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Biomarker for hypertension-preeclampsia: are we close yet?

      Hypertensive disorders are the most frequent medical complication during pregnancy. These disorders are usually categorized into those that preexist pregnancy (underlying microvascular disease) and those that develop for the first time after 20 weeks of gestation (gestational hypertension or preeclampsia).
      • Sibai B.
      • Dekker G.
      • Kupferminc M.
      Pre-eclampsia.
      • Sibai B.M.
      Diagnosis and management of gestational hypertension and preeclampsia.
      Report of the National High Blood Pressure Education Program Working group report on high blood pressure in pregnancy.
      In addition, preeclampsia can superimpose on any of the aforementioned preexisting conditions, or it can develop in women who are thought initially to have gestational hypertension.
      • Barton J.R.
      • O’Brien J.M.
      • Bergaver N.K.
      • Jacques D.L.
      • Sibai B.M.
      Mild gestational hypertension remote from term: prognosis and outcome.
      Hypertension and preeclampsia are also classified as either mild or severe on the basis of a certain threshold of systolic or blood pressure values or certain amounts of proteinuria or the presence of multisystem dysfunction.
      • Sibai B.
      • Dekker G.
      • Kupferminc M.
      Pre-eclampsia.
      • Sibai B.M.
      Diagnosis and management of gestational hypertension and preeclampsia.
      Report of the National High Blood Pressure Education Program Working group report on high blood pressure in pregnancy.
      • Barton J.R.
      • O’Brien J.M.
      • Bergaver N.K.
      • Jacques D.L.
      • Sibai B.M.
      Mild gestational hypertension remote from term: prognosis and outcome.
      • Brown M.A.
      • Hague W.M.
      • Higgins J.
      • Lowe S.
      • McCowan L.
      • Oats J.
      • et al.
      The detection, investigation and management of hypertension in pregnancy: executive summary.
      • Hauth J.C.
      • Ewell M.G.
      • Levine R.L.
      • Esterlitz J.R.
      • Sibai B.M.
      • Curet L.B.
      Pregnancy outcome in healthy nulliparous women who subsequently developed hypertension.
      See related article, page 28
      Preeclampsia is also a syndrome that is characterized by heterogenous clinical findings for which the pathogenesis can differ in women with various preexisting risk factors. The pathogenesis of preeclampsia may be different than that in women with preexisting vascular or renal disease or autoimmune disease (such as chronic hypertension, pregestational diabetes mellitus, connective tissue disease, or thrombophilias).
      • Sibai B.
      • Dekker G.
      • Kupferminc M.
      Pre-eclampsia.
      The clinical findings of preeclampsia can also manifest as either a maternal syndrome alone, a fetal syndrome (reduced fetal growth and fluid), or both. In addition, these manifestations can develop for the first time at <37 weeks of gestation, at term, in labor, or in the postpartum period.
      • Sibai B.M.
      Diagnosis and management of gestational hypertension and preeclampsia.
      Therefore, maternal and perinatal outcomes in these various disorders will depend on gestational age at the time of the onset of the disease, the severity of the condition, and the presence or absence of preexisting medical conditions. For example, women with mild gestational hypertension or mild preeclampsia that is developing at term have pregnancy outcomes that are similar to that in women with normotensive pregancies.
      • Sibai B.M.
      Diagnosis and management of gestational hypertension and preeclampsia.
      • Hauth J.C.
      • Ewell M.G.
      • Levine R.L.
      • Esterlitz J.R.
      • Sibai B.M.
      • Curet L.B.
      Pregnancy outcome in healthy nulliparous women who subsequently developed hypertension.
      In contrast, women who experience mild gestational hypertension remote from term and those with severe gestational hypertension have higher maternal and perinatal morbidities than do those with mild preeclampsia at term.
      • Sibai B.M.
      Diagnosis and management of gestational hypertension and preeclampsia.
      • Barton J.R.
      • O’Brien J.M.
      • Bergaver N.K.
      • Jacques D.L.
      • Sibai B.M.
      Mild gestational hypertension remote from term: prognosis and outcome.
      • Hauth J.C.
      • Ewell M.G.
      • Levine R.L.
      • Esterlitz J.R.
      • Sibai B.M.
      • Curet L.B.
      Pregnancy outcome in healthy nulliparous women who subsequently developed hypertension.
      In healthy, pregnant women, preeclampsia usually is diagnosed in the presence of new onset of hypertension plus proteinuria after 20 weeks of gestation.
      Report of the National High Blood Pressure Education Program Working group report on high blood pressure in pregnancy.
      However, several studies have found that either hypertension or proteinuria can be absent in 10%-15% of pregnant women who experience the syndrome of hemolysis, elevated liver enzymes, and low platelet count (HELLP)
      • Sibai B.M.
      Diagnosis, controversies, and management of HELLP syndrome.
      and in approximately 20%-25% of women who experience eclampsia.
      • Sibai B.M.
      Diagnosis, prevention, and management of eclampsia.
      The diagnostic criteria for preeclampsia in healthy women are not useful in women who have preexisting hypertension only or proteinuria only or both. In these women, the diagnosis of superimposed preeclampsia is defined as either new onset proteinuria or elevated uric acid levels (women with hypertension only) or new onset hypertension (proteinuria only) or a sudden increase in blood pressure or a sudden increase in the amount of proteinuria with or without onset of symptoms or abnormal blood tests.
      Report of the National High Blood Pressure Education Program Working group report on high blood pressure in pregnancy.
      • Brown M.A.
      • Hague W.M.
      • Higgins J.
      • Lowe S.
      • McCowan L.
      • Oats J.
      • et al.
      The detection, investigation and management of hypertension in pregnancy: executive summary.
      However, these definitions are arbitrary and lack reliable data to support their validity.
      Consequently, the current diagnostic criteria for gestational hypertension and preeclampsia and their subtypes are not as clear as one thinks, and there is difficulty identifying those who are at risk for adverse pregnancy outcome. Thus, there is an urgent need for biochemical markers that can identify women who are at risk, confirm the diagnosis in suspected cases, and identify those women who are at risk for adverse pregnancy outcome (Table I).
      TABLEPotential benefit of a biochemical marker in hypertension-preeclampsia
      Predict women at risk for subsequent preeclampsia
      Rule out the disease in suspected cases
       Women with proteinuria ± symptoms
       Women with hypertension only
      Identify women with mild disease whose condition will progress to severe disease
      Identify women with preeclampsia that is associated with adverse pregnancy outcome
      Confirm the diagnosis in women with preexisting medical conditions
       Chronic hypertension, renal disease
       Autoimmune disease
       Pregestational diabetes mellitus
       Thrombophilia
      Recently, several studies have documented that 2 antiangiogenic peptides that are produced by the placenta (soluble film-like tyrosine kinase 1 [sFlt-1] and soluble endoglin) are elevated in women with established preeclampsia.
      • Levine R.J.
      • Maynard S.E.
      • Qian C.
      • et al.
      Circulating angiogenic factors and the risk of preeclampsia.
      • Levine R.J.
      • Lam C.
      • Qian C.
      • et al.
      Soluble endoglin, a novel circulating anti-angiogenic factor in preeclampsia.
      Some of these studies have also shown that the serum levels of these peptides are significantly higher in those women who have severe preeclampsia than in those women with mild disease. In addition, these levels are elevated particularly in women with early onset preeclampsia.
      • Levine R.J.
      • Maynard S.E.
      • Qian C.
      • et al.
      Circulating angiogenic factors and the risk of preeclampsia.
      • Levine R.J.
      • Lam C.
      • Qian C.
      • et al.
      Soluble endoglin, a novel circulating anti-angiogenic factor in preeclampsia.
      In this issue, Salahuddin et al report on the diagnostic usefulness of soluble sFlt-1 and soluble endoglin in hypertensive diseases of pregnancy. In this pilot study, the authors evaluated the clinical usefulness of serum levels of SFlt-1, endoglin, and uric acid in women with gestational hypertension (n = 17 women), chronic hypertension (n = 19 women), preeclampsia (n = 19 women), and normal third-trimester pregnancies (n = 20 women). The authors found that serum sFlt-1 and endoglin levels had high sensitivity and specificity in differentiating women with preeclampsia from those with various hypertensive diseases of pregnancy. A major strength of their study is the findings of good positive and negative likelihood ratios for these peptides in differentiating preeclampsia from the other hypertensive disorders. In contrast, serum uric acid levels were not found to be adequate markers for this purpose.
      The findings of Salahuddin et al provide important clinical information for practicing physicians. In addition, they add to our knowledge regarding the pathogenesis of the various hypertensive disorders of pregnancy. However, this study warrants several comments. First, the number of women who were studied in each group is limited to draw valid conclusions. Second, 24-hour urine protein values were not obtained in all women with presumed gestational hypertension and in those with chronic hypertension, which casts doubt about these diagnoses. It is well-established that both urine dipstick protein (negative to trace values) and protein to creatinine rates correlate poorly with quantitative proteinuria. Third, the authors provided no information about the number of women who experienced superimposed preeclampsia, and they do not describe the criteria for such a diagnosis. Finally, the study does not provide answers regarding the potential value of these markers in predicting adverse pregnancy outcome in these women.
      In a related study, Masuyama et al
      • Masuyama H.
      • Suwaki N.
      • Nakatsukasa H.
      • Masumoto H.
      • Tateishi Y.
      • Hiramatrsu Y.
      Circulating angiogenic factors in preeclampsia, gestational proteinuria, and preeclampsia superimposed on chronic glomerulo-nephritis.
      measured circulating angiogenic factors in 15 women with severe preeclampsia, 10 women with gestational proteinuria (no hypertension), 15 women with chronic glomerulonephritis (5 women had superimposed preeclampsia; 5 women had exacerbated proteinuria, and 5 women had normal outcome), and in 30 women with normotensive pregnancies. The authors found that serum levels of placental growth factor were lower and that serum levels of sFlt-1 were higher in women with severe preeclampsia and in those women with gestational proteinuria, compared with normotensive pregnancies. In addition, among women with chronic glomerulonephritis, serum sFlt-1 values were significantly higher among those women who experienced superimposed preeclampsia, compared with those women who had either severe proteinuria (absent hypertension) or a normal clinical course. Again, this study had its limitations regarding the sample size and the diagnostic criteria for preeclampsia and severe proteinuria. For example, preeclampsia was defined as gestational hypertension with or without proteinuria, and severe proteinuria was defined as protein excretion of >2 g/24 hour.
      • Masuyama H.
      • Suwaki N.
      • Nakatsukasa H.
      • Masumoto H.
      • Tateishi Y.
      • Hiramatrsu Y.
      Circulating angiogenic factors in preeclampsia, gestational proteinuria, and preeclampsia superimposed on chronic glomerulo-nephritis.
      In summary, several questions remain unanswered by this study and previous studies with regard to the potential value of serum angiogenic factors in the prediction of the future development of preeclampsia in low-risk or high-risk women (Table) and in identifying those women whose condition will progress to severe disease or result in adverse pregnancy outcome. Therefore, there is an urgent need for large prospective studies to evaluate the value of these markers in both normal and high-risk women.

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