CHD are described as structural or functional defects that occur in the heart or great vessels, Reference Liu, Chen and Zühlke1 corresponding to 28% of all congenital anomalies Reference Dolk, Loane and Garne2 with a prevalence between 40 and 100 cases per 10 000 live births. Reference Miranovic3 The Latin American Network for Congenital Malformations (ReLAMC) reported a prevalence in 2019 of CHD for Latin America of 15.53 cases/10 000 LB (95% CI 15.27–15.79). Reference Orioli, Dolk and Lopez Camelo4 According to the Colombian National Institute of Health (INS), Reference Castaño5 CHD represent 20.5% of all congenital anomalies in Colombia, with a prevalence in Bogota of 59.76/10 000 LB (95% CI 51.24–68.27) and in Cali of 11.55 (95% CI 8.01–15.08) (4). Reference Orioli, Dolk and Lopez Camelo4
Worldwide, CHD are the leading cause of infant mortality during the first year of life. Reference Marelli, Mackie, Ionescu-Ittu, Rahme and Pilote6 In Colombia, between 1992 and 2008, infant mortality secondary to CHD was 32% including fetal and neonatal deaths, Reference Roncancio, Misnaza and Peña7 being 2.7% in Bogota and Cali for 2001–2014. Reference Tassinari, Martínez-Vernaza and Erazo-Morera8 Nowadays, the most frequent CHD are patent ductus arteriosus, ventricular septal defect, and atrial septal defect, representing 57.9% of all CHD (1). Nevertheless, according to the European Concerted Action on Congenital Anomalies and Twins (EUROCAT) report, between 2012 and 2017 there has been an increasing trend regarding the prevalence of hypoplastic left heart syndrome of 8.1% and for coarctation of the aorta of 1.8%. Reference Kinsner-Ovaskainen, Morris, Garne, Loane and Lanzoni9 In the Program for the Prevention and Follow-up of Congenital Defects and Orphan Diseases of Bogotá and Cali (PREVErDEc by its acronym in Spanish); ventricular septal defect, atrial septal defect, and hypoplastic left heart syndrome were found as the most frequent CHD. Reference Tassinari, Martínez-Vernaza and Erazo-Morera8
Recent studies have shown different risk factors for CHD presentation; the most relevant are the use of drugs, exposure to toxins or organic solvents, Reference Jenkins, Correa and Feinstein10 maternal age between 35 and 60 years, and body mass index > 30 kg/m2, Reference Persson, Razaz, Edstedt Bonamy, Villamor and Cnattingius11 some maternal pathologies such as pregestational diabetes, febrile symptoms, phenylketonuria, and viral infections like influenza. Reference Jenkins, Correa and Feinstein10,Reference Wu, Liu and Sun12 Our objective was to perform an epidemiological and risk factors characterisation associated with the presentation of CHD in Bogotá and Cali in the period of 2002–2020 using PREVErDEc data.
Materials and methods
The information included was obtained from administrative surveillance data regarding PREVErDEc, which is linked to the Pontificia Universidad Javeriana, Colombia, Health Secretaries of Bogotá and Cali, the Latin American Network for Congenital Malformations (ReLAMC) and the International Clearinghouse for Birth Defects Surveillance and Research. This information was collected within the programme’s hospitals through doctors, using medical records at the time of birth, and further information was obtained with maternal interviews. Doctors were previously trained to perform physical examination searching specifically congenital anomalies in the newborn; furthermore after they searched the controls and filled out the forms according to the methodology of Latin American Collaborative Study of Congenital Malformations (ECLAMC). Reference Poletta, Gili and Castilla13
A retrospective case–control study was carried out, using the methodology of the ECLAMC. Reference Poletta, Gili and Castilla13 Cases were defined as live births or stillbirths weighing 500 g or more with CHD and born in the programme’s hospitals between January 2002 and March 2020. Controls were live births without congenital anomalies from the same hospital as the cases, maintaining a 1:4 cases-to-controls ratio.
The prevalence of CHD was established according to the following classification: isolated defined as a case with a single CHD; complex isolated understood as a case with two or more CHD; polymalformed with CHD associated with a major malformation, and syndromic defined as a case of multiple congenital malformations with a recognisable pattern and genetic aetiology (ie, Edwards syndrome).
For the social characteristics, the association with the socioeconomic status was analysed according to the National Administrative Department of Statistics, which classifies individuals on the report of variables like housing characteristics and findings within its community (access to public services and transport). We compare groups 1 and 2 (low) against 3–6 (medium-high). Additionally, maternal education was classified as low educational level (incomplete secondary) or medium-high educational level (completed secondary and/or more studies).
Quantitative variables such as birth height and weight, number of pregnancies, and maternal and gestational age were analysed by comparing case and control averages with Student t test using a 95% confidence level. By means of the frequency distribution, the odds ratio with a 95% confidence level was calculated for the variables: maternal, father’s and gestational age, patient sex, maternal BMI, presence of gestational or pre-pregnancy diabetes, and folic acid consumption according to the pregestational period and the first trimester. Data were analysed using Microsoft Excel Office 365 and EpiCalc. The statistical analysis for the prevalence of CHD per 10 000 LB was calculated according to the Poisson distribution, with a 95% confidence interval.
Results
A total of 558 255 births were found between 2002 and 2020, 1 081 cases were CHD, which stand by the following distribution: 48.20% (n = 521) isolated cases, 22.39% (n = 242) complex isolated, 22.66% (n = 245) polymalformed, and 6.75% (n = 73) syndromic (Table 1). We found CHD prevalence of 19.36 per 10 000 LB per year (95% CI 18.23–20.55).
Table 1. Case distribution of CHDs
Regarding isolated cases, the most frequent CHD were non-specified CHD 30.90% (n = 161), ventricular septal defect 17.66% (n = 92), atrial septal defect 12.09% (n = 63), and hypoplastic left heart syndrome 5.76% (n = 30) (Table 2).
Table 2. Distribution of CHDs within isolated cases
CHD = congenital heart disease.
The distribution of the patients was 89.5% (n = 968) LB, 8.1% (n = 87) died during hospitalisation; 43.7% (n = 38) female and 56.3% (n = 49) male. Finally, the remaining 2.4% (n = 26) were stillbirths, distributed among 14 females, 10 males, and 2 indeterminates regarding infant sex.
Significant differences were found in birth weight and size means between cases and controls. Additionally, gestational, maternal, and paternal ages also show significant differences (Table 3).
Table 3. Quantitative variable comparison between cases and controls
It was found that a maternal age ≥ 36 years is associated with risk of developing CDH. This is enhanced when maternal age is greater than 45 years (OR: 5.05; 95% CI 1.54–16.58), even with no chromosomal anomaly associated (OR: 4.06; 95% CI 1.17–14.07). Similar findings regarding paternal age over 45 years (OR: 1.64; 95% CI 1.12–2.38), alongside a gestational age ≤ 34 weeks (OR: 2.88; 95% CI 2.55–3.24). While the sex of the newborn did not show an association for the development of CHD (OR: 0.99; 95% CI 0.87–1.14) (Table 4).
Table 4. Risk factors associated with CHDs
†CA = Chromosomal anomaly.
Additionally, pregestational diabetes is related to CHD occurrence (OR: 7.00; 95% CI 3.20–15.34). Maternal BMI ≥ 25 Kg/m2 also showed an association (OR: 1.24; 95% CI 1.03–1.48). Regarding social variables, the low educational level of the mother was linked with CHD presentation (OR: 1.22; 95% CI 1.01–1.48), similar results were found for SS ≤ 2 (OR: 1.27; 95% CI 1.04–1.55) (Table 4).
On the other hand, folic acid (FA) supplementation was demonstrated to decrease the probability of presenting CHD in the pregestational period (OR: 0.20; 95% CI 0.05–0.81) and in the first trimester (OR: 0.43; 95% CI 0.38–0.50) (Table 4).
Discussion
This study focused on the epidemiological description of CHD and the analysis of risk factors associated with the presentation of this congenital anomaly in 44 hospitals in Bogotá and Cali between 2002 and 2020.
The prevalence of CHD in this study was 19.36 per 10 000 LB (95% CI 18.23–20.55). This is considerably lower than other European countries reported in the EUROCAT, such as Spain, which had a prevalence of 79.37 per 10 000 live births between 2008 and 2017. Reference Kinsner-Ovaskainen, Morris, Garne, Loane and Lanzoni9 Such variation could be due to the under-reporting and diagnosis of CHD cases in developing countries like Colombia (8). Although the prevalence was higher than some Latin American countries such as Chile, whose prevalence was 14.76 per 10 000 during the period 2017–2019. Reference Orioli, Dolk and Lopez Camelo4
According to Tassinari et al, during the period 2001–2014, in Bogotá the prevalence of CHD was 15.1 per 10 000 LB (95% CI 13.94–16.36), Reference Tassinari, Martínez-Vernaza and Erazo-Morera8 and 11.55 (95% CI 11.01–15.08) in Cali, Reference Orioli, Dolk and Lopez Camelo4 less than what was found in our study between 2015 and 2020; being 35.94 per 10 000 LB (95% CI 32.68–39.44). We found an increasing trend over the years regarding CHD prevalence, which is presumably due to the implementation of a vigilance programme as PREVERDEC. Reference Tassinari, Martínez-Vernaza and Erazo-Morera8 However, the most frequent isolated CHD was non-specified, revealing the need to improve the prenatal and postnatal diagnostic mechanisms, optimising the specificity in the notification of this malformation. Reference Eckersley, Sadler, Parry, Finucane and Gentles14
Regarding birth size and weight, we found significant differences between cases and controls (p < 0.01) (Table 3). In spite of that result, these variables are not attributable as CHD risk factors, as they are evident after birth.
Several studies have shown that maternal age > 35 years is a risk factor for CHD, Reference Persson, Razaz, Edstedt Bonamy, Villamor and Cnattingius11,Reference Persson, Cnattingius and Villamor15,Reference Miller, Riehle-Colarusso, Siffel, Frías and Correa16 this result was also found by us, especially for those aged > 45 years, excluding cases with Down syndrome (OR: 5.05; 95% CI 1.54–16.58). However, the findings differ to some extent in comparison to studies carried out in Europe, where this association was not statistically significant. Reference Best and Rankin17–Reference Dolk, McCullough, Callaghan and Beyerlein19 We found that 82.4% (n = 28) of syndromic cases in mothers ≥ 36 years old correspond to Down syndrome, suggesting the relationship between these two variables. Reference Bruckner, Singh, Lelong and Khoshnood20 The impact of this result on public health is high in spite of increasing the probability of CHD presentation, because in 2017 in Colombia, 10.9% (n = 71 712) of births were mothers over 35 years of age. Reference Acevedo and Valle21
A previous cohort study by Joinau-Zoulovits et al. showed that paternal age greater than 35 years increases the risk of developing CHD by 16%; Reference Joinau-Zoulovits, Bertille, Cohen and Khoshnood22 while our study found that this risk occurs from an age > 45 years (OR: 1.64; 95% CI 1.12–2.38). This meta-analysis only considers paternal age without maternal age association for CHD presentation. We found that 58.3% (n = 21) of paternal > 45 years have a partner > 35 years, which increases the risk of presenting CHD as previously found; however, other explanations could be considered.
We found that gestational age ≤ 34 weeks was associated with increasing the risk for CHD (OR: 2,88; 95% CI 2.55–3.24). Similar results were obtained by Steurer et al for ≤ 38 weeks Reference Steurer, Baer and Keller23 and by Chu et al for ≤ 30 weeks. Reference Chu, Li, Kosinski, Hornik and Hill24 This could be attributable to instances of patent ductus arteriosus, which may arise as a result of prematurity. Even so, low gestational age cannot be addressed as a risk factor for CHD since it is evident after cardiac organogenesis, even though gestational time is an important factor in development. Reference Persson, Cnattingius and Villamor15,Reference Cnota, Gupta, Michelfelder and Ittenbach25 Still, it is recommended that each premature newborn have an ideal surveillance and evaluation of possible congenital anomalies.
Additionally, we did not find any association between the sex of the newborn and the risk of developing CHD (OR: 0.99; 95% CI 0.87–1.14). However, there is heterogeneity in terms of the results obtained in other studies, since the sex of the newborn was a risk factor, whether it is male, Reference Persson, Cnattingius and Villamor15 woman, Reference Persson, Razaz, Edstedt Bonamy, Villamor and Cnattingius11 or both. Reference Øyen, Diaz and Leirgul18 Although the results vary, it is important to note that differences are reported in terms of prognosis and mortality in patients with CHD according to sex, being higher for females. Reference Aubry and Demian26 Regarding maternal BMI, different studies have reported an increased risk of presenting CHD for BMI < 18Kg/m2, Reference Yuan, Liu and Zhu27 when being overweight or obese, Reference Persson, Razaz, Edstedt Bonamy, Villamor and Cnattingius11,Reference Persson, Cnattingius and Villamor15,Reference Liu, Ding and Yang28 similar to our results when the BMI ≥ 25Kg/m2 (OR: 1.24; 95% CI 1.03–1.48). Yet, Dolk et al Reference Dolk, McCullough, Callaghan and Beyerlein19 found no association for maternal BMI.
In this study, it is important to recall the association found between pre-pregnancy diabetes and the risk of presenting CHD (OR: 7.00; 95% CI 3.20–15.34), as demonstrated in different studies. Reference Jenkins, Correa and Feinstein10,Reference Øyen, Diaz and Leirgul18,Reference Dolk, McCullough, Callaghan and Beyerlein19,Reference Chen, Yang and Chen29 Risk association for transposition of great arteries, septal defects and outflow tract defects was also observed. Reference Jenkins, Correa and Feinstein10 A possible mechanism that explains the relationship between diabetes and the presentation of CHD was proposed by Engineer et al. Where pregestational diabetic patients develop oxidative stress induced by hyperglycaemia, increasing reactive oxygen species and free radicals, allowing cell damage and alteration in gene expression during cardiac morphogenesis. Reference Engineer and Greco30 Some works try to reduce the risk through exercise, although it has not been shown as a protective factor in humans. Reference Dolk, McCullough, Callaghan and Beyerlein19 On the other hand, in the same study by Dolk et al Reference Dolk, McCullough, Callaghan and Beyerlein19 gestational diabetes was not a risk factor for CHD, according to our findings (OR: 0.83 95% CI 0.55–1.26); however, it was considered a risk factor for other authors. Reference Wu, Liu and Sun12,Reference Chen, Yang and Chen29
Different studies demonstrate that FA consumption in the pre-pregnancy period and during any trimester of pregnancy. Reference Jenkins, Correa and Feinstein10,Reference Feng, Wang and Chen31 Though our findings highlight the importance of pre-pregnancy FA consumption for the prevention of CHD (OR: 0.20; 95% CI 0.05–0.81) and during the first trimester of pregnancy (OR: 0.43; 95% CI 0.38–0.50) allowing optimal levels of FA prior to the period of cardiac morphogenesis. In addition, this finding is supported by the risk of presenting CHD that is reported by the use of FA antagonists (OR: 7.7; 95% CI 2.8–21.7). Reference Hernández-Díaz and Mitchell32 In Colombia, the resolution 3280 of 2018 of the Ministry of Health and Social Protection establishes the supplementation of FA and micronutrients 0.4mg/day in the gestational period, and for those mothers with history of births with congenital defects, a dose of 4mg/day has to be initiated 3 months before pregnancy. 33
It is important to recognise the role of FA in the context of cardiac development, in that it is required for cell maintenance and division, as well as for the construction and repair of DNA. Reference Czeizel, Dudás, Vereczkey and Bánhidy34 Therefore, a daily intake of 400 μg is recommended through diet or using supplements. Reference Czeizel, Dudás, Vereczkey and Bánhidy34 In Colombia for 2011, 89 unintended pregnancies were estimated per 1 000 women of reproductive age, Reference Prada, Singh, Remez and Villarreal35 so there is a public health problem regarding late multivitamin supplementation. Thus, the fortification of rice with FA is an important prevention strategy, for 2017 it was calculated that 35% of the rice was fortified. Reference Rozo36
The meta-analysis carried out by Yu et al showed that the low SS (OR: 1.05; 95% CI 1.01–1.09) and the mother’s low educational level (OR: 1.11; 95% CI 1.03–1.21) are risk factors for the presentation of CHD, Reference Yu, Feng and Yang37 which agrees with our findings for low SS (OR: 1.27; 95% CI 1.04–1.55) and mother’s low educational level (OR: 1.22; 95% CI 1.01–1.48), respectively, similar findings in other study. Reference Peyvandi, Baer and Chambers38 On the contrary, Dolk et al did not find a significant association for any SS, but the mother’s low educational level was associated with CHD (OR: 1.63; 95% CI 1.13–2.34). Reference Dolk, McCullough, Callaghan and Beyerlein19
In developing countries, low SS is a risk factor for CHD since it represents having less access to health services and education about contraceptive mechanisms and the preconception and prenatal care that must be taken. Reference Adegbosin, Zhou, Wang, Stantic and Sun39 Additionally other factors are linked to early age pregnancies and thus with risk behaviours such as folic acid deficiency. Likewise, maternal malnutrition and exposure to teratogenic agents is reflected in low SS due to the scarcity of resources to live in optimal environments, Reference Bronberg, Groisman, Bidondo, Barbero and Liascovich40 factors that are possibly associated with the appearance of CHD, still other explanations can be considered.
In Colombia, a mandatory maternal-perinatal health care route is established for all pregnant women and its costs are covered by the health system. It includes two prenatal ultrasounds, one between weeks 11 and 14 to evaluate aneuploidies, and another between weeks 18 and 24 to evaluate structural abnormalities. Factors such as late diagnosis of pregnancy, the socio-economic conditions of patients, and the lack of adherence to prenatal programmes influence the fact that this route is not fulfilled for some pregnant women. As we have previously described, prenatal detection of CHD is around 30% in Bogotá and Cali, and this also tends to increase under-reporting. Reference García, Imbachí, Hurtado, Gracia and Zarante41
The study’s main limitations are incomplete records within the surveillance and monitoring system, affecting the sample space for the different analyzes, as well as the memory bias that occurs in mothers on behalf it is a retrospective study.
Conclusion
This study analysed the different risk and protective factors associated with the presentation of CHD. We found maternal and paternal age > 45 years, in addition to pregestational diabetes, maternal BMI ≥ 25 kg/m2, low SS, and educational level as risk factors for CDH development. We also found that folic acid intake in the pregestational period and during the first trimester of pregnancy are protective factors for the same outcome. This highlights the importance of primary prevention measures for CHD and the implementation of diagnostic and notification methods for congenital anomalies, improving the outcome of mortality and prognosis.
Acknowledgements
To the Health Secretaries of Bogotá and Cali and the Program for the Prevention and Follow-up of Congenital Defects and Orphan Diseases of Bogotá and Cali.
Author contribution
The study conception and design, material preparation, data collection, and analysis were performed by EP, VH, KS, and IZ, as well as the writing of the first draft. Verification of the data provided was performed by GG and JH. Critical analysis of the content was performed by PHV and IZ. All authors read and approved the final manuscript.
Financial support
The authors reported there is no funding associated with the work featured in this article.
Competing interests
No potential conflict of interest was reported by the authors.
Ethical standard
Ethical approval was waived by the local Ethic Committee of Pontificia Universidad Javeriana in view of the retrospective nature of the study and all the procedures being performed were part of the routine care. Approval code: FM-CIE-8324-14.
