The Incidence of Congenital Heart Defects in Offspring Among Women With Diabetes in Saudi Arabia

Background: The risk of congenital anomalies is increased in infants of diabetic mothers (IDM). The most frequent cardiac anomalies in IDMs include ventricular septal defect, transposition of great arteries, and aortic stenosis. Objective: Estimating the incidence of infants with congenital heart defects (CHD) whose mothers have diabetes in Saudi Arabia at a tertiary hospital in the National Guard Health Affairs (NGHA) system. Materials and methods: This study was a retrospective cohort. The population was all births of type 1 and type 2 diabetic mothers and non-diabetic mothers (also mothers with gestational diabetes) in NGHA by following the exclusion criteria, which were mothers over 40 and below 20 years of age, and other risk factors such as drug-induced congenital disease. The data was from deliveries from January 1st 2018 to January 1st 2019. Data were collected by chart review using the Best-Care system at NGHA hospital. Statistical Package for the Social Sciences (SPSS) version 20 (IBM Corp., Armonk, NY, USA) was used for the statistical analysis. Results: A total of 1838 diabetic mothers and non-exposure, non-diabetic mothers, with the outcome of whether the infant had CHD, were included in this study. Most of the mothers (544, 30.11%) were aged 30-34 years old. About two-thirds of mothers, 1161 (63.24%), weren't diabetic, 500 (27.23%) had gestational diabetes, 132 (7.19%) were type 2 diabetes (T2DM), and 43 (2.34%) were type 1 diabetes (T1DM). Two hundred eighteen (11.82%) offspring had CHD, and the remaining 1625 (88.17%) did not. The most frequent echocardiographic abnormalities in infants of diabetic mothers were patent ductus arteriosus (PDA) (31.75%), patent foramen ovale (PFO) (31.75%), and atrial septal defect (ASD) (23.64%). Conclusion: The incidence of CHD among infants of included mothers in this cohort study was 11.82%. The most frequent echocardiographic abnormalities in the infants of diabetics were PDA and PFO. The incidence of CHD was higher among mothers who had T1DM followed by T2DM, and whose ages were between 30-34.


Introduction
Cardiovascular disease (CVD) is the major cause of mortality and morbidity worldwide [1]. Incidence and mortality of CVD have decreased in some countries, but the prevalence of CVD has risen in children and young adults in recent decades [2,3]. The risk factors for CVD change throughout a lifetime and early onset CVD could have a different reason than CVD diagnosed in later adulthood [4].

Statistical analysis
The program used was Statistical Package for the Social Sciences (SPSS) version 20 (IBM Corp., Armonk, NY, USA). The type of data was descriptive. The categorical data were presented by percentages and frequencies such as gender, CHD, and diabetes. Simultaneously, numerical data was prescribed as mean and standard deviation such as mother's age and baby's age. The relative risk was calculated to evaluate the risk and confidence interval. Logistic regression was carried out to evaluate the risk factors. The test was considered significant if the p-value was less than 0.05.

Ethical considerations
Consent was not required because it was a chart review, all data was kept safe, and no identification data were asked, such as medical record number (MRN), names, and ID (MRN was replaced with serial number). The access to research data was kept only between the group member maintaining the confidentiality and safety of the data, and the collected data was kept safe.

Discussion
Maternal DM is a risk factor for adverse maternal and fetal outcomes, including anatomical malformations such as CHD [11]. The risk for CHD in offspring is present in mothers with all types of disease, such as type 1 or 2 diabetes mellitus existing before pregnancy, along with gestational diabetes mellitus developing during pregnancy [12,13]. Our study aimed to estimate infants with CHD whose mothers have diabetes at a tertiary hospital in NGHA in Saudi Arabia.
The incidence of CHD among infants of included mothers in this cohort study was 11.82%; similar studies were conducted by Alabdulgader et al. in the eastern province of Saudi Arabia [14] and Muhammad et al. in Peshawar-Pakistan [15] where they reported a lower incidence of CHD among infants, which was 10.7% and 9.3% respectively. However, Abu-Sulaiman and Subaih [16] reported a higher incidence of 15%. Differences in incidences of various CHD in all studies are due to different sample size selection and duration of study period. We had a very limited study period, while other studies have been conducted for five years [15].
Our results found that a total of 1838 infants were registered, out of which 677 (38.83%) were infants of diabetic mothers (IDMs). Our results did not match a local study conducted in Lahore by Aslam et al., who reported a total of 1530 newborns, out of which 84 (6%) were IDMs [17]. Among our diabetic mothers 98 (5.33%) of their infants had CHD; these results mismatched with Muhammad et al. who found a vast majority of IDMs (52.5%) had various congenital heart diseases [15]. They reported that their high incidence of congenital heart disease in IDMs could be because they had a small sample size for their hospital-based study.
We reported that 62 (63.3%) of the newborn infants of diabetic mothers were male and 36 (36.7%) were female, with an overall male to female ratio of 1.72:1; similar results were also found in the Muhammad et al. study where 66.30% were male and 33.7% were female with a ratio of 1.97:1 [15].
The incidence of congenital heart diseases in our study was slightly higher in pre-gestational infants (type 1 and type 2 diabetic mothers) than gestational ones, 50 (51%) and 48 (49%) respectively, while a similar study conducted by Behjati et al. reported that incidence of CHD was more frequent in infants of pre-gestational than gestational diabetic mothers, 49 (65%) and 36 (35%) respectively [18].
In our study, the most common echocardiographic findings in the IDMs were patent ductus arteriosus (PDA), and patent foramen ovale (PFO) were diagnosed in 48% of infants, atrial septal defect (ASD) in 35.7%, ventricular septal defect (VSD) in 15.3%, pulmonary artery aneurysm (PAA) in 3.06%, and dextro-cardia in 2.04%; these results were comparable with those of another Saudi study conducted by Abu-Sulaiman and Subaih who reported that regarding the CHD findings in IDMs, there were PDA in 70%, PFO in 68%, ASD in 5%, VSD in 4%, mitral valve prolapse in 2%, and pulmonary stenosis in 1% respectively [16]. In another study, researchers found that the most common echocardiographic findings in IDMs were asymmetrical septal hypertrophy in 80%, PFO in 37.5%, and PDA in 27.5% [19].
A recent Saudi study conducted in Jaddah by Hashim et al. [20] reported that 35 years old or younger mothers are more likely to have an infant with ASD, while babies of more than 35 years old mothers presented with VSD and patent ductus arteriosus. Our results found that the overall incidence of CHD was higher among mothers whose ages were between 30 and 34 years, at 14.52%. We found no significant correlation between mothers' age and the incidence of CHD among children.
Gestational age (GA) is a significant predictor of mortality in extremely preterm infants without congenital anomalies [21]. Bastek et al. reported that late preterm infants born at 34 to 36 weeks have a higher risk of death than term infants [22]. These results matched our results, which reported that all diabetic mothers with post-term gestational ages (two; 100%) had CHD. We also reported a significant correlation between gestational age and incidence of CHD.
Among the most consistently observed findings in newborns with CHD is reduced birth weight [23]. However, our results reported a significantly higher incidence of CHD among overweight infants.

Conclusions
The incidence of CHD among infants of included mothers in this cohort study was 11.82%, with a higher prevalence of CHD among male infants (53.21%) than female ones (46.78%). The incidence of CHD was statistically higher among infants whose mothers had T1DM, followed by T2DM. However, in GDM and nondiabetic mothers, there was no statistical significance. The most common CHDs in IDMs were patent ductus arteriosus and patent foramen ovale. The incidence of CHD was higher among mothers whose ages were between 30 and 34 years. Gestational age is the most significant predictor for the incidence of CHD, where the post gestational age infants had a higher incidence of CHD. Unexpectedly, our results reported a significantly higher incidence of CHD among overweight infants.