000, respectively. Yet, this number is likely an underestimate to the actual incidence of CHD because of difficulties in definition and unrecognized live births. The increasing incidence of CHD is primarily because of better methods of detection and data collection, as well as more advanced instruments, i.e. echocardiography, and highly skilled health officers. The increasing incidence of CHD could be due to more teratogenic environments affecting pregnant women and their offspring. Although an increased use of fetal echocardiography in pregnant women can help detect more CHD cases, many pregnancies are aborted prior to the mothers' awareness of the pregnancy and the effective assessment of a structural heart defect is still impossible for the early gestation phase. Moreover, the detection of heart malformation via fetal autopsy and heart examination remains rarely performed among the stillborns especially in developing country due to the lack of pathologists and the additional process for health professionals to request an autopsy.

#### **2.2 Birth prevalence**

Unlike incidence, the prevalence for CHD is the number of existing cases in the population of interest at one point in time. Prevalence represents the probability that a person in a given population will have the disease at a given time. Prevalence is a function of the incidence of the disease in a population and the duration of that disease. The sooner the recognition of birth prevalence of CHD, the better the planning will be by hospitals, health officers, pediatricians, pediatric cardiologists and pediatric cardiac surgeons. Social and economic support can also be found early for the patients' families. The global prevalence of CHD among newborns ranges from approximately 3.7 to 17.5 per 1,000, which account for 30-45% of all congenital defects. In Northern England, birth prevalence of CHD was as high as 79.7 per 1,000 live births (Dadvand et al., 2008). The extreme variation of the birth prevalence might be owed to a single or a combination of the following factors: inclusion criteria, for example that reports include bicuspid aortic valve and tiny muscular VSD or not, specificity and sensitivity of the diagnostic methodologies, properly trained and technique specialty of examiners, and ethnic and regional backgrounds of the examinees. Additional factors might be associated with the unavoidable limits of the retrospective studies that the data depend on previous medical records, possibly incorrect registration, missing or insufficient co-

The incidence of CHD refers to the number of newly identified cases, children or adult, depending on the degree of defective development of the individuals' heart, per unit of time or population. Incidence demonstrates the rate of disease. The incidence of congenital heart defect is difficult to precisely determine, partly because of difficulties in definition. However, not all cases of congenital heart disease are diagnosed in infancy. Incidence rates based on diagnoses in pregnant women and the first 12 months of the baby's life will, therefore, be an underestimate of true incidence. Accurate assessment of incidence of CHD is important in determining the etiology of CHD, and in comparisons between populations over time, which might reflect population genetics or environment factors to a region or country. The incidence of CHD ranges from 4 to 85.9 per 1,000 pregnancies. Many congenital heart defects have been detected in stillbirths, particularly by an early loss in gestation due to chromosome anomalies. According to Hoffman (1978), the incidence of CHD among stillbirths is 79 per 1,000, whereas Mitchell (1972) reported an incidence of CHD in stillbirths and neonatal death (death after birth and before 28 days of age) to be 27.5 per 1,000 and 73.2 per 1,000, respectively. Yet, this number is likely an underestimate to the actual incidence of CHD because of difficulties in definition and unrecognized live births. The increasing incidence of CHD is primarily because of better methods of detection and data collection, as well as more advanced instruments, i.e. echocardiography, and highly skilled health officers. The increasing incidence of CHD could be due to more teratogenic environments affecting pregnant women and their offspring. Although an increased use of fetal echocardiography in pregnant women can help detect more CHD cases, many pregnancies are aborted prior to the mothers' awareness of the pregnancy and the effective assessment of a structural heart defect is still impossible for the early gestation phase. Moreover, the detection of heart malformation via fetal autopsy and heart examination remains rarely performed among the stillborns especially in developing country due to the lack of pathologists and the additional process for health professionals to request an autopsy.

Unlike incidence, the prevalence for CHD is the number of existing cases in the population of interest at one point in time. Prevalence represents the probability that a person in a given population will have the disease at a given time. Prevalence is a function of the incidence of the disease in a population and the duration of that disease. The sooner the recognition of birth prevalence of CHD, the better the planning will be by hospitals, health officers, pediatricians, pediatric cardiologists and pediatric cardiac surgeons. Social and economic support can also be found early for the patients' families. The global prevalence of CHD among newborns ranges from approximately 3.7 to 17.5 per 1,000, which account for 30-45% of all congenital defects. In Northern England, birth prevalence of CHD was as high as 79.7 per 1,000 live births (Dadvand et al., 2008). The extreme variation of the birth prevalence might be owed to a single or a combination of the following factors: inclusion criteria, for example that reports include bicuspid aortic valve and tiny muscular VSD or not, specificity and sensitivity of the diagnostic methodologies, properly trained and technique specialty of examiners, and ethnic and regional backgrounds of the examinees. Additional factors might be associated with the unavoidable limits of the retrospective studies that the data depend on previous medical records, possibly incorrect registration, missing or insufficient co-

**2. Epidemiology of congenital heart diseases** 

**2.1 Incidence rate** 

**2.2 Birth prevalence** 

ordination of cardiac pediatricians between outpatient and private clinics, and absence of autopsy to determine the cause of certain fetal death in stillbirths. Nonetheless, the estimation for birth prevalence of CHD remains simpler and more precise compared with the estimation for incidence of CHD from the baby population. Hence, most epidemiological studies report the birth prevalence rather than the baby incidence of CHD. Table 1 compares the birth prevalence of all CHD subtypes from 4 recent studies by Hoffman & Kaplan, 2002 (review literatures); Reller et al., 2008 (Metropolian Atlanta Congenital Defects Program, MACDP); Dolk & Loane, 2009 (European Surveillance of Congenital Anomalies, Eurocat) and Wu et al., 2010 (Asian population, Taiwan). Table 2 shows different percent distribution of CHD lesions in live births from various countries


\*Live births

\*\*Non-chromosomal CHD prevalence (Includes: Live birth, Fetal death and Termination of pregnancy for fetal anomaly)

\*\*\*Excluding bicuspid non-stenosis aortic valves, isolated partial anomalous pulmonary venous connection and silent ductus arteriosus

Table 1. Prevalence of CHD based on CHD subtypes and per 1,000 births compared among the four recent studies.

More importantly, the trend for birth prevalence of CHD was found to be increasing, highlighting three chief concerns. First, the increased number of CHD prevalence among the newborns could represent the greater number of adults with CHD and the likely increased number of CHD in their offspring in the future. This poses the concern about the overall

Similar to the knowledge of birth prevalence, the knowledge of adult prevalence can estimate the need for adult cardiology services. The accurate prevalence of CHD in the adult population is difficult to know. Although some patients with CHD have spontaneous recovery, for instance 35% of infants with VSD had their lesion close spontaneously (Mitchell et al., 1971), an overall number of adult diagnosed with CHD continues to rise and is now higher than that of the diagnosed pediatric cases. It was estimated that in 2000 there were fewer than 150,000 adults diagnosed with CHD in the UK. Of these, around 11,500 had the more complex forms of the disease, requiring life-long expert supervision and intervention (Report of the British Cardiac Society Working Party, 2002). It was also further estimated that by the year 2010 there would be over 185,000 adults in the UK living with CHD (over 17,000 with the complex form), a rise of around 25% in simple and 50% in complex conditions since 2000. Using a birth prevalence of CHD of 8.8 per 1,000 live births, it is estimated that more than 8,500 individuals with surgical repair of congenital heart defects reach adulthood each year in the USA (Morris, 2004). In year 2000, approximately 500,000 American adults were reported to have moderate to complex congenital heart defects. By 2020, nearly 760,000 adults will have CHD in the USA, with 200,000 having severe CHD, disregarding all those born before 1990 (Webb et al., 2002). Our review has only one study that reports exactly the adult prevalence of CHD. This study was done in a general population from 1985 to 2000 in Canada, it revealed the prevalence of CHD was 4.09 per 1,000 adults for all CHD and 0.38 per 1,000 for those with severe lesions (Table3). 57% of the adult CHD population was female (Marelli et al., 2007). The authors extrapolated a prevalence of 4.09 per 1,000 to a Canadian and US population corresponds to 96,000 patients in Canada and 856,000 patients in the United States. A recent study in the Netherlands studied 8,595 adults with CHD, and found the most common defects in the distribution of CHD were ASD (17%), VSD (16%), AS/BAV (14%), TOF (10%) and Coarc (10%) but the highest mortality was found in patients with TA (14.7%) and patients with UV and double

Two main reasons can explain this situation. First, there is the process of natural selection in which children with previously undetected CHD or children with inoperable CHD survive into adulthood with uncorrected lesions. Up to 75%of children with CHD did not exhibit clinical signs of diseases until the diseases became severe. Moreover, around 10% of CHD are not diagnosed until adulthood (Mettler & Peeler, 2009), in particular secundum atrial septum defect, ventricular septal defect, pulmonary stenosis, anormalous coronary arteries, Ebstein's anomaly and congenitally corrected transposition of great arteries. One of the more recent CHD studies in Thailand reported 0.41 to 1.05 prevalent cases of unrecognized CHD for every 1,000 elementary-age students. This variation was due to the topography and the limitation of medical staff and facilities in the study areas. In this population, the most frequently identified heart defects were VSD 41.4%, PS 16.1%, PDA 12.6% and ASD 9.2% (Sayasathid, et al., 2010). The second reason is the improvement of surgical therapy and postoperative care of neonates and infants in the past few decades, this has led to increased survival of children with CHD. Currently, more than 90% of children born with CHD can survive into adulthood (Moons et al., 2009). From 1979 through 1997, mortality associated with CHD (all ages) declined 39% from 2.5 to 1.5 per 100,000 (Boneva et al., 2001). Although many children with CHD cannot be cured, the initial therapy, including corrective and palliative, allows the adult prevalence of CHD to continue to increase. At Mayo clinic, the number of adult patients with CHD who undergo operation has grown to approximately

**2.3 Adult prevalence** 

inlet left ventricle (11.4%)(Zomer et al., 2010).

increasing prevalence of CHD. A study in Hungary, estimates the prevalence of CHD to be 4.9% in offspring of individuals with CHD. More than half of these had the same malformation as the parent (Ceizel et al., 1981). Another study in 2001 showed the prevalence of CHD was 3.1% in offspring of individuals with CHDs and 1.3% in offspring of individuals without CHDs. The adjusted risk for offspring of parents with CHDs was 1.73 (95% CI, p=0.02) (Romano-Zelekha et al., 2001). On the other hand, if the high prevalence is due to the more common use of postnatal echocardiography for abnormal heart diagnosis, the greater birth prevalence of CHD signifies an underestimation of CHD among live births in the past and the importance for public health officers to have an accurate number of cases. For instance, fetal echocardiography screening could be performed to decide pregnancy termination of fetuses with severe cardiac malformation, and thereby reduce the birth prevalence of CHD. Finally, the rapid development of the world may increase many risk factors to develop CHD such as pollutants and teratogens. The number of births with CHD in Dallas county suggests an apparent increase in prevalence from approximately 5% in 1971 to 8% in 1984 (Fixler et al., 1990). Within the Baltimore-Washington Infant Study Group, the prevalence of CHD increased from 2.8 per 1,000 live births in 1981 to 4.3 per 1,000 live births in 1988 (Ferencz et al., 1989) and a recent report from North England demonstrated the total prevalence of CHD increased from 5.4 per 1,000 births and terminations of pregnancy in 1985 to 11.6 per 1,000 births and terminations of pregnancy in 2003 (Dadvand et al., 2008).


1Mitchell et al., 1971, 2Bound & Logan, 1977, 3Dickinson et al., 1981, 4Ferncz et al., 1985, 5Khalil et al., 1994, 6Alabdulgader, 2006, 7Amro, 2009, 8 Fatema et al., 2008, 9Lindinger et al., 2010 \*Saudi = Saudi Arabia, and Bangla = Bangladesh

Table 2. Percent distribution of CHD lesions in live births in USA, UK, India, Saudi Arabia, Jordan, Bangladesh and Germany.

#### **2.3 Adult prevalence**

52 Congenital Heart Disease – Selected Aspects

increasing prevalence of CHD. A study in Hungary, estimates the prevalence of CHD to be 4.9% in offspring of individuals with CHD. More than half of these had the same malformation as the parent (Ceizel et al., 1981). Another study in 2001 showed the prevalence of CHD was 3.1% in offspring of individuals with CHDs and 1.3% in offspring of individuals without CHDs. The adjusted risk for offspring of parents with CHDs was 1.73 (95% CI, p=0.02) (Romano-Zelekha et al., 2001). On the other hand, if the high prevalence is due to the more common use of postnatal echocardiography for abnormal heart diagnosis, the greater birth prevalence of CHD signifies an underestimation of CHD among live births in the past and the importance for public health officers to have an accurate number of cases. For instance, fetal echocardiography screening could be performed to decide pregnancy termination of fetuses with severe cardiac malformation, and thereby reduce the birth prevalence of CHD. Finally, the rapid development of the world may increase many risk factors to develop CHD such as pollutants and teratogens. The number of births with CHD in Dallas county suggests an apparent increase in prevalence from approximately 5% in 1971 to 8% in 1984 (Fixler et al., 1990). Within the Baltimore-Washington Infant Study Group, the prevalence of CHD increased from 2.8 per 1,000 live births in 1981 to 4.3 per 1,000 live births in 1988 (Ferencz et al., 1989) and a recent report from North England demonstrated the total prevalence of CHD increased from 5.4 per 1,000 births and terminations of pregnancy in 1985 to 11.6 per 1,000 births and terminations of pregnancy in

1Mitchell et al., 1971, 2Bound & Logan, 1977, 3Dickinson et al., 1981, 4Ferncz et al., 1985, 5Khalil et al.,

Table 2. Percent distribution of CHD lesions in live births in USA, UK, India, Saudi Arabia,

1994, 6Alabdulgader, 2006, 7Amro, 2009, 8 Fatema et al., 2008, 9Lindinger et al., 2010

\*Saudi = Saudi Arabia, and Bangla = Bangladesh

Jordan, Bangladesh and Germany.

2003 (Dadvand et al., 2008).

Similar to the knowledge of birth prevalence, the knowledge of adult prevalence can estimate the need for adult cardiology services. The accurate prevalence of CHD in the adult population is difficult to know. Although some patients with CHD have spontaneous recovery, for instance 35% of infants with VSD had their lesion close spontaneously (Mitchell et al., 1971), an overall number of adult diagnosed with CHD continues to rise and is now higher than that of the diagnosed pediatric cases. It was estimated that in 2000 there were fewer than 150,000 adults diagnosed with CHD in the UK. Of these, around 11,500 had the more complex forms of the disease, requiring life-long expert supervision and intervention (Report of the British Cardiac Society Working Party, 2002). It was also further estimated that by the year 2010 there would be over 185,000 adults in the UK living with CHD (over 17,000 with the complex form), a rise of around 25% in simple and 50% in complex conditions since 2000. Using a birth prevalence of CHD of 8.8 per 1,000 live births, it is estimated that more than 8,500 individuals with surgical repair of congenital heart defects reach adulthood each year in the USA (Morris, 2004). In year 2000, approximately 500,000 American adults were reported to have moderate to complex congenital heart defects. By 2020, nearly 760,000 adults will have CHD in the USA, with 200,000 having severe CHD, disregarding all those born before 1990 (Webb et al., 2002). Our review has only one study that reports exactly the adult prevalence of CHD. This study was done in a general population from 1985 to 2000 in Canada, it revealed the prevalence of CHD was 4.09 per 1,000 adults for all CHD and 0.38 per 1,000 for those with severe lesions (Table3). 57% of the adult CHD population was female (Marelli et al., 2007). The authors extrapolated a prevalence of 4.09 per 1,000 to a Canadian and US population corresponds to 96,000 patients in Canada and 856,000 patients in the United States. A recent study in the Netherlands studied 8,595 adults with CHD, and found the most common defects in the distribution of CHD were ASD (17%), VSD (16%), AS/BAV (14%), TOF (10%) and Coarc (10%) but the highest mortality was found in patients with TA (14.7%) and patients with UV and double inlet left ventricle (11.4%)(Zomer et al., 2010).

Two main reasons can explain this situation. First, there is the process of natural selection in which children with previously undetected CHD or children with inoperable CHD survive into adulthood with uncorrected lesions. Up to 75%of children with CHD did not exhibit clinical signs of diseases until the diseases became severe. Moreover, around 10% of CHD are not diagnosed until adulthood (Mettler & Peeler, 2009), in particular secundum atrial septum defect, ventricular septal defect, pulmonary stenosis, anormalous coronary arteries, Ebstein's anomaly and congenitally corrected transposition of great arteries. One of the more recent CHD studies in Thailand reported 0.41 to 1.05 prevalent cases of unrecognized CHD for every 1,000 elementary-age students. This variation was due to the topography and the limitation of medical staff and facilities in the study areas. In this population, the most frequently identified heart defects were VSD 41.4%, PS 16.1%, PDA 12.6% and ASD 9.2% (Sayasathid, et al., 2010). The second reason is the improvement of surgical therapy and postoperative care of neonates and infants in the past few decades, this has led to increased survival of children with CHD. Currently, more than 90% of children born with CHD can survive into adulthood (Moons et al., 2009). From 1979 through 1997, mortality associated with CHD (all ages) declined 39% from 2.5 to 1.5 per 100,000 (Boneva et al., 2001). Although many children with CHD cannot be cured, the initial therapy, including corrective and palliative, allows the adult prevalence of CHD to continue to increase. At Mayo clinic, the number of adult patients with CHD who undergo operation has grown to approximately

migration of pre-cardiac cells from the primitive streak and assembly of the paired cardiac crescents at the myocardial plate, (2) coalescence of the cardiac crescents to form the primitive heart tube, establishment of the definitive heart, (3) cardiac looping, assurance of proper alignment of the future cardiac chambers, (4) septation and heart chamber formation, and (5) development of the cardiac conduction system and coronary vasculature (McFadden & Olson, 2002; Moorman & Christoffels, 2003; Gittenberger-de Groot et al., 2005). From a series of complex processes, each component occurs at the right time under the orchestration of a cascade of genes and gene products, resulting in the coordination of cell migration and the formation of the extracellular matrix. Thus, CHD is usually caused by altered development of embryonic structure, or a failure of the structure to develop beyond an early embryonic or fetal stage. The anatomical defect generally influences further structural and functional development. Although descriptions of abnormal heart development in fetuses and babies have remained unclearly defined, substantial knowledge about the etiology of CHD have been made during the last decade. Some malformations may be directly inherited through vertical gene transfer, underlying the individuals' genetic disorder, or be associated with the consequences of an environmental toxin or diet. Alternatively, random errors in cell migration leading to improper cardiac development are possible. Together, the findings emphasize the complex and multifactorial causes of the CHD where additional research

Better understanding for the etiology and risk factors of CHD is important, and will help pave the way for proper preventative measures and treatment guidelines by physicians as well as public health officers. The followings represent all reported potential causes of CHD

The human genome, which contains approximately 20,000 to 25,000 genes, is comprised of coding and non-coding regions that are essential for proper protein structure and expression. The coding DNA sequence determines the amino acid sequence and subsequently the protein structure, and structure determines function (Lander, 2011; Reid-Lombardo & Bartelings, 2010). The non-coding sequences may contain promoters and regulation of transcription. In general, the DNA sequences remain relatively unchanged during vertical genetic transfer to the offspring. Nonetheless, occasional changes in the nucleotide sequences, referred to as mutations, and horizontal gene transfer do occur. Mutations range from a single nucleotide substitution, also called single nucleotide polymorphism (SNP), to a deletion or insertion of a DNA fragment. Some mutations only appear visible at the level of the chromosome (chromosome abnormalities), while some

Any change in the DNA sequence, including SNPs, insertion, deletion and shuffling of DNA fragment, that results in frameshift mutation of the gene-encoding sequence likely affects protein folding and protein function. Abnormal protein folding structure and function can cause an improper development of many organs, including the heart. Hence, genetics is responsible for one major role in cardiovascular malformation, and indeed the genetic disorders represent the most common cause of CHD. Certain chromosome abnormities were linked to specific types of congenital heart lesions, and several types have been reported to be associated with specific gene defects. For instances, AVSD are often diagnosed in patients

mutations cause phenotypic changes and a heritable trait to the offspring.

remain needed.

**3.1 Genetic disorders** 

with trisomy 21.

to date.

300-400 patients per year (Brown et al., 2009). These patients have elevated risk of premature morbidity and mortality. CHD is often more severe and has more complicated treatment in adults than children. Moreover, a recent analysis of the United States administrative database found that mortality was greater for adults with CHD when the operations were performed by adult cardiac surgeons, compared with pediatric (congenital-trained) heart surgeons (4.8% versus 1.9%, P<0.001) (Brown et al., 2009, as cited in Karamalou et al., 2008). For CHD adults, arrhythmias are more common, cardiac chambers often enlarge, and ventricles tend to develop systolic dysfunction. The main causes of death were progressive heart failure 26% and sudden cardiac arrest 22% (Zomer et al., 2010). Multidisciplinary care may also be required.


Table 3. The prevalence of adult CHD based on subtypes in year 2000, Canada (Marelli et al., 2007).

Another problem that should be of concern is the transfer system from pediatric to adult health care. Many children with CHD did not follow-up when they were discharged from pediatric care and referred to adult care. In a Canadian study, only 47% of teenagers with CHD had transferred successfully to adult care (Reid et al., 2004). The results were similar in a German study, 76% of patients with CHD did not have follow-up care as an adult in a 5 year period (Wacker et al., 2005). The prevalence of adults with CHD is underestimated if it does not include this group of patients. These patients received medical care again when their diseases had progressed and their symptoms had become severe. This lack of care as an adult made it difficult to manage the disease and resulted in high morbidity & mortality in these patients. Patients with CHD must recognize the necessesity of ongoing surveillance and the transfer system must be developed to prevent the loss of follow-up patients.
