Background
Methods/Design
Objectives
Primary study objectives
Secondary study objectives
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To collect evidence that low ratios of sFlt-1/PlGF correlate with absence (within 1 week of baseline visit), and high ratios correlation with presence (within 4 weeks), of maternal preeclampsia-related adverse outcomes (other than preeclampsia/eclampsia/HELLP syndrome, which is included in the primary objective) or fetal preeclampsia-related adverse outcomes.
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weekly increase of ratios of sFlt-1/PlGF and diagnosis of preeclampsia/eclampsia/HELLP syndrome within 4 weeks after the baseline visit.
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preeclampsia severity, sFlt-1/PlGF ratio and sFlt-1 and PlGF levels at the time of preeclampsia diagnosis.
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preeclampsia severity, changes in sFlt-1/PlGF ratio and sFlt-1 and PlGF levels during the week before diagnosis of preeclampsia/eclampsia/HELLP syndrome.
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high ratios of sFlt-1/PlGF and preterm delivery.
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ratios of sFlt-1/PlGF and time to delivery.
Study design
Target population
Inclusion criteria
Clinical signs and symptoms | |
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a. New onset of elevated blood pressurea
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b. Aggravation of pre-existing hypertension | |
c. New onset of protein in urineb
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d. Aggravation of pre-existing proteinuria | |
e. One or more other reason(s) for clinical suspicion of preeclampsia (see i. and ii.) | |
i. Preeclampsia-related symptoms:
| 1. Epigastric pain |
2. Excessive edema/severe swelling, (face, hands, feet) | |
3. Headache | |
4. Visual disturbances | |
5. Sudden weight gain (>1 kg/week in the third trimester) | |
ii. Preeclampsia-relatedfindings:
| 1. Low platelets |
2. Elevated liver transaminases | |
3. (Suspected) intrauterine growth restriction | |
4. Abnormal uterine perfusion detected by Doppler sonography with mean pulsatility index >95th percentile in the second trimester and/or bilateral uterine artery notching |
Exclusion criteria
Definitions of preeclampsia-associated conditions and of maternal and fetal outcomes (diagnostic criteria)
Condition/outcome | Definition |
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Preeclampsia-associated conditions
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Hypertension | • Systolic BP ≥140 mmHg and/or diastolic BP ≥90 mmHg (on two occasions ≥6 hours apart, but within 1 week) |
• Hypertension according to diagnostic criteria above (documented in medical history) controlled by antihypertensive drug use irrespective of current systolic and diastolic BP values | |
Chronic hypertension | • Hypertension (systolic BP ≥140 mmHg and/or diastolic BP ≥90 mmHg) diagnosed before conception or in the first half of pregnancy (<20 weeks of gestation) persisting >12 weeks postpartum |
Proteinuria | • ≥0.3 g protein/24 hours |
• In emergency cases only if a 24-hour urine protein collection cannot be obtained: dipstick ≥2+ or ≥30 mg/dL protein in spot urine or spot urine protein/creatinine ratio ≥30 mg protein/mmol creatinine | |
Gestational hypertension | • New onset of hypertension (systolic BP ≥140 mmHg and/or diastolic BP ≥90 mmHg) alone without proteinuria after gestational week 20 |
Preeclampsia [1] | • New onset of both hypertension (systolic BP ≥140 mmHg and/or diastolic BP ≥90 mmHg) and proteinuria after 20 weeks’ gestation |
Suspected preeclampsia | • Suspicion of clinical diagnosis of preeclampsia according to inclusion criteria |
Severe preeclampsia [20] | Preeclampsia plus one or more of the following criteria: |
• Systolic BP ≥160 mmHg and/or diastolic BP ≥110 mmHg (on two occasions ≥6 hours apart, but within 1 week) | |
• Proteinuria (>5 g protein/24 hours or dipstick ≥3+ on two random urine samples collected at least 4 hours apart) | |
• Impaired renal function (serum creatinine ≥0.9 mg/dL or oliguria <500 mL/24 hours) | |
• Pulmonary edema | |
• Impaired liver function (elevated liver enzymes, epigastric or right upper-quadrant pain) | |
• Neurologic symptoms (cerebral or visual disturbances, severe headache) | |
• Hematologic disorders (thrombocytopenia, hemolysis) | |
• IUGR | |
Eclampsia [20] | • New onset of tonic-clonic seizures in a woman with preeclampsia, which cannot be assigned to any other cause |
Superimposed preeclampsia | • Chronic hypertension plus new onset of proteinuria after gestational week 20 or |
• Chronic hypertension and proteinuria before gestational week 20 | |
AND | |
• Sudden increase of proteinuria or | |
• Sudden increase of BP or | |
• Clinical or laboratory signs/symptoms of severe preeclampsia | |
Early-/late-onset preeclampsia [22] | • Early-onset preeclampsia: onset at <34 + 0 weeks of gestation |
• Late-onset preeclampsia: onset at ≥34 + 0 weeks of gestation | |
HELLP syndrome [21] | • Increased aspartate transaminase (>70 IU/L) |
• Reduced thrombocyte counts (<100,000/μL) | |
• Increased lactate dehydrogenase levels (>600 IU/L) | |
Maternal and fetal outcomes
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Intrauterine growth restriction [24] | • Estimated fetal weight or abdominal circumference <5th percentile (adjusted for gender and ethnicity according to the charts routinely used by the study site) |
• Presence of pathologic process that inhibits expression of normal intrinsic growth potential. Pathologic process to be demonstrated on at least one occasion after gestational week 22 by one of the below criteria: | |
-Oligohydramnios (Amniotic Fluid Index <10th percentile) | |
-Pathologic flow in umbilical artery (pulsatility index >95th percentile) | |
• Serial ultrasonography growth curve anomalies* | |
• Serial growth curve anomalies based on local measurement technique (manual measurement)* | |
Small for gestational age [24] | • Estimated fetal weight or abdominal circumference <5th percentile (adjusted for gender and ethnicity according to charts routinely used by the study site) |
• Absence of pathologic process (i.e. absence of pathologic criteria for oligohydramnios and umbilical artery flow as per IUGR criteria) | |
Preterm delivery [23] | • Birth before the completion of 37 weeks’ gestation (e.g. 36 weeks + 6 days is recorded as 36 completed weeks of gestation, so the baby is defined as preterm) |
Study procedures: assessments and data collection
Measurement of sFlt-1 and PlGF in maternal serum
Setting/locations
Statistical methods
Sample size calculations
Primary analyses
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Group 1: Subjects who develop preeclampsia/eclampsia/HELLP syndrome within the first week after the baseline visit.
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Group 2: Subjects who develop preeclampsia/eclampsia/HELLP syndrome after the first week and within 4 weeks after the baseline visit.
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Group 3: Subjects who do not develop preeclampsia/eclampsia/HELLP syndrome within 4 weeks after the baseline visit.