Yongfu Yu, Guoyou Qin, and Jiong Li
Cardiovascular diseases (CVD) are the leading cause of morbidity and mortality worldwide.  Despite remarkable achievements in prevention and treatment, the prevalence of CVD has increased in children and young adults in recent decades. [2,3] Therefore, research to further our understanding of early-onset CVD’s etiology is important for reducing the disease burden.
A growing body of evidence has emerged concerning non-genetic intergenerational connections between maternal illness and risk factors for CVD among offspring. Therefore, poorly controlled maternal illness during pregnancy may exert effects on the development of CVD through “early life programming” and contribute significantly to increasing heart disease among offspring—a trend that will continue over time, constituting a new health challenge.
The prevalence of pregestational and gestational diabetes among women of childbearing age has been increasing globally. [4,5] Prenatal exposure to maternal diabetes has been associated with increased risks of several diseases, including obesity, diabetes, and congenital heart diseases, and asthma.  Previous studies have suggested that the offspring of mothers with diabetes are at an increased risk of metabolic syndrome and they have higher prevalence of risk factors for cardiovascular disease. However, it is not known whether and the extent to which intrauterine exposure to maternal diabetes may lead to an excessive risk of early-onset CVD in offspring from childhood to early adulthood.
To answer our research question, we conducted this population-based cohort study including over 2.4 million live births born in Denmark during 1977-2016. We examined the associations between maternal diabetes and early-onset of CVD in offspring. Our study shows that children of mothers with diabetes, especially mothers with CVD history or diabetic complications, had increased rates of early-onset CVD throughout the early decades of life. If the associations are causal, then preventing and treating diabetes in women of childbearing age could have a significant impact on the reduction of CVD incidence in the next generation.
One strength of this population-based cohort study is using the high-quality prospectively collected data covering all Danish residents with nearly complete follow-up, thus minimizing the possibility of recall or selection bias. However, we still face a few methodological challenges. Although we adjusted for a wide range of potential confounders, the nature of an observational study could not rule out residual confounding by some uncontrolled genetic or familial environment or lifestyle characteristics.
We performed various sensitivity analyses to address these challenges, including additional adjustment for maternal prepregnancy BMI, sibship design, the use of paternal diabetes as the “control” exposure, and evaluation of the CVD risk in offspring in relation to the timing of maternal diabetes diagnoses with respect to childbirth (pregestational diagnoses and diagnoses ≤2, 2-5, and >5 years after childbirth). The strongest associations were seen in those born to mothers with a diagnosis of diabetes prior to childbirth, and the association was attenuated when maternal diabetes was diagnosed after childbirth. Our sibship design and additional adjustment for maternal BMI yielded results similar to those in the primary analyses. These findings suggest that non-genetic effects are important determinants of early-onset CVD in offspring, and that the observed associations could not be entirely attributable to confounding by genetics and familial environment. In addition, the considerably greater influence of maternal diabetes, compared to paternal diabetes, on the risk of CVD in offspring, further supports that our findings are unlikely to be entirely attributable to uncontrolled confounding.
Our findings highlight the importance of effective strategies for screening and preventing diabetes in women of childbearing age. We need to monitor CVD risks in offspring of diabetic mothers and implement life-course interventions that may reduce the occurrence of CVD. The presence of a history of CVD or diabetic complications in women with diabetes should be taken into account in designing public health strategies that target offspring at an elevated risk of early-onset CVD. Future research should examine the degree of glycemic control during pregnancy that would minimize CVD risks in offspring throughout their life.
Yongfu Yu, postdoctoral researcher, Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark. Twitter: @YongfuYu
Guoyou Qin, professor, Department of Biostatistics, School of Public Health, and The Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, China
Jiong Li, associate professor, Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.
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