Congenital Malformations in Experimental Diabetic Pregnancy: Aetiology and Antioxidative Treatment

Abstract

Diabetes mellitus in pregnancy causes congenital malformations in the offspring. The aim of this work was to characterize biochemical and morphologic anomalies in the conceptus of an animal model of diabetic pregnancy. In addition, a preventive treatment against diabetes-induced dysmorphogenesis was developed.

Congenital cataract was often found in the offspring of diabetic rats. The fetal lenses had increased water accumulation, sorbitol concentration and aldose reductase activity compared to control lenses. The results suggest that the cataracts form via osmotic attraction of water due to sorbitol accumulation in the fetal lens.

Another set of malformations, with possible neural crest cell origin, occurred frequently in offspring of diabetic rats. These included low set ears, micrognathia, hypoplasia of the thymus, thyroid and parathyroid glands, as well as anomalies of the heart and great vessels. Furthermore, diabetes caused intrauterine death and resorptions more frequently in the late part of gestation.

When the pregnant diabetic rats were treated with the antioxidants butylated hydroxytoluene, vitamin E or vitamin C., the occurrence of gross malformations was reduced from approximately 25% to less than 8%, and late resorptions from 17% to 7%. This suggests that an abnormal handling of reactive oxygen species (ROS) is involved in diabetes-induced dysmorphogenesis in vivo. Indeed, an increased concentration of lipid peroxides, indicating damage caused by ROS, was found in fetuses of diabetes rats. In addition, embryos of diabetic rats had low concentrations of the antioxidant vitamin E compared to control embryos. These biochemical alterations were normalized by vitamin E treatment of the pregnant diabetic rats.

The antioxidants are likely to have prevented ROS injury in the embryos of the diabetic rats, in particular in the neural crest cells, thereby normalizing embryonic development. These results provide a rationale for developing new anti-teratogenic treatments for pregnant women with diabetes mellitus.