Study Sheds Light On Birth Defects In Diabetic Pregnancy
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A cascade of events that begins with high blood glucose has been offered as an explanation for why diabetic pregnancies result in a high rate of birth defects.
The high blood glucose levels early in pregnancy deprive the embryo of oxygen, leading to high levels of free radicals that reduce expression of a key gene called Pax3, said Mary R. Loeken, Ph.D., of Harvard Medical School.
In a study reported by Dr. Loeken and colleagues in the October issue of the American Journal of Physiology: Endocrinology and Metabolism, researchers performed a series of experiments on pregnant mice with induced Diabetes.
They explored the role of the Pax3 gene, which is required for forming a healthy brain and spinal cord, and has been implicated by previous research in birth defects in diabetic pregnancies. Human diabetic pregnancies are two to five times more likely to result in birth defects.
The researchers measured oxygen concentrations in the embryos of these mice, analyzed Pax3 expression, measured markers of oxidative stress, and examined embryos for neural tube defects. They also measured the effects of reduced oxygen supply and increased oxygen supply on embryonic development.
Compared with healthy controls, oxygen concentrations in the embryos of diabetic mice were reduced by 30% (P<.005). The researchers believed that because the embryos had to break down higher levels of glucose, they used up oxygen faster than it could be delivered.
Furthermore, both pregnant mice with diabetes and those housed in a low (12%) oxygen environment showed a fivefold decrease in Pax3 expression and an eightfold increase in neural tube defects compared with controls (P<.001). Conversely, a high-oxygen (30%) environment blocked these effects in pregnant diabetic mice.
Both oxygen-restricted and diabetic pregnant mice showed increased levels of markers of oxidative stress compared with healthy controls (P<.001). But in mice who received high supplementation of the antioxidant vitamin E, oxidative stress was reduced and decreased Pax3 expression and neural tube defects were prevented. The exact mechanism by which oxidative stress leads to inhibition of Pax3 expression is unknown.
These results have clinical implications both for women with diabetes and women who are obese who intend to become pregnant, Dr. Loeken said.
“Women with diabetes should be consulting with their healthcare team to be sure they have good glycemic control before becoming pregnant,” she added. Maintaining blood glucose control continues to be important throughout the pregnancy, she said, but it is particularly important during the first eight weeks, when an embryo’s organs are forming.
In addition, “Many obese individuals have type 2 diabetes and do not know it, so it is a good idea to bring glucose levels to within the normal range before becoming pregnant, and to monitor women with pre-diabetes closely during pregnancy to make sure that they don’t develop Diabetes,” Dr. Loeken advised.
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