Congenital heart defects (CHD) represent the most common congenital malformations globally and constitute a leading cause of neonatal mortality, with early maternal risk factors playing significant roles in their development. A comprehensive systematic review and meta-analysis by Zihan Suo and colleagues investigated the relationships between various maternal factors during the first trimester and the risk of CHD in offspring, providing robust evidence for public health strategies aimed at reducing CHD incidence. The study protocol was registered on PROSPERO (CRD42023476855), ensuring methodological transparency and rigor.
The research team conducted extensive systematic searches across MEDLINE, Embase, and Cochrane TRIALS databases to identify eligible cohort and case-control studies examining maternal risk factors and CHD outcomes. Following strict inclusion criteria and quality assessment protocols, seventy-eight studies were ultimately included, encompassing 393,534 cases and 29,493,495 controls. This substantial sample size provided sufficient statistical power to detect meaningful associations and conduct reliable subgroup analyses. The primary outcome focused on the risk of fetuses developing CHD under the influence of various maternal factors, with results expressed as odds ratios (ORs) and 95% confidence intervals (CIs) using random-effects models to account for between-study heterogeneity.
Maternal pre-pregnancy diabetes emerged as the strongest modifiable risk factor, demonstrating a nearly three-fold increased risk of overall CHD in offspring (OR 2.91, 95% CI 2.10–4.03). This finding aligns with established biological mechanisms whereby maternal hyperglycemia during critical periods of cardiac development disrupts normal embryonic heart formation through multiple pathways, including altered gene expression, increased oxidative stress, and disruption of essential signaling molecules necessary for cardiovascular morphogenesis. The consistency of this association across multiple studies underscores the critical importance of optimal glycemic control before conception and during early pregnancy.
Maternal obesity showed a modest but statistically significant association with increased CHD risk (OR 1.23, 95% CI 1.13–1.33). The biological plausibility of this association stems from metabolic disturbances accompanying obesity, including insulin resistance, chronic low-grade inflammation, and altered lipid metabolism, which may impair fetal cardiac development. Interestingly, maternal underweight was not associated with overall CHD risk; however, subgroup analysis revealed a slight association with ventricular septal defect (OR 1.10, 95% CI 1.02–1.18), suggesting that nutritional status extremes may differentially affect specific cardiac structures.
Tobacco exposure demonstrated significant dose-response relationships with CHD risk. Active maternal smoking during early pregnancy was associated with a 28% increased risk of overall CHD (OR 1.28, 95% CI 1.03–1.57), while passive smoking showed an even stronger association (OR 2.67, 95% CI 1.30–5.46). These findings highlight that tobacco smoke constituents, including nicotine and various toxic compounds, interfere with cardiac development through multiple mechanisms, including vasoconstriction, reduced oxygen delivery, and direct teratogenic effects on cardiac progenitor cells. The stronger association observed with passive smoking may reflect particular vulnerability to environmental tobacco exposure during critical developmental windows.
Chronic hypertension emerged as another significant risk factor, with maternal chronic hypertension associated with a 39% increased risk of overall CHD (OR 1.39, 95% CI 1.02–1.90). The underlying mechanisms likely involve altered placental perfusion, chronic hypoxia, and vascular dysfunction that compromise normal cardiac development. This association emphasizes the importance of blood pressure optimization prior to conception and throughout pregnancy for women with pre-existing hypertension.
The systematic review employed rigorous methodological standards, including assessment of publication bias, sensitivity analyses, and evaluation of study quality. The consistency of findings across diverse populations and study designs strengthens the reliability of these associations. However, the authors appropriately acknowledge limitations, including the observational nature of included studies, which precludes definitive causal inference, and potential residual confounding from unmeasured variables.
From a public health perspective, these findings carry substantial implications for preconception care and early pregnancy management. The modifiable nature of several identified risk factors—particularly diabetes, obesity, smoking, and hypertension—offers opportunities for intervention. Preconception counseling should emphasize optimization of maternal health status, including achievement of target glycemic control in diabetic women, weight management, smoking cessation, and blood pressure control. Healthcare systems should prioritize access to preconception care services to enable women to address these risk factors before conception, when cardiac development begins.
The meta-analysis also highlights areas requiring further investigation. The differential effects of various maternal factors on specific CHD subtypes warrant additional exploration, as understanding these patterns may elucidate distinct teratogenic mechanisms and inform targeted prevention strategies. Additionally, the potential interactions between multiple risk factors and their combined effects on CHD risk represent important directions for future research.
In conclusion, this comprehensive systematic review and meta-analysis provides robust evidence that maternal pre-pregnancy diabetes, obesity, active and passive smoking, and chronic hypertension significantly increase the risk of congenital heart defects in offspring. These findings underscore the critical importance of optimizing maternal health and lifestyle factors before and during early pregnancy, offering a foundation for evidence-based public health interventions aimed at reducing the global burden of congenital heart disease..
Frontiers of Medicine
Experimental study
Not applicable
Risk assessment of congenital heart defects based on maternal factors in early pregnancy—a systematic review and meta-analysis
15-Dec-2025