sFlt-1:PlGF Ratio in Diagnosing Superimposed Preeclampsia
Condition: Preeclampsia
MeSH terms: Pre-Eclampsia
Study type: Observational

Summary: 
      Preeclampsia: associated with poor placentation, incomplete uteroplacental spiral arteries
      remodeling. Result: ischemia, re-perfusion injury, oxidative stress.

      A low-grade systemic inflammatory response is more pronounced in preeclampsia. This results
      in an imbalance between maternal circulating pro-angiogenic (PlGF & VEGF) & anti-angiogenic
      factors (sFlt-1).

      PlGF & VEGF function as vasodilators & preserve structure & function of glomerular
      endothelium. sFlt-1 blocks these actions, resulting in hypertension, endothelial dysfunction
      & nephropathy.

      Various stressors, including hypoxia, villous crowding, angiotensin II, & oxidative stress
      are associated with preeclampsia & mediate secretion of soluble vascular growth factor 1
      (sVEGFR-1 or sFlt-1) by GADD45 (Growth Arrest and DNA Damage-45). GADD45 is one of a family
      of stress-induced genes sFlt-1 releases into maternal circulation. Excess sFlt-1 leads to
      endothelial dysfunction, hypertension & proteinuria.

      Exogenously administered sFlt-1 results in syndrome of nephrotic range proteinuria,
      hypertension, and glomerular endotheliosis in animal models.

      Women with preeclampsia tend to have higher sFlt-1 & lower PlGF, resulting in an increased
      ratio (sFlt-1:PlGF). The difference is greater in women who develop early-onset preeclampsia
      (before 34 wks gestation).

      Verlohren, et al., showed an increased sFlt-1/PlGF ratio in patients with preeclampsia as
      compared to controls & patients with chronic/gestational hypertension.

      Other work has examined the longitudinal changes in the individual values of sFlt-1 & PlGF
      over the course of the pregnancy, as well as the ratio.

      Given the low prevalence of preeclampsia in the population, the positive predictive value
      remained low, however the negative predictive value approached 97% late in gestation. This
      suggests that the utility of the sFlt-1/PlGF may be in its ability to rule out preeclampsia.

      More recently the PROGNOSIS study was designed to investigate the value of the sFlt-1/PlGF
      ratio for the prediction of the presence or absence of preeclampsia in the short term & found
      that a cutoff point of 38 for the sFlt-1/PlGF ratio is useful for predicting the short-term
      absence of preeclampsia in women with suspected disease (Negative predictive value 99.3% for
      ruling out preeclampsia within 1 week).

      Hypothesis: In women with chronic hypertension, the sFlt-1/PlGF ratio will better predict the
      development of superimposed preeclampsia than clinical criteria alone.
    

Detailed description: 
      Subjects with a diagnosis of chronic hypertension made prenatally or in the first 20 weeks of
      pregnancy (+/- medical therapy). The clinical diagnosis of preeclampsia will follow the
      current criteria outlined by ACOG (American College of Obstetricians & Gynecologists) 10.

      Study/Project Procedures:

        -  Blood draw at the time of initial presentation at the time of a clinically indicated
           blood draw (10cc maternal blood via venipuncture)

        -  Blood draw at 2-7 days after initial presentation if undelivered at the time of a
           clinically indicated blood draw(10 cc maternal blood via venipuncture)

        -  Laboratory analysis will be performed in batches after all clinical history, clinically
           indicated laboratory information, delivery information, and clinical outcomes recorded
           for sFlt-1 level, PlGF level, and the sFlt-1/PlGF ratio (not part of routine care and
           will be performed for research purposes only at the cost of the investigators).

        -  Urine protein creatinine ratio performed as clinically indicated (will not be altered
           for research purposes)

        -  Maternal CBC (Complete Blood Count), CMP (Complete Metabolic Profile), LDH (Lactate
           dehydrogenase), Uric acid as indicated clinically (will not be altered for research
           purposes)

        -  Ultrasound performed by the investigators for research purposes only evaluating the
           uterine artery Doppler, middle cerebral artery Doppler, umbilical artery Doppler,
           estimated fetal weight, and amniotic fluid volume on a weekly basis from the time of
           enrollment until delivery.

        -  Medical record abstraction of medical history, laboratory and clinical findings for both
           the mother and fetus.
    

Observational model: Case-Control
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        150 pregnant subjects and their respective fetuses (total 300 subjects)

        Prospective cohort:

          -  Group 1: elevated sFlt-1/PlGF ratio;

          -  Group 2: normal sFlt-1/PlGF ratio.
      
Biospecimen description: 
      When blood sampling is clinically indicated, 10cc of maternal blood collected: at initial
      presentation, and at 2-7 d after initial, if undelivered.

      Lab analysis performed in batches: sFlt-1 level, PlGF level, & sFlt-1/PlGF ratio (for
      research purpose only at cost of investigators), post-collection of history, lab data,
      delivery data & outcomes.

      As clinically indicated (not altered for research purposes): Results for maternal
      urine-protein/creatinine ratio, CBC, CMP, LDH, & Uric acid will be collected.

      Ultrasound, performed by investigators for research purpose only, on weekly basis from the
      time of enrollment until delivery, to evaluate uterine artery Doppler, middle cerebral artery
      Doppler, umbilical artery Doppler, estimated fetal weight, & amniotic fluid volume.