Maternal Diabetes and the Elevated Risk of Early-Onset Cardiovascular Disease in Offspring: Insights from a Swedish Nationwide Cohort Study

Highlight

Maternal diabetes during pregnancy is associated with a 16% increased risk of overall cardiovascular disease (CVD) in offspring, rising to nearly 30% with pregestational diabetes. Specific CVD subtypes such as heart failure, atrial fibrillation, cerebrovascular diseases, and venous thromboembolism show elevated risks. Key perinatal factors—including congenital heart disease (CHD), preterm birth, and large for gestational age (LGA)—mediate a substantial proportion of these associations.

Study Background

Cardiovascular disease remains a leading cause of morbidity and mortality worldwide, with increasing recognition that early-life factors critically influence lifelong cardiovascular health. Maternal diabetes, encompassing both pregestational (type 1 and type 2 diabetes) and gestational diabetes mellitus (GDM), is a common metabolic disorder in pregnancy. While short-term perinatal complications of maternal diabetes are well described, its long-term implications for offspring cardiovascular health are less clear. Understanding these associations is vital given the rising prevalence of diabetes in pregnancy and the potential for early preventive interventions targeting offspring at risk.

Study Design

This population-based cohort study used extensive linked national registers in Sweden to include all live-born individuals between 1973 and 2014, with follow-up until 2023, comprising over 4.2 million individuals. Maternal diabetes exposure was categorized into pregestational diabetes (type 1 and type 2) and gestational diabetes. Outcomes included overall and subtype-specific incident cardiovascular diseases (CVDs), identified through national inpatient and outpatient registries. Employing Cox proportional hazards regression models, adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated. Sibling analyses controlled for familial genetic and environmental confounders, while mediation analyses quantified the contributions of perinatal factors including congenital heart disease (CHD), preterm birth, and large for gestational age (LGA) in linking maternal diabetes to offspring CVD risk.

Key Findings

The cohort encompassed 4,274,414 individuals, with 1.46% exposed to maternal diabetes. Over a median follow-up of 27.6 years, 7.36% were diagnosed with some form of CVD. Maternal diabetes corresponded to a modest but statistically significant 16% increase in offspring’s overall CVD risk (HR 1.16; 95% CI, 1.12–1.20). Notably, pregestational diabetes imposed a stronger risk (HR 1.29; 95% CI, 1.21–1.38) compared to gestational diabetes (HR 1.11; 95% CI, 1.05–1.17).

Specific CVD subtypes showing increased incidence included:

• Heart failure: HR 1.65 (95% CI, 1.37–2.00)
• Cerebrovascular diseases: HR 1.31 (95% CI, 1.12–1.52)
• Atrial fibrillation: HR 1.27 (95% CI, 1.05–1.54)
• Venous thromboembolism: HR 1.20 (95% CI, 1.07–1.34)

Sibling analyses reinforced these associations, indicating that familial genetic and environmental shared factors do not fully explain the observed risks.

Mediation analyses revealed that congenital heart disease accounted for approximately 32% of the diabetes-to-CVD association, while preterm birth and large for gestational age explained 16% and 14%, respectively. These findings elucidate that both direct and indirect pathways through adverse perinatal outcomes contribute to heightened cardiovascular vulnerability in offspring.

Expert Commentary

This landmark Scandinavian cohort study significantly advances our understanding of how maternal metabolic health influences cardiovascular trajectories in offspring. The robust design incorporating over four decades of data and sibling controls strengthens causal inference. The amplified risks related to pregestational diabetes underscore the critical importance of optimizing glycemic control before and during pregnancy to mitigate long-term cardiovascular sequelae in children.

Furthermore, elucidation of mediation by perinatal factors such as CHD, preterm birth, and LGA emphasizes the need for integrated prenatal care strategies targeting these intermediate conditions. Clinicians should be aware that offspring of diabetic mothers constitute a population warranting early surveillance and possible cardiovascular risk factor modification from childhood onward.

Limitations include the observational nature preventing absolute causality confirmation and the generalizability mainly to populations with healthcare infrastructures and ethnic composition similar to Sweden. Future research should investigate mechanistic pathways at molecular and epigenetic levels linking maternal hyperglycemia to offspring vascular biology.

Conclusion

This large-scale longitudinal study provides compelling evidence that maternal diabetes, particularly pregestational types, confers a significant and enduring increased risk of early-onset cardiovascular diseases among offspring. The interplay of perinatal complications partially mediates these effects, suggesting opportunities for prevention. These findings highlight the paramount importance of preconception care, stringent diabetes management during pregnancy, and vigilant early-life cardiovascular risk assessment among exposed offspring to improve lifelong cardiovascular outcomes.

Funding and Clinical Trials Registration

The study was conducted using Swedish national registers; specific funding sources were not disclosed in the abstract. No clinical trial registration is applicable as this was an observational cohort study.

References

• Mo X, Janszky I, Wang H, et al. Maternal Diabetes and Risk of Early-Onset Cardiovascular Diseases in Offspring. JAMA Cardiol. 2026;11(7):642-650. doi:10.1001/jamacardio.2026.12857.
• Gunderson EP, Lewis CE, Tsai AL, et al. A prospective study of maternal hyperglycemia and offspring cardiovascular risk factors. Diabetes Care. 2020;43(9):2210-2217.
• Zhu Y, Zhang C. Prevalence of gestational diabetes and risk of progression to type 2 diabetes: a global perspective. Curr Diab Rep. 2016;16(1):7.
• Gaillard R, Durmus B, Hofman A, et al. Childhood cardiometabolic outcomes of maternal diabetes in pregnancy: the Generation R Study. Diabetologia. 2016;59(2):337-345.