Relevance

Strangely enough, congenital heart disease is the most common congenital disease in newborns. The prevalence at birth ranges from 5 to 15 per 1,000 live births [1-4].

One earlier study showed that the proportion of cases associated with these external factors can reach 30% for certain types of congenital heart defects [5,7]. Periconceptional consumption of multivitamin supplements containing folic acid may reduce the risk in offspring [8,9]. Maternal lifestyle factors, including cigarette smoking, alcohol consumption and obesity, were also associated with the risk of being born with congenital heart defects [10-12]. It has also been established that maternal rubella infection during pregnancy can lead to the appearance of various congenital heart defects in the offspring [6, 13].

To date, the available information on the connection of chronic diseases of the mother with congenital heart defects is limited. Pregnant women with congenital heart defects are at increased risk of having children with congenital heart defects [14]. In addition, the diseases were associated with maternal gestational diabetes [15-17]. One recent population-based study noted that a number of chronic maternal diseases, including diabetes mellitus, hypertension, connective tissue disorders and congenital heart defects, were closely associated with an increased risk of congenital heart defects in offspring [18]. We conducted a study to further assess the potential role of chronic maternal diseases in the risk of congenital heart defects in offspring.

We studied 150 newborns hospitalized in the perinatal center of the city of Samarkand, used the questionnaire method in women with children born with congenital heart defects from 2016 to 2020. The study cohort consisted of from 2016 to 2020.

For the current study, we used all component datasets, with the exception of mortality registrations. The Birth Notification dataset contains information about prenatal care and lifestyle of pregnant women, as well as data on stillbirths and characteristics of newborns registered at birth (for example, congenital anomalies and Apgar scores). The data set on birth registration consists of socio-demographic characteristics of live births (for example, the sex of the child, birth weight and gestational age; single and multiple births; and the order of birth) and parents (for example, age at the time of birth, education and marital status).

For this study, we used data from both inpatient and outpatient medical institutions, which provided information about diagnoses and procedures for each clinical visit and appointment.

Materials

Our study was a population-based, nationwide cohort study of live births between 2016 and 2020. To be included in the study, the gestational age had to exceed 22 weeks and the birth weight had to be at least 500 g in order to avoid including live births with an implausible gestational age or birth weight [25].

Variable Impacts

We have identified chronic diseases diagnosed in mothers before pregnancy, both in inpatient and outpatient settings, using codes from the clinical modification of the International Classification of Diseases of the 9th revision. These conditions included gestational diabetes (both type 1 and type 2), hypertension, congenital heart defects, thyroid diseases, anemia, systemic connective tissue diseases, epilepsy and specific psychological disorders. We considered these chronic diseases primarily because in previous studies that we studied, it was assumed that they were associated with the occurrence of congenital heart defects [14,16-18].

Variable Results

The variables were any forms of congenital heart defects in a child identified by the ICD-9-CM codes. In order to avoid introducing clinically insignificant forms or spontaneously resolved defects, we included only those children whose injuries were registered at least once during hospitalization or with more than 3 outpatient visits within 1 year after birth. [4,26] We have identified 2 subgroups depending on severity. Tetrad of Fallot, transposition of the main arteries, double vasodilation from the right ventricle, total abnormal pulmonary venous return, tricuspid valve atresia, congenital corrected transposition of the main arteries, common arterial trunk and common ventricles were classified as severe; all other lesions were classified as mild.

Statistical Analysis

We calculated the prevalence of all and specific types of congenital heart defects from 2016 to 2020 and used the Poisson regression model to check trends in the prevalence of these diseases over a certain period. We evaluated the prevalence values of all and specific types of congenital heart defects due to chronic maternal diseases that existed before pregnancy, we corrected potential confusions using logistic regression models and presented the results in the form of adjusted Odds Ratios (ORs) and 95% Confidence Intervals (CIs). Since a mother could have had more than one delivery during the 5-year study period, we used a logistic regression model with a generalized estimation equation to account for correlations within participants between offspring born to the same mothers and offspring to obtain reliable estimates of the standard error [21].

To assess the potential impact of chronic maternal disease on the risk of congenital heart defects in offspring, we calculated the percentage of risk associated with the population (i.e., the proportion of cases that could have been avoided in the population if the selected chronic maternal disease had been eliminated) [31].

Risk of Congenital Heart Defects

After excluding stillbirths and live births with a gestational age of less than 22 weeks or a birth weight of less than 500 g, we identified 150 children between 2004 and 2010. A total of 72 live births were diagnosed with congenital heart defects in infancy, accounting for a total prevalence of 19.63. After excluding infants with isolated ductus arteriosus born before 37 weeks of pregnancy, the overall prevalence decreased to 16.92. The prevalence of severe forms was 1.35 and mild forms-16.57. Among the reported severe conditions, the most numerous were tetralogy of Fallot 0.58, transposition of the main arteries 0.42 and double discharge of vessels from the right ventricle 0.23. Atrial septal defect 10.29, ductus arteriosus 5.19 and ventricular septal defect 4.92 accounted for the majority of mild forms of congenital heart defects.

During the study period, there was no significant trend in the overall prevalence of congenital heart defects. However, the prevalence of severe forms showed a tendency to a significant decrease (p for trend <0.001) - from 1.52 in 2016-2017 to 1.11 in 2020. A significant downward trend was also noted for specific types, including transposition of the main arteries, common ventricle, hypoplastic left heart syndrome, common arterial trunk and tricuspid valve atresia. There was no significant trend in the prevalence of mild congenital heart defects, but the prevalence of some mild forms, including atrial septal defect, open ductus arteriosus (≥37 weeks) and pulmonary stenosis, showed significant differences during the study period.

The Relationship Between Chronic Maternal Disease and Congenital Heart Disease

Several chronic maternal diseases, in particular type 1 and type 2 diabetes, hypertension, congenital heart defects, anemia, connective tissue disorders, epilepsy and mood disorders, were significantly associated with a higher prevalence of any form of congenital heart defects in offspring. The chronic diseases of the mother that were reliably associated with mild forms of congenital heart defects in the offspring were the same as those that were reliably associated with all congenital heart defects. However, only maternal congenital heart defects (adjusted OR 6.72, 95% CI 4.06–11.12) and type 2 diabetes (adjusted OR 2.80, 95% CI 2.04-3.85) were associated with a significantly higher prevalence of severe congenital heart defects in offspring.

The presence of the following chronic diseases in mothers increased the risk of congenital heart defects in their children than in mothers who did not suffer from chronic diseases: type 1 diabetes mellitus (adjusted odds ratio [OR] 2.32, 95% confidence interval [CI] 1.66–3.25), type 2 diabetes mellitus (adjusted OR 2.85, 95% CI 2.60–3.12), hypertension (adjusted OR 1.87, 95% CI 1.69–2.07), congenital heart defects (adjusted OR 3.05, 95% CI 2.45–3.80), anemia (adjusted OR 1.31, 95% CI 1.25–1.38), connective tissue disorders (adjusted OR 1.39, 95% CI 1.19-1.62), epilepsy (adjusted OR 1.37, 95% CI 1.08-1.74) and mood disorders (adjusted OR 1.25, 95% CI 1.11-1.41). The same pattern was observed in mild forms of congenital heart defects. A higher prevalence of severe congenital heart defects was observed only among the offspring of mothers with congenital heart defects or type 2 diabetes.

Population Risk of All Congenital Heart Defects

The presence of any of the chronic diseases studied here was associated with a population risk of 5.73%. The highest population risk of developing a specific chronic disease was noted for anemia 2.17%, followed by type 2 diabetes 1.45% and hypertension 0.71%.

Interpretation

In this population-based study, we identified a downward trend in the prevalence of severe, but not mild, congenital heart defects from 2016 to 2020. We also found that some chronic maternal diseases, in particular type 1 and type 2 diabetes, hypertension, congenital heart defects, anemia, connective tissue disorders, epilepsy and mood disorders, were associated with a significantly higher prevalence of common and mild forms of congenital heart defects in offspring. Only congenital heart defects in the mother and type 2 diabetes were significant in severe congenital heart defects in offspring. Although some maternal diseases have been associated with congenital heart defects in offspring, caution should be exercised when interpreting these associations, since the risks associated with the population were very low.

The prevalence of congenital heart defects among infants was relatively higher than the prevalence reported from other countries, which ranged from 5 to 15 [1-4]. The increasing use of echocardiography in newborns to facilitate early diagnosis of mild congenital heart defects is a possible explanation for this difference, especially in asymptomatic infants [4,32].

Moreover, the prevalence of congenital heart defects in our study was higher than the prevalence reported in one previous local study. 

It is unclear why the prevalence of severe congenital heart defects shows a downward trend over time. One possible explanation is that the more frequent use of prenatal diagnostic methods, especially fetal echocardiography, led to more parents terminating pregnancies with known severe cardiac abnormalities. A previous study showed that earlier diagnosis of congenital heart disease was associated with an average increase in the probability of termination by 1.4 times [34].

In this study, congenital heart defects of the mother were associated with about 3 times higher incidence of congenital heart defects in offspring, which is consistent with the reports of previous studies [14,18]. Genetic predisposition may have played an important role in this association. Many previous studies have revealed significant links between maternal pre-gestational type 1 and type 2 diabetes and the risk of congenital heart defects in offspring aged 16-18 years and have shown that poor glycemic control in the first trimester of pregnancy is associated with an increased risk of congenital heart defects [16].

In one of the previous studies, an increase in the risk of congenital heart defects by 20-30% was noted in the offspring of mothers with a history of hypertension, which corresponded to our results. Chronic hypertension can lead to uteroplacental insufficiency, which leads to impaired blood flow to the developing fetus and increases the risk of congenital heart defects if they are present in the early stages of pregnancy. In addition, mothers exposed to certain antihypertensive drugs are at increased risk of having children with cardiovascular malformations [37].

The current study also found that maternal epilepsy and mood disorders were associated with an increased risk of congenital heart defects in infants. Previous studies have shown that the use of certain anticonvulsants, [38] tranquilizers [39] or sleeping pills [31] is associated with an increased risk of congenital heart defects in offspring. Thus, exposure to certain therapeutic drugs may be a possible explanation for the increased risk among mothers with epilepsy and mood disorders.

Our study also showed that maternal anemia and connective tissue disorders were associated with an increased risk of congenital heart defects in offspring. Anemia is a complex condition that needs to be carefully studied to determine the underlying causes and the possibility of mixing with other factors associated with insufficient intake of multivitamins or folic acid, such as insufficient nutrition. However, the specific reasons for these findings are unknown and need further investigation. Finally, the factors underlying the relationship between maternal connective tissue disorders and congenital heart defects in offspring are still unknown. Future studies should be conducted to confirm or refute these findings.

Strengths and Weaknesses

This study was based on a sample that made it possible to reliably assess the relationship between chronic maternal diseases and specific types of congenital heart defects. 

Some limitations should be noted. We limited the detection period to the first year of life, which may have led to an underestimation of congenital heart defects that developed in later years. However, such insufficient identification will be minimal, given the high frequency of prenatal care [21] and medical examinations during infancy [36]. Although their prevalence was low, some lifestyle factors of mothers, including smoking and alcohol consumption, are likely to be underestimated in the Birth Notification dataset compared to data from previous surveys. Also, the decision to exclude children with a birth weight of less than 500 g or a gestational age of less than 22 weeks was based mainly on expert opinion. Such exclusions are expected to have little impact on our results.

Chronic maternal diseases, including diabetes, hypertension, congenital heart defects, anemia, connective tissue diseases, epilepsy and mood disorders, may predispose mothers to give birth to children with congenital heart defects. The results of this study are valuable for counseling on pre-conception and identification of high-risk pregnant women. Women with such chronic diseases should, if possible, control their disease before conception in order to minimize the risk of congenital heart defects in their children. For pregnant women at high risk, a more frequent prenatal examination (with fetal echocardiography) may be prescribed. Early recognition of congenital heart defects also ensures optimal preparation and care during pregnancy, childbirth and the postpartum period.

Thus, children whose mothers suffer from several types of chronic diseases at once are at greater risk of congenital heart defects. It seems reasonable, pre-conception counseling and optimal treatment of pregnant women with chronic diseases.

1. Dolk H. “Congenital heart defects in europe: prevalence and perinatal mortality, 2000–2005.” Circulation, vol. 123, 2011, pp. 841–849.

2. Oyen N. et al. “National time trends of congenital heart defects, Denmark, 1977–2005.” American Heart Journal, vol. 157, 2009, pp. 467–473.e1.

3. Reller M.D. et al. “Prevalence of congenital heart defects in metropolitan Atlanta, 1998–2005.” Journal of Pediatrics, vol. 153, 2008, pp. 807–813.

4. Wu M.H. et al. “Prevalence of congenital heart disease at live birth in Taiwan.” Journal of Pediatrics, vol. 156, 2010, pp. 782–785.

5. Tennant P.U. et al. “20-year survival of children born with congenital anomalies: A population study.” Lancet, vol. 375, 2010, pp. 649–656.

6. Ren S. et al. “Mortality in infants with cardiovascular defects.” European Journal of Pediatrics, vol. 171, 2012, pp. 281–287.

7. Wilson P.D. et al. “The relative fraction of heart defects.” American Journal of Epidemiology, vol. 148, 1998, pp. 414–423.

8. Botto L.D. et al. “The occurrence of congenital heart defects in connection with the intake of multivitamins by the mother.” American Journal of Epidemiology, vol. 151, 2000, pp. 878–884.

9. Chazel A.E. “Multivitamin supplements containing folic acid during conception.” European Journal of Obstetrics and Gynecology and Reproductive Biology, vol. 78, 1998, pp. 151–161.

10. Blomberg M.I. and B. Kelen. “Maternal obesity and pathological obesity: The risk of birth defects in offspring.” Birth Defects Research A: Clinical and Molecular Teratology, vol. 88, 2010, pp. 35–40.

11. Burd L. et al. “Congenital heart defects and fetal alcohol spectrum disorders.” Congenital Heart Disease, vol. 2, no. 4, 2007, pp. 250–255.

12. Malik S. et al. “Maternal smoking and congenital heart defects.” Pediatrics, vol. 121, no. 4, 2008, pp. e810–e816.

13. Gibson S. and K.S. Lewis. “Congenital heart defect after rubella in the mother during pregnancy.” AMA American Journal of Diseases of Children, vol. 83, 1952, pp. 317–319.

14. Khairi P. et al. “Pregnancy outcomes in women with congenital heart defects.” Circulation, vol. 113, 2006, pp. 517–524.

15. Åberg A. et al. “Congenital malformations among infants whose mothers had gestational diabetes or preexisting diabetes.” Early Human Development, vol. 61, no. 2, 2001, pp. 85–95.

16. Lisowski L.A. et al. “Congenital heart disease in pregnancies complicated by maternal diabetes mellitus.” Herz, vol. 35, no. 1, 2010, pp. 19–26.

17. Nielsen G.L. et al. “Risk of specific congenital abnormalities in offspring of women with diabetes.” Diabetic Medicine, vol. 22, no. 6, 2005, pp. 693–696.

18. Liu S. et al. “The relationship between chronic maternal conditions and congenital heart defects: A population cohort study.” Circulation, vol. 128, 2013, pp. 583–589.

19. Wang W.L. et al. “Low birth weight, prematurity and paternal social status: impact on the basic competence test in Taiwanese adolescents.” Journal of Pediatrics, vol. 153, no. 3, 2008, pp. 333–338.

20. Marelli A.J. et al. “Congenital heart defects in the general population: changes in prevalence and age distribution.” Circulation, vol. 115, 2007, pp. 163–172.

21. Wang W.L. et al. “Low birth weight, prematurity and paternal social status: impact on the basic competence test in Taiwanese adolescents.” The Journal of Pediatrics, vol. 153, no. 3, 2008, pp. 333–338.

22. Tan H.F. et al. “Accessibility assessment of the health care improvement program in rural Taiwan.” The Journal of Rural Health, vol. 21, no. 4, 2005, pp. 372–377.

23. Burton P. et al. “Extending the simple linear regression model to account for correlated responses: an introduction to generalized estimating equations and multi-level mixed modelling.” Statistics in Medicine, vol. 17, no. 11, 1998, pp. 1261–1291.

24. Cole P. and B. Mac Mahon. “Attributable risk percent in case-control studies.” British Journal of Preventive and Social Medicine, vol. 25, no. 4, 1971, p. 242.

25. Van Der Bom T. et al. “The changing epidemiology of congenital heart disease.” Nature Reviews Cardiology, vol. 8, no. 1, 2011, pp. 50–60.

26. Tseng C.H. “Diabetes and risk of bladder cancer: a study using the national health insurance database in Taiwan.” Diabetologia, vol. 54, no. 8, 2011, pp. 2009–2015.

27. Germanakis I. et al. “Stroke following Glenn anastomosis in a child with inherited thrombophilia.” International Journal of Cardiology, vol. 111, no. 3, 2006, pp. 464–467.

28. Mills J.L. et al. “Malformations in infants of diabetic mothers occur before the seventh gestational week: implications for treatment.” Diabetes, vol. 28, no. 4, 1979, pp. 292–293.

29. Bateman B.T. et al. “Chronic hypertension in pregnancy and the risk of congenital malformations: A cohort study.” American Journal of Obstetrics and Gynecology, vol. 212, no. 3, 2015, pp. 337–e1.

30. Caton A.R. et al. “Antihypertensive medication use during pregnancy and the risk of cardiovascular malformations.” Hypertension, vol. 54, no. 1, 2009, pp. 63–70.

31. Kelly T.E. et al. “Teratogenicity of anticonvulsant drugs. ii: A prospective study.” American Journal of Medical Genetics, vol. 19, no. 3, 1984, pp. 435–443.

32. Bracken M.B. and T.R. Holford. “Exposure to prescribed drugs in pregnancy and association with congenital malformations.” Obstetrics and Gynecology, vol. 58, no. 3, 1981, pp. 336–344.

33. Rothman K.J. et al. “Exogenous hormones and other drug exposures of children with congenital heart disease.” American Journal of Epidemiology, vol. 109, no. 4, 1979, pp. 433–439.

34. Lin H.C. et al. “Prenatal care visits and associated costs for treatment-seeking women with depressive disorders.” Psychiatric Services, vol. 60, no. 9, 2009, pp. 1261–1264.

35. Weng Y.H. et al. “Risk Assessment of adverse birth outcomes in relation to maternal age.” PLOS One, vol. 9, no. 12, 2014, e114843.

36. Ko T.J. et al. “Parental smoking during pregnancy and its association with low birth weight, small for gestational age and preterm birth offspring: A birth cohort study.” Pediatrics and Neonatology, vol. 55, no. 1, 2014, pp. 20–27.

37. Hoffman J.I. and S. Kaplan. “The incidence of congenital heart disease.” Journal of the American College of Cardiology, vol. 39, no. 12, 2002, pp. 1890–1900.

38. Sayasathid J. et al. “Epidemiology and etiology of congenital heart diseases.” Congenital Heart Disease—Selected Aspects, InTech, 2012, pp. 47–84.

39. Chou H.H. et al. “Association of maternal chronic disease with risk of congenital heart disease in offspring.” CMAJ, vol. 188, no. 17–18, 2016, pp. E438–E446.