Prevalence of congenital heart disease according to the echocardiography findings in 8145 neonates, multicenter study in southern Iran

Abstract Introduction Congenital heart disease (CHD), the lethal congenital anomaly in newborns, is multifactorial, with environmental and genetic factors contributing to its occurrence. Although some studies on the prevalence of CHD have been conducted throughout the country, this large‐scale study aims to provide information on the prevalence of various types of CHDs in newborns according to the echocardiography findings. Patients and Methods Over 3 years, 8145 neonates with suspected CHD who underwent echocardiography by a trained pediatric cardiologist were included in this multicenter, cross‐sectional observational study. CHD was categorized into two major groups; cyanotic and acyanotic heart disease. The SPSS version 22 software was used to analyze the data with a significance level set at 0.05. Results Of 8145 neonates who were referred to our centers with CHD symptoms, 6307 were indicated for echocardiography. The mean age of the studied population was 8.5 ± 9.3 days and the male‐to‐female ratio was 2.6, especially in the arterial septal defect (ASD), ventricular septal defect (VSD), and patent ductus arteriosus (PDA) groups. 77.2% of patients had acyanotic heart disease (100 in 1000 neonates) with ASD as the most common one and 9% were diagnosed with cyanotic heart disease (11 in 1000 neonates) with transposition of the great arteries as the most common form and the aortopulmonary window was the rarest form. Conclusion This large prospective, multicenter screening study reported arterial septal defect (85%) and patents with ductus arteriosus (32%) as the most frequent type of CHD. Moreover, the prevalence of male patients was significantly higher. This information would be helpful for health policy makers, stakeholders, and general practitioners in regions where there are no trained pediatric cardiologist fellowships and limited access to echocardiography devices for better management of CHD.


| INTRODUCTION
Congenital heart disease (CHD) is a group of abnormalities in the heart structure or cardiovascular function occurring from birth, even if diagnosed later. 1 These cardiac defects range from minor lesions with no clinical manifestations to potentially fatal conditions. 2 The top five most common acyanotic CHDs are the followings: arterial septal defect (ASD); pulmonary stenosis (PS); ventricular septal defect (VSD), and patent ductus arteriosus (PDA), and tetralogy of Fallot (TOF). 3 Despite numerous published studies, the exact causes of CHD have not yet been fully discovered. CHD appears to be a multifactorial disease caused by environmental and genetic factors. 4 Environmental factors include a history of maternal illness during pregnancy, a positive familial history, the number of pregnancies, maternal hypertension, and medication exposure during pregnancy. 5 Moreover, mortality has increased over the past decades due to a lack of appropriate diagnostic and treatment facilities in low-and middle-income countries. 6 CHD is newborn's most common lethal congenital disorder, accounting for roughly one-third of all congenital birth defects. 2,7 At least 1.5 million children are born each year with CHD, 8 and it is a great emerging problem in pediatric global health. Although we may not be able to change the prevalence of CHDs, resources and screening, as well as effective interventions, are required to improve patients' survival and prognosis. 9 All types of CHDs may severely reduce the quality of life of all family members, impose high costs on the health care system, necessitate adulthood follow-ups, repeated surgical procedures. 1 In our country, several studies have reported a prevalence between 4 and 8 per 1000 live births. 10 The systematic review conducted in 2019 found a broad range of CHD prevalence in Iran which necessitates further extensive epidemiological studies in our region. The prevalence of CHD varies greatly among populations and geographic locations. Therefore, it is essential to study the epidemiology of CHD in different countries and populations for understanding its underlying causes, risk factors, and potential preventive measures. As compared to earlier published articles, there are a number of novel aspects to the present study. First, the sample size of more than 8000 inpatient neonates is relatively large, providing a more robust representation of the population under study, increasing the statistical power of the study, and enabling researchers to detect smaller differences and associations between factors. Secondly, our study is unique in terms of its focus on Iran, a country that has not been extensively studied regarding CHD epidemiology. As such, this study can provide important insights into the prevalence and distribution of different subtypes of CHD in our region, which can aid the identification of high-risk groups and inform strategies for the early detection and management of CHD in neonates. Finally, this study can provide valuable information on the clinical and demographic characteristics of neonates with CHD in Iran, including the types of defects and associated comorbidities. This information can help clinicians and researchers better understand the clinical course of CHD and its impact on neonatal health not only in Iran but also in other neighborhood countries.
The current study aims to assess the epidemiology and prevalence of common CHD subtypes in a huge group of neonates referred to our hospitals in southern Iran . The study province   comprises central facilitated cardiology departments in Iran, and each year, many CHD patients from all over the country seek treatment at our hospitals.

| PATIENTS AND METHODS
This cross-sectional, retrospective, and multicenter study was During the study period, 8145 live-born newborns were suspected of having CHD and were subjected to echocardiography.
Data of the current study were obtained from patients' records and online discharge sheets filled out by medical students and cardiology attendings at the SUMS Clinical database (http://ped.sums.ac.ir).
Echocardiography reports and demographic information such as age, gender, and admission date were recorded in the excel sheet for further coding and data analysis.

| Echocardiography
A board-certified cardiologist performed a thorough history and physical examination of the patients. In the event of any suspicion of CHD, echocardiography was performed in accordance with standard transthoracic echocardiography guidelines. 11 The M-mode, twodimensional, and color Doppler parameters were obtained using a Samsung HS70 or a GE Vivid 3 echocardiography machine and recorded in the university's database system. Two-dimensional and color doppler imaging from standard views were part of the examination protocol (Parasternal Long Axis, Parasternal Short Axis, Apical 4 Chamber, Subxiphoid (Subcostal), and apical). Sedation was not routinely used, and most cases were performed while the patient was sleeping in the echocardiography room. Furthermore, the echocardiography data of Complex CHD were reviewed and confirmed by second-hand pediatric cardiologists before entering into the database system.
Indications of echocardiography: 1. Cyanosis and low O2 saturation early after birth.
3. Pathologic cardiac murmurs in routine physical examination.
4. High-risk neonates (history of diabetic Mellitus in mother, an autoimmune disease in mother, maternal hypertension, group x medications exposure during pregnancy.) 5. History of complex CHD in other siblings. 6. Neonates with antenatally diagnosed with CHD.

| Statistical analysis
The data is described using mean, standard deviation, frequency, and percent. The statistical package for social sciences (SPSS Inc.) version 22.0 was used for all statistical analyses. The χ 2 test was performed to compare two genders in each disease, with the significance level set at 0.05. We also used two proportion test to compare the frequency between genders with the significance level of 0.05.
Normality of data was assessed using Kolmogorov-Smirnov test.

| RESULTS
After thorough history taking and physical examination of 8147 neonates with suspected CHD, 6307 (77.4%) cases were indicated for echocardiography. The average age of the studied population (those who underwent echocardiography) was 8.5 ± 9.3 days, ranging from 0 to 30 days. Overall, the prevalence of CHD was significantly higher in male neonates, resulting in a male-to-female ratio of 2.6 (p < 0.001). According to the χ 2 test, the prevalence of male patients was significantly higher in cyanotic patients with single-ventricle, TGA, DoRV, and TOF disease and in the acyanotic patients with MPV, RVH, LVH, PDA, and VSD disease (p < 0.05).
Whereas the proportion of male-to-female was significant in all types of acyanotic and in abnormal situs, PA, and AVSD among cyanotic types as shown in Figure 1A Six thousand two hundred and ninety (77.22%) of 6307 neonates who underwent echocardiography had acyanotic heart disease (100 in 1000 neonates) of which, ASD was the most common one, accounting for 65.9% (85 in 1000 neonates) especially PFO and small ASD second types. PDA was the second most common acyanotic heart disease comprising for 32.5%, followed by VSD (15.4%). CoA was the least common defect in the acyanotic category (7 in 1000 neonates). Only 731 (8.97%) participants diagnosed with cyanotic heart disease (11 in 1000 neonates). TGA was the most common cyanotic CHD, accounting for 1.8% (2 in 1000 neonates), followed by TOF, the presence of a single ventricle (primarily in patients with hypoplastic right ventricle), and pulmonary vein anomalies respectively. On the other hand, truncus arteriosus and AP window were the least common types of CHD, respectively (0.04 in 1000 neonates).

| DISCUSSION
In the present population-based study we identified 6307 patients with CHD among 8145 live neonates suspected to CHD. Our results revealed that the most common cyanotic defects were TGA (2 in 1000 neonates), TOF, and single ventricle, whereas the most common acyanotic defects were ASD (85 in 1000 neonates), followed by PDA and VSD. The study also showed a significantly higher prevalence of CHD among male neonates, with a male-tofemale ratio of 2.6. This is consistent with previous studies, which have suggested a higher incidence of CHD among male neonates. 12 It has been found differences in the prevalence of CHD by type, with acyanotic heart diseases being more common than cyanotic heart diseases. The results of this research offer significant epidemiological insights regarding the occurrence and categories of CHD among newborns in Iran. The high prevalence of CHD among neonates highlights the need for effective screening programs and early detection strategies to ensure timely and appropriate care.
The prevalence of congenital heart defects varies significantly across countries. The prevalence of CHD in Iranians ranges from 4.2 to 8.6 per 1000 live births. 13,14 Rahim et al. examined 3061 patients in western and southern Iran over 9 years and found that ASD was the most common type of congenital anomaly which was in line with our findings. Another study by Nikyar et al. conducted over 2 years reached the same conclusion. 14,15 In a recent article published in China, ASD was the most common CHD among all participants. 16 In contrast to our study, VSD was reported as the most common CHD in some other studies. 15,17,18 According to a study on 177 neonates, VSD was the most common type of congenital defect (44%), followed by ASD (21%). 13 VSD has also been reported as the most common CHD in China and Japan. 19,20 In contrast to most published studies, in which ventricular defects (ASD or VSD) are the most common types of CHD, our results showed PDA to be the second most common type of congenital anomaly (32%) among all patients. Our findings revealed a higher incidence of PDA than in previous studies. 13 Gender as a neonatal factor has been reported to have a significant effect on the type and presence of CHD so it can be considered a risk factor. 22,23 Our results show that the ratio of male to female neonates is 2.6, which means that CHD is more prevalent in male infants. The prevalence of male patients ranged from 45% to 73% of all conditions in the present study. The highest male propensity was found in neonates with PA and PS among cyanotics and acyanotic respectively. However, the incidence of TOF was higher in male infants in the earlier study, which is consistent with the results of the current study. These differences between studies may suggest that CHD is multifactorial and that maternal and environmental factors vary widely from study to study.
It is also worth noting that according to the National Organization for Civil significantly higher than that of female newborns (130720) during the study period. 28 The current study's findings on the prevalence and types of CHD among neonates might have important impacts on healthcare providers, influencing targeted strategies to enhance the timely and appropriate care of this patient population. For instance, these findings can inform the development of screening programs that target high-risk neonates for early detection and management of CHD, through initiatives such as encouraging early prenatal care and screening. Such programs can help to reduce mortality rates and improve long-term health outcomes. In addition, the findings of this epidemiological study can inform the allocation of healthcare resources, including medical staff, equipment, and funding, to NICUs and pediatric cardiology centers, thereby ensuring that these facilities are adequately equipped to meet the specific needs of neonates with CHD. Furthermore, these findings can assist pediatricians and general physicians in better understanding the clinical course of CHD, including the types of abnormalities and associated comorbidities. 29 Finally, the large study population of neonates is the main strength of this clinical survey. As a result, our findings can accurately represent the newborn population in southern Iran. Furthermore, we broadened this study's scope by looking at various cyanotic and acyanotic CHD abnormalities. All neonates in this study were subjected to an echocardiographic examination without being sedated. The absence of sedation was a double-edged sword. On the one hand, there was no concern about the medication's side effects, which made it easier for the mothers to participate in the study. On the other hand, because echocardiography was usually performed during the newborns' sleeping time, this was one of the T A B L E 1 Echocardiographic profile of cyanotic congenital heart disease.

ACKNOWLEDGMENTS
The authors would like to express gratitude to Pediatrics' cardiology department and the center for developing clinical research in Namazee hospital, Shiraz, Iran, for their editorial assistance.

CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest.

DATA AVAILABILITY STATEMENT
The data supporting the present study's findings are available on request from the corresponding author. However, they are not publicly available due to privacy and ethical restrictions.

ETHICS STATEMENT
The manuscript has been approved by all authors and has never been published or under the consideration for publication elsewhere. We confirm that all figures and tables are original and created by authors. We guarantee that all authors listed on the title page have read the manuscript and attest to the validity and legitimacy of the data. We would also like to undertake that

TRANSPARENCY STATEMENT
The lead author Amir Naghshzan affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.