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    Editorial: Incremental progress in predicting preeclampsia


    The major breakthrough occurred in 2004, when Levine and colleagues conducted a nested case-control study and reported that circulating sFlt-1 levels normally increased across gestation while levels of a placental pro-angiogenic growth factor, PlGF, decreased during the last 2 months of pregnancy and that these physiological changes occurred earlier in women destined to develop preeclampsia.9  Hypoxia was subsequently shown to be the driver of these antiangiogenic placental changes.10  Thus, increased levels of sFlt-1, and perhaps decreased PlGF levels, appear to provide a crucial link between the pathognomonic placental lesion in preeclampsia and its maternal manifestations.

    Recommended: How the Perinatal Episode of Care Mode will effect your care of high-risk patients?

    Direct support for the connection then came from an unlikely source: the fundamental maternal features of the disorder—hypertension, proteinuria, renal dysfunction, increased platelet turnover, and hemolysis—are commonly elicited in nonpregnant women and men undergoing treatment for cancer with inhibitors of VEGF.11 Despite this robust pathogenic relationship, studies of maternal sFLT1 and PlGF levels have shown them to be only modestly predictive of preeclampsia and, although their ratio adds to predictive accuracy, the precise clinical utility of the sFlt-1/PlGF ratio remained to be established.12,13

    Can the ratio of sFlt-1 to PlGF predict preeclampsia?

    Given the absence of preventative treatments beyond minimally effective low-dose aspirin therapy, the greatest practical utility of a marker of preeclampsia would be its ability to differentiate impending preeclampsia from nonprogressive or less-pathological conditions such as chronic and gestational hypertension. For example, it is often difficult to decide how to triage a woman found to have increased blood pressure or minimal proteinuria. Should she be delivered if at term or given corticosteroids and hospitalized if preterm? A test that predicted risk for maternal or perinatal morbidity or who did or did not require medical intervention would be very helpful.

    A recent prospective, multicenter, international observational study (PROGNOSIS) sought to help answer these questions by deriving and validating a serum sFlt-1/PlGF ratio that was predictive of the absence of preeclampsia within 1 week or its presence within 4 weeks in women with signs and symptoms suggestive but not diagnostic of the disorder.14  Suggestive signs included having a singleton pregnancies between 24 to 37 weeks with 1 or more of the following: new elevation in blood pressure < 140/90 mmHg, new proteinuria but < 2+ on dipstick, and preeclampsia-related laboratory findings not meeting strict criteria for HELLP syndrome. Suggestive symptoms included edema, headache, visual changes, and sudden weight gain.

    In a development cohort of 500 women, the authors identified a sFlt-1/PlGF ratio of 38 as the optimal predictive cut-off value. They then performed a validation study with another 550 women and found that a cut-off ≤ 38 was associated with the absence of preeclampsia or HELLP syndrome in the next week (ie, a negative predictive value) in 99.3% (95% CI: 97.9–99.9) of such women, while values above 38 were associated with the diagnosis of preeclampsia or HELLP syndrome within 4 weeks with a positive predictive value of 36.7% (95% CI: 28.4–45.7), a sensitivity of 66.2% (95% CI: 54.0–77.0), and a specificity of 83.1% (95% CI: 79.4–86.3). Strengths of this study included the use of both discovery and validation cohorts and its large size.

    NEXT: How increasing knowledge will help answer questions.

    Charles J. Lockwood, MD, MHCM
    Dr. Lockwood, Editor-in-Chief, is Dean of the Morsani College of Medicine and Senior Vice President of USF Health, University of South ...


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