Editorial Commentary The Role of Angiogenic Factors in the Prediction and Diagnosis of Preeclampsia Superimposed on Chronic Hypertension

Hypertension in pregnancy covers a spectrum of conditions, including preeclampsia, gestational hypertension, chronic hypertension, and preeclampsia superimposed on chronic hypertension (Figure).1 Preeclampsia, unlike other hypertensive pregnancy disorders, is associated with proteinuria and affects 3% to 5% of all pregnancies and remains a leading cause of both maternal and fetal mortality worldwide. It may occur both in previously healthy women (de novo preeclampsia) and in those with a history of chronic hypertension before their pregnancies (superimposed preeclampsia). Superimposed preeclampsia affects 30% of pregnancies in women with chronic hypertension and is heralded by either the new onset of proteinuria or increase in preexisting proteinuria, worsening of blood pressure control, and/or laboratory abnormalities consistent with HELLP syndrome (Hemolysis, Elevated Liver enzymes, Low Platelet count), which represents a deceptive, albeit severe, form of preeclampsia. Compared with women with preeclampsia who are normotensive at the time of conception, women with superimposed preeclampsia are at greater risk for peripartum complications, such as placental abruption and maternal cerebrovascular incidents. The only tool currently available for the prediction of superimposed preeclampsia is a previously validated clinical prediction model, consisting of serum uric acid ( 3.6 mg/dL), plasma renin activity ( 4 ng/mL per hour), and systolic blood pressure ( 140 mm Hg), measured at 20 weeks of gestation.2 Few biological markers have been validated to date.3 In this issue, Perni et al4 present results from a carefully performed longitudinal prospective study as to the role of angiogenic markers in the prediction and diagnosis of superimposed preeclampsia in 109 women with chronic hypertension that predated their pregnancies. Seminal studies of these markers have indicated that preeclampsia is associated with elevated levels of the soluble receptor for vascular endothelial growth factor of placental origin.5 This soluble receptor, commonly referred to as sFlt-1 (from fms-like tyrosine kinase receptor 1), may bind and neutralize vascular endothelial growth factor and placental growth factor (PlGF), which are required for active fetal and placental angiogenesis during pregnancy. The same group also identified soluble endoglin as another antiangiogenic marker, which is upregulated in preeclampsia and may amplify vascular damage by binding and neutralizing transforming factor, thus contributing to the pathophysiology of HELLP syndrome.6 In the current study, proangiogenic PlGF and antiangiogenic markers, sFlt-1 and soluble endoglin, were measured at 12, 20, 28, and 36 weeks, as well as postpartum. Consistent with the rates reported in the literature, superimposed preeclampsia occurred in 34% (n 37) of women, and was classified as early onset (before 34 weeks of gestation) in 9 and late onset ( 34 weeks) in the remaining 28 pregnancies. At the time of delivery, both women with early and late-onset preeclampsia demonstrated lower PlGF levels, a higher ratio of sFlt-1/ PlGF, and elevated circulating levels of sFlt-1 and soluble endoglin compared with pregnancies with uncomplicated chronic hypertension. At 20 weeks of gestation, only women who went on to develop early preeclampsia, and not those with late onset, demonstrated significantly higher sFlt-1 levels and elevated sFlt-1/PlGF ratios compared with women who did not develop preeclampsia. Finally, only the sFlt-1/ PlGF ratio improved the predictive accuracy of the clinical prediction model in a clinically modest fashion (area under the curve increasing from 0.764 to 0.852). Perni et al4 conclude that their findings suggest similarities in the pathogeneses of preeclampsia (de novo) and superimposed preeclampsia and that measuring angiogenic factors to predict/ diagnose superimposed preeclampsia is of potential clinical significance. Should these results affect the care of pregnant patients with a history of chronic hypertension? Clinical studies of urine and serum measurements of circulating angiogenic markers using current techniques have not provided a reliable screening tool for preeclampsia,7,8 leading to studies that have combined biomarkers and other clinical tests in an attempt to improve on the predictive values of individual angiogenic markers. For example, combining angiogenic markers into a single angiogenic index, such as the sFlt-1/PlGF ratio,9 which captures their reciprocal changes in preeclampsia, has demonstrated a better predictive value for preeclampsia than any single marker. Most published studies suggest that measurements of these markers, although not predictive of late-onset preeclampsia in term pregnancies, may be useful in predicting early onset and severe disease. These findings raise the possibility of using these tests in special patient subgroups, such as those with chronic hypertension, who may be at a higher than average risk for preeclampsia and preeclampsia-related complications. Of note, a study of the role of angiogenic markers in The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN. Correspondence to Vesna D. Garovic, Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. E-mail [email protected] (Hypertension. 2012;59:555-557.) © 2012 American Heart Association, Inc.