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 anomaliesin the conceptus of an animal model of diabetic pregnancy. In addition, apreventive treatment against diabetes-induced dysmorphogenesis was developed.Congenital cataract was often found in the offspring of diabetic rats. The fetal lenseshad increased water accumulation, sorbitol concentration and aldose reductaseactivity compared to control lenses. The results suggest that the cataracts form viaosmotic attraction of water due to sorbitol accumulation in the fetal lens.Another set of malformations, with possible neural crest cell origin, occurredfrequently in offspring of diabetic rats. These included low set ears, micrognathia,hypoplasia of the thymus, thyroid and parathyroid glands, as well as anomalies ofthe heart and great vessels. Furthermore, diabetes caused intrauterine death andresorptions more frequently in the late part of gestation.When the pregnant diabetic rats were treated with the antioxidants butylatedhydroxytoluene, vitamin E or vitamin C, the occurrence of gross malformationswas reduced from approximately 25% to less than 8%, and late resorptions from17% to 7%. This suggests that an abnormal handling of reactive oxygen species(ROS) is involved in diabetes-induced dysmorphogenesis in vivo. Indeed, anincreased concentration of lipid peroxides, indicating damage caused by ROS, wasfound in fetuses of diabetes rats. In addition, embryos of diabetic rats had lowconcentrations of the antioxidant vitamin E compared to control embryos. Thesebiochemical alterations were normalized by vitamin E treatment of the pregnantdiabetic rats.The antioxidants are likely to have prevented ROS injury in the embryos of thediabetic rats, in particular in the neural crest cells, thereby normalizing embryonicdevelopment. These results provide a rationale for developing new anti-teratogenictreatments for pregnant women with diabetes mellitus.