Glycemic and nonglycemic mechanisms of congenital malformations in hyperglycemic pregnancies: a narrative review

Congenital malformations are more frequently found among children born to mothers with diabetes than in the background population. There are several complex mechanisms involved in the development of congenital malformations in the offspring of mothers with hyperglycemia, such as the overexpression of glucose transporters (GLUTs) 1 and 2, the increased activity of the hexosamine biosynthetic pathway and the reduced expression of the PAX3 gene with a consequent increase in p53 protein expression. These alterations can lead to increased glucose and free radical concentrations in the embryo, thus promoting the process of apoptosis and causing malformation. The most frequent malformations found in the offspring of mothers with diabetes are heart and neural tube defects, urinary tract and kidney malformations, and cleft lip with or without cleft palate. Strict glycemic control should be obtained before and during pregnancy, aiming to avoid or minimize the risk of congenital malformations in the offspring. Beyond hyperglycemia, several factors may also be associated with increased risks of malformations in the offspring of these women, such as obesity, multiple pregnancies, advanced maternal age, folic acid deficiency, use of angiotensin converting enzyme inhibitors and angiotensin receptor blockers, assisted reproduction techniques, and exposure to different types of environmental pollutants.