Maternal Micronutrients, Environmental Exposures, and Congenital Heart Disease: Expanding Opportunities for Prevention

Congenital heart disease (CHD) remains the most common congenital anomaly worldwide and a leading cause of infant morbidity and mortality. Despite remarkable advances in prenatal diagnosis, surgical correction, and long-term cardiac care, prevention of CHD remains an unmet global health priority. The etiology of CHD is multifactorial, arising from complex interactions between genetic predisposition and environmental influences during critical stages of embryonic development. Consequently, increasing attention has focused on identifying potentially modifiable risk factors that may reduce the incidence of CHD and improve maternal-child health outcomes [1,2]. In this context, the study by Öncül et al. [3] provides important evidence regarding the potential contribution of maternal micronutrient status and parental environmental exposures to the development of CHD and associated extracardiac anomalies. The authors observed significantly lower maternal serum zinc and vitamin A concentrations, alongside higher homocysteine levels, among mothers of infants with CHD compared with mothers of healthy controls. Additionally, paternal smoking was significantly more prevalent in families of affected children. These findings are particularly compelling because each of these factors represents a potentially modifiable exposure. If validated through larger prospective investigations, such observations could inform targeted preconception and antenatal interventions aimed at reducing the burden of congenital cardiovascular disease. The relationship between maternal nutrition and fetal cardiovascular development has garnered substantial interest in recent years. Micronutrients are fundamental regulators of embryogenesis, influencing cellular proliferation, differentiation, oxidative homeostasis, and epigenetic programming. Zinc plays a critical role in DNA synthesis, gene expression, and cellular growth, while vitamin A and its active metabolites regulate developmental signaling pathways essential for cardiac morphogenesis, including neural crest cell migration and outflow tract formation [3]. Elevated homocysteine concentrations, frequently reflecting disturbances in one-carbon metabolism and folate-dependent pathways, have similarly been associated with adverse pregnancy outcomes and congenital malformations [4-6]. Although previous studies examining the association between micronutrient deficiencies and CHD risk have yielded inconsistent results, the findings reported by Öncül et al. add to a growing body of evidence suggesting that maternal nutritional status may influence fetal cardiac development and potentially contribute to congenital cardiac defects [3]. An important contribution of this study is its examination of extracardiac anomalies among infants with CHD. Approximately one-third of affected infants exhibited associated non-cardiac malformations, reinforcing the concept that CHD often reflects broader disturbances in embryonic development rather than isolated organ-specific defects [7,8]. The predominance of gastrointestinal and central nervous system abnormalities within this cohort is clinically relevant and underscores the importance of comprehensive multisystem evaluation in infants diagnosed with CHD. Early identification of associated anomalies facilitates coordinated multidisciplinary care, optimizes clinical outcomes, and may improve long-term developmental trajectories. The study also highlights the potential role of paternal smoking, an exposure that has historically received less attention than maternal risk factors in congenital disease research. Emerging evidence suggests that paternal tobacco exposure may influence reproductive and fetal outcomes through multiple pathways, including sperm DNA damage, oxidative stress, epigenetic alterations, and indirect environmental exposure during pregnancy [9,10]. The association identified in this study further supports the inclusion of prospective fathers in reproductive health counseling and smoking cessation initiatives. Such strategies may represent an underutilized avenue for reducing preventable congenital anomalies and improving overall pregnancy outcomes. Several limitations warrant careful consideration. The retrospective design limits the ability to establish causality and introduces susceptibility to recall and selection bias. Maternal micronutrient concentrations were measured postpartum rather than during the critical window of cardiac organogenesis, making it difficult to determine whether these measurements accurately reflected fetal exposure during early pregnancy. The relatively small sample size may have limited statistical power to detect associations across specific CHD subtypes. Moreover, the absence of genetic and genomic analyses precludes evaluation of potential gene–environment interactions that likely contribute substantially to CHD pathogenesis. These factors necessitate cautious interpretation of the findings and highlight important directions for future research. Despite these limitations, the study delivers a timely and important public health message. While genetic susceptibility remains a cornerstone of CHD pathogenesis, environmental and nutritional determinants may provide tangible opportunities for prevention. Optimizing maternal nutritional status before conception and throughout pregnancy, strengthening prenatal care programs, ensuring adequate micronutrient intake, and minimizing tobacco exposure are practical interventions with the potential to improve not only cardiovascular outcomes but also broader maternal and child health indicators. Looking forward, prospective longitudinal studies incorporating serial micronutrient assessments, comprehensive dietary evaluations, biomarker profiling, environmental exposure monitoring, and genomic analyses will be critical to elucidating causal mechanisms and identify high-risk populations. Such investigations may ultimately facilitate the development of precision-prevention strategies that integrate nutritional, environmental, and genetic risk factors into comprehensive maternal health programs [4,5,11]. The study by Öncül et al. [3] advances our understanding of the potential interplay between maternal micronutrient status, paternal environmental exposures, and congenital heart disease risk. Beyond highlighting novel associations, these findings reinforce a broader paradigm shift toward prevention-focused cardiovascular care beginning before birth. As the global burden of CHD continues to challenge healthcare systems, integrating nutritional optimization, environmental risk reduction, and reproductive health education into routine maternal care may represent one of the most promising strategies for reducing the incidence of congenital cardiovascular disease and improving lifelong health outcomes. References Jenkins KJ, Correa A, Feinstein JA, Botto L, Britt AE, Daniels SR, et al. Noninherited risk factors and congenital cardiovascular defects: current knowledge: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young. Circulation. 2007;115(23):2995-3014. doi:10.1161/CIRCULATIONAHA.106.183216 Pierpont ME, Brueckner M, Chung WK, Garg V, Lacro RV, McGuire AL, et al. Genetic basis for congenital heart disease: revisited: a scientific statement from the American Heart Association. Circulation. 2018;138(21):e653-e711. DOI: 10.1161/CIR.0000000000000606 Öncül Y, Koçak G, Karakurt C, Taşkapan MÇ. Maternal Micronutrient Levels, Environmental Factors, and Their Association with Congenital Heart Disease and Extracardiac Anomalies in Infants: A Retrospective Analysis. Pak Heart J. 2026;59(03):[Ahead of Print]. DOI: 10.47144/phj.v59i3.2942 Mires S, Caputo M, Overton T, Skerritt C. Maternal micronutrient deficiency and congenital heart disease risk: a systematic review of observational studies. Birth Defects Res. 2022;114(17):1079-91. DOI: 10.1002/bdr2.2072 Yang J, Kang Y, Chang Q, Zhang B, Liu X, Zeng L, et al. Maternal zinc, copper, and selenium intakes during pregnancy and congenital heart defects. Nutrients. 2022;14(5):1055. DOI: 10.3390/nu14051055 Dilli D, Doğan NN, Örün UA, Koç M, Zenciroğlu A, Karademir S, et al. Maternal and neonatal micronutrient levels in newborns with congenital heart disease. Cardiol Young. 2018;28(4):523-9. DOI: 10.1017/S1047951117002372 Chang CS, Hong SY, Kim SY, Kim YM, Sung JH, Choi SJ, et al. Prevalence of associated extracardiac anomalies in prenatally diagnosed congenital heart diseases. PLoS One. 2021;16(3). DOI: 10.1371/journal.pone.0248894 Huang X, Gao Y, Chen W, Sheng W, Huang G. Noncardiac anomalies in children with congenital heart disease. Front Cardiovasc Med. 2023;10:1293210. DOI: 10.3389/fcvm.2023.1293210 Peng J, Meng Z, Zhou S, Zhou Y, Wu Y, Wang Q, et al. The non-genetic paternal factors for congenital heart defects: a systematic review and meta-analysis. Clin Cardiol. 2019;42(7):684-91. DOI: 10.1002/clc.23194 Zhao L, Chen L, Yang T, Wang L, Wang T, Zhang S, et al. Parental smoking and the risk of congenital heart defects in offspring: an updated meta-analysis of observational studies. Eur J Prev Cardiol. 2020;27(12):1284-93. DOI: 10.1177/2047487319831367 Sahin-Uysal N, Gulumser C, Kocaman E, Varan B, Bayraktar N, Yanık F. Maternal and cord blood homocysteine, vitamin B12, folate, and B-type natriuretic peptide levels at term for predicting congenital heart disease of the neonate: a case-control study. J Matern Fetal Neonatal Med. 2020;33(15):2649-56. DOI: 10.1080/14767058.2019.1633300