Anti-angiogenic factors and pre-eclampsia in type 1 diabetic women

Abstract

Aims/hypothesis Elevated anti-angiogenic factors such as soluble fms-like tyrosine kinase 1 (sFlt1), a soluble form of vascular endothelial growth factor receptor, and endoglin, a co-receptor for TGFβ1, confer high risk of pre-eclampsia in healthy pregnant women. In this multicentre prospective study, we determined levels of these and related factors in pregnant women with type 1 diabetes, a condition associated with a fourfold increase in pre-eclampsia. Methods Maternal serum sFlt1, endoglin, placental growth factor (PlGF) and pigment epithelial-derived factor were measured in 151 type 1 diabetic and 24 healthy non-diabetic women at each trimester and at term. Diabetologia (2009) Results Approximately 22% of the diabetic women developed pre-eclampsia, primarily after their third trimester visit. In women with pre-eclampsia (diabetic pre-eclampsia, n=26) vs those without hypertensive complications (diabetic normotensive, n=95), significant changes in angiogenic factors were observed, predominantly in the early third trimester and prior to clinical manifestation of pre-eclampsia. Serum sFlt1 levels were increased approximately twofold in type 1 diabetic pre-eclampsia vs type 1 diabetic normotensive women at the third trimester visit (p<0.05) and the normal rise of PlGF during pregnancy was blunted (p<0.05). Among type 1 diabetic women, third trimester sFlt1 and PlGF were inversely related (r 2 =42%, p<0.0001). Endoglin levels were increased significantly in the diabetic group as a whole vs the non-diabetic group (p<0.0001). Conclusions/interpretation Higher sFlt1 levels, a blunted PlGF rise and an elevated sFlt1/PlGF ratio are predictive of pre-eclampsia in pregnant women with type 1 diabetes. Elevated endoglin levels in women with type 1 diabetes may confer a predisposition to pre-eclampsia and may contribute to the high incidence of pre-eclampsia in this patient group.

Obstetric Nephrology

“…Throughout pregnancy, ANP levels were 34% higher in these women (41). As in pre-eclampsia in nondiabetic women, pre-eclampsia in women with type 1 diabetes is also associated with elevated levels of antiangiogenetic factors in the third trimester (27). However, the function of placenta in the early stage of pregnancy judged by the level of activin A and inhibin A is often well preserved in diabetic women developing pre-eclampsia (42).…”

“…However, supplementation with vitamins C and E in a randomized study including 762 women with type 1 diabetes did not reduce the risk of pre-eclampsia (30). As in pre-eclampsia in women without diabetes, pre-eclampsia in women with type 1 diabetes is also associated with elevated levels of antiangiogenetic factors in the third trimester (27).…”

“…The prevalence of pre-eclampsia in women with diabetic nephropathy is up to 64% (4,6,11,25), especially in the presence of reduced kidney function (26), hypertension at the start of pregnancy, or nephrotic proteinuria (4,6). Women with type 1 diabetes and microalbuminuria are at increased risk of developing pre-eclampsia compared with women with type 1 diabetes and normal urinary albumin excretion (25,27). Pre-eclampsia often leads to preterm delivery (25) and preterm delivery before 34 gestational weeks has been reported in up to 45% (8,25).…”

Plasma Lipoproteins and Preeclampsia in Women with Type 1 Diabetes: A Prospective Study

“…Interestingly, these factors have also been implicated in the pathogenesis of the vascular complications of diabetes (12,13), suggesting that common mechanisms might underlie PE and diabetic vascular complications. Our own studies show a general elevation of endoglin among T1DM women in later pregnancy (ϳ30 wk, but before PE onset) (14). Because endoglin is one of only two antiangiogenic factors that, together, are thought to constitute a prerequisite for PE (8), this could explain the high prevalence of PE in diabetes.…”

“…The study was conducted according to the principles of the Declaration of Helsinki, and all study participants provided written informed consent at the study centers (Australia, Norway, and United States) as previously reported (14). In the first trimester of pregnancy, 151 women with established T1DM and 24 healthy nondiabetic women were recruited.…”