Markers and Mechanisms of Preeclampsia in Type I Diabetes

The History of MAMPED

The study was initiated by Dr. Lyons with the realization that pre-eclampsia (PE) is a complication of diabetes that develops within months, during pregnancy – thus an accelerated ‘model’ for prospective study. It was initiated in 2001 and was the first of its kind. PE is a complication of pregnancy characterized by high blood pressure, leakage of protein into the urine, and fluid retention (edema) occurring after the 20th week of gestation. PE is life threatening to both mother and fetus. There is no cure other than pre-term delivery or abortion. PE is common, affecting about 5% of pregnancies, but the risk is dramatically increased in women with Type 1 diabetes, in whom 10 to 30% of pregnancies are affected.

The causes of PE are poorly understood. Most studies have been performed late in pregnancy when the condition has already become established. They show that PE is associated with oxidative stress, abnormal blood lipids (cholesterol and triglycerides) and altered function of cells which line blood vessels. This suggests that PE is a disease of blood vessels, probably beginning in the placenta.  However, it was not clear what is cause and what is effect. The complications of diabetes are also diseases of blood vessels, and exhibit associations similar to those for PE. Moreover, as with the eye and kidney complications of diabetes, the risk of PE in pregnant diabetic women is related to blood sugar control. There were few studies investigating risk factors for PE in the general population from early pregnancy through to term, and almost none investigating PE in diabetic women.

In initiating this study, we concluded: (1) PE in diabetes is a common and serious problem which has been inadequately investigated; (2) prospective studies are urgently needed; (3) many potential markers and mechanisms for PE in diabetes are amenable to investigation; (4) prospective studies may lead to identification of early warning signs, and preventive and therapeutic strategies to block the development of PE in diabetes; (5) such studies may also lead to improved understanding of the mechanisms of PE in general, and also of the vascular complications of diabetes; and (6) PE may represent an accelerated model of vascular disease processes in diabetes, progressing from start to finish in the course of pregnancy, and thereby providing opportunities for prospective studies over much shorter periods of time than is possible with diabetic eye and kidney disease.

To address these questions, we conducted an international (US, Norway, Australia) prospective study of 151 pregnant women with Type 1 diabetes. Participants had detailed clinical assessments throughout their pregnancies. Blood and urine samples were collected at three time points during gestation (10, 20, 30 weeks) and at term. Laboratory analyses were performed (mostly in the Lyons laboratory, some in Oslo, Norway), to determine how measures of oxidative stress, abnormal plasma lipids, and markers of altered endothelial cell function affect the risk for later PE. Pregnant non-diabetic, healthy, women will also be studied to define normal values for the tests being performed. The study has identified new markers (warning signs) for subsequent PE as early as 12 weeks of gestation. We expect it to provide a basis for preventive and therapeutic measures to improve the health of women with diabetes and their children, and to provide a greater understanding of PE in general, and, we hope, of the complications of diabetes.