The association of circulating angiogenic factors and HbA1c with the risk of preeclampsia in women with preexisting diabetes

OBJECTIVE To assess whether glycemic control, soluble fms-like tyrosine kinase 1 (sFlt1) and placental growth factor (PlGF) were associated with the development of preeclampsia (PE) or gestational hypertension (GHTN) in women with preexisting diabetes. METHODS Maternal circulating angiogenic factors (sFlt1 and PlGF) measured on automated platform were studied at four time points during pregnancy in women with diabetes (N = 159) and reported as multiples of the median (MOM) of sFlt1/PlGF ratio (median, 25th-75th percentile) noted in non-diabetic non-hypertensive control pregnant population (N = 139). Diagnosis of PE or GHTN was determined by review of de-identified clinical data. RESULTS PE developed in 12% (N = 19) and GHTN developed in 23% (N = 37) of the women with diabetes. Among diabetic women without PE or GHTN, median sFlt1/PlGF levels at 35-40 weeks was threefold higher than in non-diabetic controls [MOM 3.21(1.19-7.24), p = 0.0001]. Diabetic women who subsequently developed PE had even greater alterations in sFlt1/PlGF ratio during the third trimester [MOM for PE at 27-34 weeks 15.18 (2.37-26.86), at 35-40 weeks 8.61(1.20-18.27), p ≤ 0.01 for both windows compared to non-diabetic controls]. Women with diabetes who subsequently developed GHTN also had significant alterations in angiogenic factors during third trimester; however, these findings were less striking. Among women with diabetes, glycosylated hemoglobin (HbA1c) during the first trimester was higher in subjects who subsequently developed PE (7.7 vs 6.7%, p = 0.0001 for diabetic PE vs diabetic non-PE). CONCLUSIONS Women with diabetes had a markedly altered anti-angiogenic state late in pregnancy that was further exacerbated in subjects who developed PE. Altered angiogenic factors may be one mechanism for the increased risk of PE in this population. Increased HbA1c in the first trimester of pregnancies in women with diabetes was strongly associated with subsequent PE.