Maternal type 1 diabetes increases congenital heart defect risk in children

Takeaways:

A Finnish study found that maternal type 1 diabetes (T1D) is a significant risk factor for almost all subtypes of congenital heart defects (CHDs) in offspring.
Maternal T1D showed a 3.77-fold increased risk for any CHD, while overweight and obesity in pregnancy were associated only with specific defect types.
Maternal T1D had distinct teratogenic mechanisms, with varied changes in odds for different CHD subgroups, while overweight and obesity showed different associations for complex defects and outflow tract obstruction defects.
Maternal T1D had the greatest increase in the risk of transposition of great arteries, left ventricular outflow tract obstruction, right ventricular outflow tract obstruction, isolated atrial septal defect, isolated ventricular septal defects, and other septal defects.
Maternal overweight was associated with left ventricular outflow tract obstruction and ventricular septal defects, while maternal obesity was associated with complex defects and right outflow tract obstruction.

A new study emphasized the role of maternal type 1 diabetes (T1D) as a risk factor for nearly all subtypes of congenital heart defects (CHDs) among offspring, while overweight and obesity in pregnancy were associated only with certain defect types.1

Results from the nationwide register study in Finland revealed maternal T1D exhibited a 3.77-fold increased risk for any CHD in offspring, while maternal overweight and obesity showed an increased risk only for complex defects and outflow tract obstruction defects, and a decreased likelihood of ventricular septal defects.

“These results may suggest that maternal diabetes and overweight and obesity have distinct teratogenic mechanisms given that associated changes in odds were different for many CHD subgroups, and in some cases even opposite,” wrote the investigative team, led by Riitta Turunen, MD, PhD, Pediatric Research Center, New Children’s Hospital, Helsinki University Hospital.

Despite most children surviving to adulthood, CHDs in children are associated with significant mortality, morbidity, and an impacted quality of life.2 Evidence has indicated a hereditary component associated with CHDs, with T1D a well-documented risk, but the role of gestational diabetes and maternal obesity and overweight is less understood.

As these conditions often occur concurrently, Turunen and colleagues suggested an improved understanding of each factor’s contribution to offspring CHD risk could aid prevention, and direct future research into the molecular-level connection.2 The investigative team evaluated the association between maternal pre-gestational diabetes, gestational diabetes, and overweight and obesity with the risk of CHDs among a nationwide population in Finland.

The nationwide register study was conducted in a birth cohort consisting of all children born between 2006 and 2016 and their mothers. Outcomes for the study included an isolated CHD diagnosis, categorized into 9 groups based on anatomical origin, in the children obtained from the Finnish Register of Congenital Malformations.

Maternal pregnancy body mass index (BMI), calculated from reported weight and height, was categorized as underweight (<18.5), normal (18.5 - 24.9), overweight (25.0 - 29.9), and obese (30). Maternal diabetes status was classified as no diabetes, T1D, type 2 or other diabetes, and gestational diabetes, according to information obtained from national registers.

In the study, the population consisted of 620,751 children (316,802 males [51.0%) born in Finland during the study period to mothers aged 20 to 30 years (92.3%). Among this population, 10,254 children (1.7%) had an isolated CHD, and the other children did not. The prevalence of T1D among mothers remained stable at approximately 0.7% in 2006 and 2016.

Multivariable logistic regression analysis revealed maternal T1D was associated with increased odds of having a child with any CHD (odds ratio [OR], 3.77 [95% CI, 3.26 - 4.36]), compared with no maternal diabetes. When CHDs were analyzed as a single group in the analysis, investigators identified no association between maternal obesity (OR, 1.00 [95% CI, 0.94 - 1.07]) or overweight (OR, 0.98 [95% CI, 0.93 - 1.03]).

After adjusting for other covariates, the analysis showed T1D was associated with the greatest increase in risk for transposition of great arteries (OR, 7.39 [95% CI, 3.00-18.21]), left ventricular outflow tract obstruction (OR, 4.85 [95% CI, 3.32-7.09]), right ventricular outflow tract obstruction (OR, 4.00 [95% CI, 2.61-6.13]), isolated atrial septal defect (OR, 5.03 [95% CI, 3.21-7.87]), isolated ventricular septal defects (OR, 3.50 [95% CI, 2.91-4.21]), and other septal defects (OR, 3.28 [95% CI 1.55-6.95]), compared with no maternal diabetes.

Meanwhile, compared with normal maternal BMI, maternal overweight was associated with left ventricular outflow tract obstruction (OR, 1.28 [95% CI, 1.10 - 1.49]) and ventricular septal defects (OR, 0.92 [95% CI, 0.86 - 0.98]), while maternal obesity was associated with complex defects (OR, 2.70 [95% CI, 1.14 - 6.43]) and right outflow tract obstruction (OR, 1.31 [95% CI, 1.09 - 1.58]).

The investigative team, citing the smaller risk increase in those with overweight and gestational diabetes, noted these data were obtained from a high-resource setting with universal antenatal care. Considering the growing global prevalence of both gestational diabetes and maternal overweight status, Turunen and colleagues suggested the risk for CHD at the population level remains substantial.

“It has been shown that standard treatment of maternal diabetes is associated with reduced risk of anatomical malformations in offspring,” investigators wrote. “Thus, primary prevention of maternal overweight and obesity and careful treatment of pre-gestational diabetes may hold the opportunity to reduce the burden of disease.”