Gestational Diabetes Mellitus and Developmental Programming

Editor(s): Anne H.Y. Chu, Keith M. Godfrey .

Key insights

Gestational diabetes mellitus (GDM) affects an estimated 14% of pregnancies worldwide. It is now clear that children born to mothers with GDM have an increased lifetime risk of metabolic diseases compared to unexposed children. Other long-term adverse consequences in the offspring include cardiovascular abnormalities, dysregulation of glucose metabolism, increased risk of allergic/respiratory disease, and
neurodevelopmental abnormalities. Together, these findings highlight the importance of the intra-uterine environment as a driver of epigenetic changes in the offspring.

Current knowledge

Several human studies have examined the association between in utero GDM exposure and DNA methylation in placentas, and offspring cord or infant blood. The findings have
revealed several differentially methylated genes in the fetal tissues of babies born to mothers with GDM: of interest are those related to metabolic regulation, such as leptin, adiponectin, and the SLC2A1/GLUT1 and SLC2A3/GLUT3 genes. The effects of GDM, however, are not limited to offspring metabolism. Current research indicates that the epigenetic adaptations triggered by maternal glycemia also affect other developing
organ systems in the infant, including neurodevelopment.

Practical implications

Infants born to mothers who receive GDM treatment (such as dietary advice, blood glucose monitoring, and insulin therapy) have improved perinatal outcomes. However, long-term follow-up studies suggest that this treatment may not be sufficient to reduce childhood obesity in the offspring. The current indicates that interventions delivered during pregnancy may only partly alter fetal growth and development, pointing towards the peri-conceptional period as an early modulator of health outcomes in the offspring. Further studies are needed to understand how we can leverage the peri-conceptional period as a window of opportunity for optimizing the health of future generations.
Recommended reading
Antoun E, Kitaba NT, Titcombe P, Dalrymple KV, Garratt ES, Barton SJ, et al. Maternal dysglycaemia, changes in the infant’s epigenome modified with a diet and physical activity intervention in pregnancy: Secondary analysis of a randomised control trial. PLoS Med. 2020;17(11):e1003229.
 

Key Messages

• A mother’s glycaemic status and weight during before conception and pregnancy influence the long-term health of the offspring.
• The offspring’s future health can be programmed through the role of epigenetic changes induced by a hyperglycaemic environment in utero.
• More longitudinal studies are warranted to investigate the causality and underlying mechanisms of GDM on offspring’s long term health to provide a basis for developing effective interventions during this critical period, with the aim of improving lifelong health and wellbeing.

Keywords

Developmental origins of health and disease · Epigenetics ·
Gestational diabetes · Life course epidemiology ·
Non-communicable disease

Abstract

During normal pregnancy, increased insulin resistance acts as an adaptation to enhance materno-foetal nutrient transfer and meet the nutritional needs of the developing foetus, particularly in relation to glucose requirements. However, about 1 in 6 pregnancies worldwide is affected by the inability of the mother’s metabolism to maintain normoglycaemia, with the combination of insulin resistance and insufficient insulin secretion resulting in gestational diabetes mellitus (GDM). A growing body of epidemiologic work demonstrates longterm implications for adverse offspring health resulting from exposure to GDM in utero. The effect of GDM on offspring obesity and cardiometabolic health may be partly influenced by maternal obesity; this suggests that improving glucose and weight control during early pregnancy, or better still before conception, has the potential to lessen the risk to the offspring. The consequences of GDM for microbiome modification in the offspring and the impact upon offspring immune dysregulation are actively developing research areas. Some studies have suggested that GDM impacts offspring neurodevelopmental and cognitive outcomes; confirmatory studies will need to separate the effect of GDM exposure from the
complex interplay of social and environmental factors. Animal and human studies have demonstrated the role of epigenetic modifications in underpinning the predisposition to
adverse health in offspring exposed to suboptimal hyperglycaemic in utero environment. To date, several epigenomewide association studies in human have extended our knowledge linking maternal diabetes-related DNA methylation marks with childhood adiposity-related outcomes. Identification of such epigenetic marks can help guide future research to develop candidate diagnostic biomarkers and preventive or therapeutic strategies. Longer-term interventions and longitudinal studies will be needed to better understand the causality, underlying mechanisms, or impact of GDM
treatments to optimize the health of future generations.