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

Abstract

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.

Association between Maternal Birth Weight and Prevalence of Congenital Malformations in Offspring: The Japanese Environment and Children’s Study

“…Hyperglycaemia has been well studied in both human and animal models. Hyperglycaemia during embryogenesis induces hypoxia, leading to reduced PAX3 expression, which can cause CDH [ 30 , 31 ]. Together with these observations, oxidative stress or epigenetic changes induced by inappropriate nutrition during pregnancy, the preconception period, or even much before pregnancy, which are related to low and high MBW, might be one of the presumed mechanisms by which MBW can cause CDH.…”

Prevalence, trend, and associated risk factors for cleft lip with/without cleft palate: a national study on live births from 2016 to 2021

“…This is in accordance with the findings of previous studies. It has been shown that CL/P is one of the most frequent congenital malformations among mothers with diabetes [ 23 – 25 ]. One study that examined orofacial clefts among American mothers have found similar results, and reported that pregestational diabetes was significantly associated with CL/P, even after adjustment [ 26 ].…”

Obesity in prenatal medicine: a game changer?

“…The altered pathways which may lead to a higher incidence of congenital abnormalities in fetuses of OWO mothers are not fully understood, but might be influenced by the higher levels of serum glucose often seen in OWO women periconceptionally and in the early stages of the pregnancy. Maternal hyperglycaemia leads to an increase of glucose levels in the embryonic environment, due to an overexpression of glucose transporters, as well as to oxidative stress and elevated free radical concentration, leading to a decreased expression of embryonic PAX3-gene and increased expression of the p53-gene [ 67 ]. As a consequence, apoptosis is increased which may be the link to the higher prevalence of fetal malformations.…”