Conotruncal heart malformations in Egypt: An epidemiological study


Conotruncal malformations of the heart are a major category of birth defects. No previous epidemiological studies on these malformations have been carried out in Egypt; therefore our study aimed to describe associations with maternal and infant factors in order to identify possible risk factors. Cases (N = 255) were children up to two years of age whose heart malformations were confirmed by echocardiography; they were enrolled at the Cardiology Department of the Pediatric Hospital of Cairo University. Controls (N = 155) were free of congenital heart malformations, matched to the cases by age, and recruited from outpatients of the same hospital. Mothers of cases (97%) and controls (89%) provided consent to participate in an interview about their medical, familial, and occupational histories. Odds ratios (OR) and exact 95% confidence intervals (CI) assessed the magnitude and statistical significance of case-control differences. Cases were divided into two groups based on the presence of d-transposition of the great arteries (TGA): there were 139 with TGA and 116 with normally-related great arteries (NGA). Maternal diabetes prevalence was elevated in both the TGA (OR = 3.4) and NGA (OR = 5.5) subgroups. Several agricultural factors were associated with increased risk: raising animals (for TGA: OR = 2.4, 95% CI 1.2-4.6), raising poultry (for NGA: OR = 1.8, 95% CI 1.1-3.2), and using chemical rodenticides (for all conotruncal cases: OR = 3.2, 95% CI 1.1-13.2). These results are consistent with previous studies of associations of maternal diabetes and pesticide exposure with conotruncal malformations. Further research is warranted to explore such associations and determine avenues for prevention.

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Saleh, D. , Ezzat, S. , Hamza, H. , Abdel-Hamid, M. , Kuehl, K. and Loffredo, C. (2013) Conotruncal heart malformations in Egypt: An epidemiological study. Open Journal of Epidemiology, 3, 169-176. doi: 10.4236/ojepi.2013.34025.


Congenital cardiovascular malformations (CCVM) are defects of the heart that are present at birth. They are among the most prevalent structural birth defects and are the leading cause of death among infants with birth defects, accounting for nearly one third of such deaths [1]. Conotruncal heart malformations in particular are structural abnormalities of the outflow tract of the heart, encompassing a wide array of phenotypes, the most prevalent of which are tetralogy of Fallot (TOF) and transposition of the great arteries (TGA). They are potentially life-threatening conditions, often requiring surgical intervention [2].

In the Baltimore Washington Infant Study (BWIS), the largest epidemiological study of CCVM to date, conotruncal heart defects were classified into two main subgroups, namely with and without TGA [3], and in subsequent analyses the individual phenotypes were separately assessed. The BWIS classification of TGA included cases with intact ventricular septum (IVS), ventricular septal defect (VSD), double outlet right ventricle (DORV), or complex phenotypes with pulmonary or tricuspid atresia. The group of outflow tract defects with normally related great arteries (NGA) included TOF, DORV, truncus arteriosus, and several rare phenotypes. The statistical analysis of potential risk factor associations revealed considerable heterogeneity across these groupings of conotruncal malformations, confirming the usefulness of a classification system based on the presence or absence of TGA [3,4].

In the BWIS, conotruncal heart defects represented 14.5% of total CCVM cases in a population-based study, and their combined prevalence was 7.1 per 10,000 live births [3]. Other regional registries have reported similar figures [5], but in much of the world there are no registries to track and report occurrence rates. This situation is particularly striking in developing countries, where the magnitude of the public health problem of CCVM remains largely unknown. A study conducted in one Egyptian maternity hospital, for example, reported CCVM in 95 of 3000 (3.2%) hospital births [6]. Given the 1.9 million births per year in Egypt, such an estimate would predict a large number of patients with CCVM generally and conotruncal anomalies specifically. Since conotruncal heart malformations require intensive interventions, with high costs that the public health system of a country with limited resources can ill afford, prevention and control strategies are urgently needed to relieve this burden on individuals, families, and society.

Previous studies have presumed a multifactorial model for conotruncal malformations, with both genetic [7] and non-inherited, potentially modifiable factors [8] as their causes. Maternal diabetes was previously found to be associated with the development of conotruncal malformations, especially those with normally related great arteries (OR = 6.6, 95% CI 3.2 - 13.3) [9], while rodenticidal chemicals were associated with the development of TGA (OR = 4.7, 95% CI 1.4 - 12.1) [10]. To our knowledge, such studies have not been conducted in Egypt. In this epidemiological case-control study, we assessed potential risk factor associations for conotruncal heart malformations in Egypt.


2.1. Subject Recruitment and Interviews

This study was a hospital based case-control study conducted at the Pediatric Hospital of Cairo University, Egypt, under the clinical supervision of a pediatric cardiologist (H.H.). It was approved by the institutional review boards of Cairo University Hospital and of Georgetown University. Interviews were conducted with mothers of cases with conotruncal heart malformations and with mothers of controls without conotruncal heart malformations. Mothers were approached by the interviewers at the clinic, were invited to join the study, and were asked to provide informed consent. The informed consent included the mother’s agreement to conduct a brief interview, to donate a sample of cells from inside her mouth (buccal cells) and the mouth of her child by oral brush, and to provide a few drops of blood by thumb prick of the mother and by heel prick of the child.

Details of the recruitment, eligibility, and participation of cases and controls are shown in Figure 1. Cases were infants and children up to the age of 2 years diagnosed with conotruncal (outflow tract) types of CCVM. The controls were infants and children free from congenital heart defects; they were recruited during the same time period as the cases, from the outpatient clinic of the same hospital, and were frequency matched to cases by age category (1 - 3 months, 4 - 12 months, >12 months).

The classification of the cases was reviewed by the consulting pediatric cardiologist (K.S.K.). Malformations of the cardiac outflow tract were divided for statistical analysis into those with d-transposition of great arteries (TGA) or with normally related great arteries (NGA). The TGA group consisted of cases with or without ventricular septal defect (VSD), pulmonary atresia, tricuspid atresia, or double outlet right ventricle (DORV). The NGA group included aortic-pulmonary window, supracristal VSD, DORV without TGA, common arterial trunk, and TOF.

2.2. Data Collection

Mothers were interviewed at the hospital by trained interviewers using a structured questionnaire, which was modeled on the instrument used in the Baltimore-Washington Infant Study [3]. It was translated into Arabic and modified to be culturally relevant for the Egyptian population. The questionnaire included the following areas of inquiry: socio-demographic factors; expected and actual date of the child’s birth; child factors (sex, plural birth, birthweight, place of delivery, and any associated congenital conditions); familial birth disorders (type and specific relative who was affected); environmental exposure during the pregnancy, including acute or chronic illnesses, medications, personal habits, and the husband’s habits (alcohol, drugs, or smoking); and any occupational or household exposures to chemicals or pesticides. The critical window for environmental exposure was defined as the period from 3 months before pregnancy through the first trimester.

2.3. Statistical Analysis

We compared cases and controls for possible differences in the questionnaire variables. Chi-square tests were performed to screen categorical variables for statistical significance, and Fisher’s exact test was performed if 25% or more of the cells had expected counts less than 5. The Student’s t-test evaluated continuous variables for association with case-control status. P-values less than 0.05

Figure 1. Recruitment of cases and controls.

were considered statistically significant. Odds ratios and 95% confidence intervals were then calculated as measures of association and statistical significance, respectively, for each of the associations detected above, in each of the cardiac diagnostic groups separately, and in an analysis that combined all cases into one group. Due to the small sample size of several subgroups, exact confidence intervals were calculated for every association reported here, using StatXact software (Cytel Software Corp., Cambridge, MA).


3.1. Study Population

A total of 255 infants with conotruncal heart malformations and 155 controls were enrolled in the study and analyzed for statistical associations with potential risk factors (Figure 1). There were 139 infants in the TGA group and 116 in the NGA group. The diagnostic subdivisions of these cases are shown in Table 1. Within the TGA group there were 60 cases with VSD (6 of whom also had either pulmonary or tricuspid atresia), and 60 with an IVS and no intracardiac defects. Other cases included in the TGA group were 16 with DORV, 1 with pulmonary atresia, and 2 with tricuspid atresia. The NGA group was dominated by TOF (n = 76), among which 63 cases had pulmonic stenosis and 13 had pulmonary atresia. There were also 32 cases with DORV, 6 with common arterial trunk, 1 with aortic-pulmonary window, and 1 with supracristal VSD.

Table 1. Distribution of cardiac outflow tract anomalies.

3.2. Infant Characteristics

Among the total group of 255 cases, 8 (3.1%) occurred in twin births: 5 (3.6%) from the TGA group, and 3 (2.6%) from the NGA group, compared to 7 of 154 controls (4.5%). Six mothers of cases and six mothers of controls reported the co-twin sex: 4 with different sex (2 in TGA with VSD, 2 in TGA with IVS) and 2 with same co-twin sex among cases (1 in TOF, 1 in common arterial trunk), compared to 1 different and 5 same co-twin sex among controls. Different co-twin sex (4/4) was significantly associated with the TGA group (p = 0.048) compared to the controls (1/5).

Table 2 shows characteristics of the recruited motherinfant pairs for the major groups of TGA and NGA and their subsets, in comparison to controls. Maternal age distribution and urban vs. rural area of residency were similar across all groups. Male predominance was found in almost all case subsets compared to controls and was greatest in TGA with IVS (75% males vs. 59% of cases; p = 0.045). Gestational age and birthweight were reported by 92% and 53% of the mothers of cases and controls respectively. Among those who reported the information, prematurity was associated with non-significant elevations in the odds ratios for the TGA group, TGA with DORV, and DORV with NGA. Low birthweight (≤2500 g) was not significantly associated with any of the case subsets.

Mothers of eleven of the cases reported that the child had other associated congenital anomalies; 4 (2.9%) from the TGA group and 7 (6%) from NGA group.

Congenital defects included: four with blood disorders (one in a case of TGA with IVS and in three with NGADORV), two with limb deformities (one NGA-DORV and one TOF), one with congenital blindness (TGA with VSD), one with cleft palate (TOF), one with hypothyroidism (NGA-DORV), one with a hydrocele (TGA and VSD), and one with a brain anomaly (TGA with IVS).

3.3. Maternal Illnesses and Conditions

Among all the cases, six mothers (2.4%) reported having congenital anomalies, compared to one mother of a control (0.6%). Three of the mothers of cases had CCVM themselves, compared to a single control. Maternal CCVM was significantly associated with the risk of having a child with NGA-DORV. Having other family members or other siblings with congenital disorders was not significantly associated with any of the conotruncal anomalies.

Overt (or preexisting) diabetes, with or without insulin or oral hypoglycemic treatment, was associated with the TOF subgroup (OR = 8.6, 95% CI 0.8 - 424.0), as shown in Table 3. The odds ratio for diabetes was also elevated in several other groups (i.e. the TGA group and all its subsets), but the small numbers of exposed cases resulted in wide confidence intervals. The absence of treated controls precluded case-control comparisons on this characteristic.

Table 2. Characteristics of the mothers and infants.

Table 3. Maternal diabetes associations with conotruncal heart malformations in their infants.

Neither fever, bleeding during pregnancy, nausea or vomiting, thyroid disease, urinary tract infection, asthma, nor pneumonia were significantly associated with case status in this study (data not shown). A statistically significant association with hypertension was detected for TGA with DORV (OR = 4.57, 95% CI 1.20 - 15.75), but not when the analysis was restricted to those receiving treatment. Similarly, having a weight problem during the critical period was reported by 14.4% of TGA group vs. 6.5% of controls, but receiving treatment was not significantly associated with any of the case subsets. This same pattern of results was observed for self-reported headache symptoms and the common cold: none remained statistically significant when the analysis was restricted to those who received medical treatment.

3.4. Environmental Exposure

None of the mothers were self-reported tobacco smokers. Neither paternal smoking characteristics nor maternal exposure to environmental tobacco smoke were associated with elevated risk of having a child with conotruncal anomalies. As expected in this majority Muslim society, none of the mothers reported drinking alcohol.

Table 4 shows potential environmental risk factors that were associated with one or more types of cases. Maternal exposure to rodenticidal chemicals was significantly associated with elevated risk of all conotruncal cases combined (OR = 3.21, 95% CI 1.05 - 13.15). Raising animals, especially poultry (chickens, ducks, or pigeons), was significantly associated with both the TGA group (OR = 1.71, 95% CI 1.02 - 2.88) and NGA group (OR = 1.83, 95% CI 1.06 - 3.16), and especially with the TGA-IVS group (OR = 2.35, 95% CI 1.21 - 4.57).

Conflicts of Interest

The authors declare no conflicts of interest.


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