ABSTRACT
characteristics and assess the association of congenital heart defects (CHDs) with parental risk factors, particularly maternal chronic disease and socioeconomic status.
Methods
This case-control study included 376 subjects. Extensive patient histories, including the subjects’ anthropometric parameters and paternal risk factors, were collected from multiple hospitals in Lahore between March 2021 and April 2022. Children’s physical parameters, including body mass index, were measured according to the Centre’s for Disease Control and Prevention guidelines. Statistical analyses were conducted using R-manager and GraphPad Prism.
Results
In the current study, 65.8% of CHD subjects and 64.9% of healthy subjects were male. The comparative assessment of the patient’s anthropometric parameters suggested no significant association with the heart defect. However, compared to healthy subjects, CHD patients were significantly underweight (p < 0.0001). However, the difference was not significant for the comparison between cyanotic and acyanotic CHD groups. The assessment of maternal risk factors showed significant associations for maternal hypertension [3.09 95% confidence interval (CI): 1.64-5.79] and maternal diabetes [2.92 (95% CI: 1.24-6.88)]. In addition, the impact of parental socioeconomic status was substantial: 25.7% and 46.6% of patients were from poor and middle-income families, respectively.
Conclusion
CHD in children was significantly associated with patients’ health status, including maternal hypertension and diabetes. However, this relationship was not found between cyanotic and acyanotic patients. In addition, parental socioeconomic status patients’ poses a significant burden on patients’ families and the healthcare system.
INTRODUCTION
Globally, congenital heart defects (CHDs) remained the top reason of infant morbidity and mortality. Thus, included as one of the major agendas in the 2015 sustainable development goals of the United States (1). Worldwide, 10% of all births are affected by this disease; however, due to recent advancements in pediatric cardiology treatment, overall mortality has declined. While in comparison to high-income countries (HICs) a higher mortality rate was observed in lower-middle-income countries and lower-income countries with an average of 1.2 deaths per 100,000 cases and 4.9 deaths per 100,000 cases respectively (2). A meta-analysis of 260 studies suggested that overall, after every five years the prevalence of congenital heart malformation increased by 10% due to milder lesions with the highest prevalence in Asian regions as compared to Africa (3). It is a complex birth defect that occurs during cardiogenesis and may involve a complex interaction between genetic and environmental risk factors, particularly maternal factors (4). Depending on the clinical severity of the disease, CHDs can be further classified as mild, moderate, and severe. Moreover, the clinical presentation of patients is further divided into two major categories cyanotic or a-cyanotic (5-7). Although several studies have been conducted to analyze the underlying cause of the disease, the exact mechanism of pathogenesis remains unclear. One poorly understood mechanism in pathophysiology is the role played by modifiable risk factors, including maternal health (particularly during pregnancy), use of medications during pregnancy, a history of stillbirths, smoking, and diabetes mellitus. In addition, these risk factors may vary across different populations and cultures (8, 9). Over the past few decades, several studies identified genetic variants and chromosomal abnormalities in syndromic CHD but the etiology of complex non-syndromic CHD needs further studies that can provide us better insights into disease pathogenesis and may provide us a new direction for future prevention of disease (10). To date, the majority of research studies have focused on the genetics of CHD compared with other extrinsic factors, while few extrinsic factors have been studied. This study comprehensively analyzed all the crucial paternal and anthropometric parameters in non-syndromic CHD, which may help us strengthen management guidelines and improve genetic counseling, thereby reducing future disease risk.
MATERIALS AND METHODS
This study was designed as a case-control study to compare the baseline characteristics and maternal risk factors. Ethical approval was obtained from the Punjab University Ethical Committee, Faculty of Economics and Management Sciences, University of the Punjab (approval number: 84/DFEMS, date: 05.04.2021) and Institutional Review Board of The Children’s Hospital & The Institute of Child Health, Lahore (approval number: 2021-282-CHICH, date: 18.05.2021). This study includes paediatric cardiologist-confirmed cases of both cyanotic and acyanotic CHD. After obtaining informed consent, all critical information was collected from the study subjects. The information collected from participants was divided into two phases: first, the patient’s baseline parameters were studied; second, parental risk-factor analysis was performed and is described in the detailed sections below.
Patient’s and Healthy Subjects Characteristics
The baseline parameters from subjects with cyanotic or acyanotic CHDs and control subjects were recorded for comparative evaluation. The following information was collected: age, gender, weight in kg, height in cm, and body mass index (BMI) in kg/m2. The BMI results were further used to classify the study subjects as underweight, healthy weight, overweight, and obese. BMI was calculated according to the Centers for Disease Control and Prevention (CDC) guidelines. The following cut-off points were used for classification: less than the 5th percentile for underweight, 5th percentile to up to the 85th percentile for healthy subjects, 85th to less than the 95th percentile for overweight, and equal to, or greater than the 95th percentile for obese subjects (11).
Parental Risk Factors
The paternal risk-factor analysis was divided into four major sections: demographics, family history, chronic disease evaluation, and maternal pregnancy complications. The demographic data further include the parental age, and socioeconomic status evaluation according to the Kuppuswamy scale, and data were divided into upper-class, middle-class, poor class, and very-poor class (12, 13). Maternal risk factors recorded were smoking, of medicines, a history of chronic disease or complicated pregnancy, and the number of children aborted.
Statistical Analysis
Categorical data were represented as percentages or frequencies, and continuous data as means with standard deviation, respectively. The t-test and chi-square test were used to compare continuous and categorical variables, respectively. The associations were further expressed as odds ratios (ORs) and 95% confidence intervals (CIs). A p-value <0.05 was considered statistically significant. The statistical analyses were performed using R-Manager, the Statistical Package for the Social Sciences 22.0, and GraphPad Prism version 5.
RESULTS
A total of 376 subjects were recruited, including 225 cases and 151 controls. Among CHDs, 101 were cyanotic and 124 were acyanotic. The cases had 148 males and 77 females, while the controls had 98 males and 53 females (p = 0.95). The comparative assessment of baseline characteristics between patients with CHDs and healthy subjects revealed no significant differences except for BMI (p < 0.0001, Table 1).
The comparison of health status suggested a significant difference between the two categories: the percentages of healthy, underweight, overweight, and obese individuals were 92.54%, 0%, 4.48%, and 2.98% in controls, and 58.59%, 37.37%, 4.04%, and 0% in cases (Figures 1 and 2).
There was no statistically significant difference in anthropometric parameters between cyanotic and acyanotic CHDs (p > 0.05, Table 1). The percentages of healthy, underweight, overweight, and obese in cyanotic and a-cyanotic groups were 60%, 37.78%, 2.22%, and 0%, and 57.41%, 37.04%, 5.55%, and 0%, respectively (Figure 3). The impact of paternal socioeconomic status was significant in the Pakistani population, as the majority of patients (46.67%) belonged to the middle class and 25.78% to the poor class. Moreover, high-cost treatment strategies were a key reason for the burden on patients’ families and the healthcare system. However, in 79.56% of cases, clinical outcomes improved after open-heart, closed-heart, or interventional treatments.
The maternal age was 27.64 ± 5.64 and 26.88 ± 4.51 (p = 0.16), and the paternal age was 30.79 ± 5.35 and 30.37 ± 4.43 (p = 0.42) in congenital heart disease and healthy subjects, respectively. Similarly, there was no statistically significant difference between cyanotic and a-cyanotic CHD for maternal and paternal age (p = 0.51, p = 0.41) (Table 2).
Assessment of underlying maternal chronic disease conditions suggested a significant association between maternal hypertension and CHDs when patients were compared with controls (OR: 3.09, 95% CI: 1.64-5.79, p = 0.0003). Similarly, maternal diabetes was significantly associated with CHD in children (OR: 2.92, CI: 1.24-6.88, p = 0.01). Child mortality due to maternal pregnancy complications and the use of medicines was non-significant (p = 0.78 and 0.58), respectively. The maternal and paternal histories also showed no significant association with congenital heart disease (p > 0.05) in the Pakistani population (Tables 3 and 4).
DISCUSSION
The current study was the first comprehensive report from the Pakistani cohort that comparatively analyzed the role of patients’ baseline characteristics and parental risk factors. The results of this study suggested an association between underlying maternal chronic disease conditions, including hypertension and diabetes, and congenital heart disease in children. In addition, the findings of this study indicated that CHD patients had a compromised health status compared with healthy subjects. Furthermore, it posed a substantial burden on patients’ families and the healthcare system, as the majority of patients in Pakistan are from middle- or low-income families. The expensive surgical treatments are considered a major challenge for cardiac surgeons, patients’ families, and Pakistan’s healthcare system.
The low BMI of patients indicates poorer nutritional status compared with healthy subjects. Okoromah et al. (14) also reported severe malnutrition and underweight in congenital heart disease patients as compared to controls.
This study’s findings were similar to results from another cohort that reported 21% of CHD patients were underweight (p < 0.001). While cyanotic vs. a-cyanotic CHD analysis showed that cyanotic were more underweight (15).
Xiang et al. (16) reported a 97% survival rate after surgeries of pediatric patients and suggested that middle and low-income families were at high risk of poor prognosis after cardiac surgery. The overall percentage of low and middle-income status patients was 69% (16). A population-based study from California showed a significant association between patient socioeconomic status and environmental triggers with high CHD incidence (17). Maternal occupation and socioeconomic disparities also showed a significant association (p < 0.001) with the disease in Iran (18). Paternal low socioeconomic status and remoteness of residence were associated with high patient mortality and adverse disease outcomes (19).
A cohort study reported no significant association between paternal age and CHDs in the Danish population (20). However, findings from the Indian cohort showed an association between maternal and paternal age and heart defects in children (21). This study’s results were in accordance with the study of Taylor et al. (22) as they reported a 0.96 OR and 0.85-1.07, 95% CI for paternal smoking (22). Other case-control results suggested a relationship between maternal smoking and the high risk of CHD in children (23). Likewise, maternal hypertension (p < 0.01), maternal smoking (p < 0.01), and maternal diabetes (p < 0.01) were found as strongly associated risk factors for congenital heart malformation in children (24). Hypertensive disorder of pregnancy has been shown to be associated with a threefold increase in CHD (OR 2.51, 95% CI: 2.38-2.64, p ≤ 0.001), and the OR for maternal diabetes and CHD in children was 5.14 (95% CI: 5.04-5.23, p ≤ 0.001) (25). The OR for maternal drug use was 2.68 (p < 0.05), the OR for family history was 4.14, and for maternal abortions was 1.12 (26). Maternal hypertension, diabetes, preeclampsia, and smoking during pregnancy showed a statistically significant association with CHDs in the pediatric population (p < 0.001) (27).
CONCLUSION
The findings of this study suggest a potential role for maternal risk factors, including hypertension, diabetes, and socioeconomic status. Furthermore, the analysis revealed that children with CHD were more likely to be underweight compared with healthy subjects. However, in the cyanotic group, anthropometric parameters, including BMI, were not statistically different from those in the acyanotic group. In addition, maternal and paternal ages did not differ between the CHDs and control groups, and between the cyanotic and a-cyanotic groups. Appropriate measures should be taken to screen for parental risk factors and family history, which may help us strengthen future CHD prevention guidelines. It is further recommended to conduct additional studies with larger cohorts across different subgroups to provide a more definitive conclusion.
