Nuffield Department of Obstetrics & Gynaecology
Advances in
Preeclampsia Testing Use of the Biomarkers sFlt-1 &
PlGF in Preeclampsia Testing
Dr. Manu Vatish
Preeclampsia
Diagnostic “Gold Standard”
Preeclampsia diagnosis today UK NICE guidelines: hypertension combined with proteinuria
Hypertension1
Proteinuria1
In a woman with previously normal blood pressure ≥140 mm Hg systolic or ≥ 90 mm Hg diastolic after 20 weeks of gestation
In a woman with pre-existing chronic hypertension Systolic increased > 30 mm Hg or diastolic increased > 15 mm Hg
≥ 0.3 g of protein in a 24h urine collection
+
However, both hypertension and proteinuria are poor in predicting the clinical
onset of the disease and its progression2
1. NICE (2011). Hypertension in pregnancy: the management of hypertensive disorders during pregnancy 2. Rana et al (2012). Circulation 125:911-919
page 4
Prediction of Adverse Outcomes by CommonDefinitions of Hypertension in Pregnancy
JUN ZHANG, PhD, MD, MARK A. KLEBANOFF, MD, MPH, AND
JAMES M. ROBERTS, MD
Objective: To examine the ability of five common definitions
of hypertension in pregnancy to predict adverse maternal
and perinatal outcomes.
Methods: We studied 9133 singleton nulliparous pregnan-
cies with early prenatal care from the Collaborative Perinatal
Project, a large cohort study conducted between 1959 and
1965. Definitions from five different groups were evaluated.
Severe maternal and perinatal morbidity and mortality were
used as the outcome measurements. Sensitivity, specificity,
and positive predictive value for outcomes were compared
across various definitions.
Results: Blood pressure alone had very poor discrimina-
tory power to predict adverse outcomes. Positive predictive
values of adverse outcomes by the diagnosis of preeclampsia
were 18–20% based on antepartum and intrapartum blood
pressures and 22–36% based on antepartum blood pressure
only. Mild hypertension occurring for the first time in labor
and isolated mild systolic hypertension were not associated
with adverse outcomes. Similarly, an increase in diastolic
blood pressure of 15 mmHg that did not achieve an absolute
value of 90 mmHg did not predict adverse outcome.
Conclusion: Neither blood pressure nor blood pressure
and proteinuria are accurate predictors of severe adverse
maternal and perinatal outcomes. Mild hypertension occur-
ring for the first time in labor and isolated mild systolic
hypertension should not be considered indicators for hy-
pertensive disorders in pregnancy in a research definition.
(Obstet Gynecol 2001;97:261–7. © 2001 by The American
College of Obstetricians and Gynecologists.)
Hypertension in pregnancy, often defined as bloodpressure (BP) reaching 140/ 90 mmHg,1–5 is a common
complication affecting maternal and fetal health. Cur-rently, five definitions are widely used, most of which
rely primarily on diastolic BP. However, the origin of
these thresholds has been poorly documented and
careful validation of these definitions has never been
done. The purpose of this study was to examine quan-titatively the validity of several different definitions of
hypertension in pregnancy. In addition, we addressedthe following questions: 1) Is mild hypertension with or
without proteinuria occurring for the first time in labor
or delivery associated with adverse pregnancy out-comes? 2) Besides diastolic BP, does systolic BP contrib-
ute additional information to the definition of hyper-tension in pregnancy? 3) Does a rise in diastolic BP
above 15 mmHg but below 90 mmHg affect pregnancy
outcomes?
Materials and Methods
We used data from the Collaborative Perinatal Project.6
Women who attended prenatal care at 12 hospitals from
1959 to 1965 were invited to participate in this prospec-
tive observational study. At entry, detailed demo-graphic, socioeconomic, and behavioral information
was collected by in-person interview. Medical historiesand physical examinations were also obtained. Women
were interviewed and physical findings were recorded
at all following prenatal visits. Detailed findings inlabor or delivery and postpartum were collected.
Blood pressures were recorded at entry, during eachprenatal visit, during labor and delivery, and postpar-
tum. Korotkoff phase 4 (muffling) or phase 5 (disap-
pearance) was used for diastolic BP.7 Random urinesamples were tested for albumin at each prenatal visit.
A validation study in which information on BP andurinary albumin was checked against that in the origi-
nal medical records showed remarkable accuracy.7 In
that study, investigators selected 772 recordings sus-pected of error because of wide deviations from the
sequence of BPs recorded in that patient during thecourse of pregnancy. The percentage of error for these
BP readings was 1.8%. In a random sample of urinary
albumin data, the percentage of error was 0.08%. There-
From the Epidemiology Branch, National Institute of Child Health andHuman Development, NIH, Bethesda, Maryland; and the Magee Wom-ens Research Institute and Department of Obstetrics, Gynecology andReproductive Sciences, University of Pittsburgh, Pittsburgh, Pennsyl-vania.
261VOL. 97, NO. 2, FEBRUARY 2001 0029-7844/ 01/ $20.00
PII S0029-7844(00)01125-X
Prediction of Adverse Outcomes by CommonDefinitions of Hypertension in Pregnancy
JUN ZHANG, PhD, MD, MARKA. KLEBANOFF, MD, MPH, AND
JAMESM. ROBERTS, MD
Objective: To examine the ability of five common definitions
of hypertension in pregnancy to predict adverse maternal
and perinatal outcomes.
Methods: We studied 9133 singleton nulliparous pregnan-
cies with early prenatal care from the Collaborative Perinatal
Project, a large cohort study conducted between 1959 and
1965. Definitions from five different groups were evaluated.
Severe maternal and perinatal morbidity andmortality were
used as the outcome measurements. Sensitivity, specificity,
and positive predictive value for outcomes were compared
across various definitions.
Results: Blood pressure alone had very poor discrimina-
tory power to predict adverse outcomes. Positive predictive
values of adverse outcomes by the diagnosis of preeclampsia
were 18–20% based on antepartum and intrapartum blood
pressures and 22–36% based on antepartum blood pressure
only. Mild hypertension occurring for the first time in labor
and isolated mild systolic hypertension were not associated
with adverse outcomes. Similarly, an increase in diastolic
blood pressure of 15 mmHg that did not achieve an absolute
value of 90 mmHg did not predict adverse outcome.
Conclusion: Neither blood pressure nor blood pressure
and proteinuria are accurate predictors of severe adverse
maternal and perinatal outcomes. Mild hypertension occur-
ring for the first time in labor and isolated mild systolic
hypertension should not be considered indicators for hy-
pertensive disorders in pregnancy in a research definition.
(Obstet Gynecol 2001;97:261–7. © 2001 by The American
College of Obstetricians and Gynecologists.)
Hypertension in pregnancy, often defined as blood
pressure (BP) reaching 140/ 90 mmHg,1–5 is a commoncomplication affecting maternal and fetal health. Cur-
rently, five definitions are widely used, most of which
rely primarily on diastolic BP. However, the origin ofthese thresholds has been poorly documented and
careful validation of these definitions has never been
done. The purpose of this study was to examine quan-titatively the validity of several different definitions of
hypertension in pregnancy. In addition, we addressedthe following questions: 1) Is mild hypertension with or
without proteinuria occurring for the first time in labor
or delivery associated with adverse pregnancy out-comes? 2) Besides diastolic BP, does systolic BP contrib-
ute additional information to the definition of hyper-tension in pregnancy? 3) Does a rise in diastolic BP
above 15 mmHg but below 90 mmHg affect pregnancy
outcomes?
Materials and Methods
We used data from the Collaborative Perinatal Project.6
Womenwho attended prenatal care at 12 hospitals from
1959 to 1965 were invited to participate in this prospec-tive observational study. At entry, detailed demo-
graphic, socioeconomic, and behavioral information
was collected by in-person interview. Medical historiesand physical examinations were also obtained. Women
were interviewed and physical findings were recorded
at all following prenatal visits. Detailed findings inlabor or delivery and postpartum were collected.Blood pressures were recorded at entry, during each
prenatal visit, during labor and delivery, and postpar-
tum. Korotkoff phase 4 (muffling) or phase 5 (disap-pearance) was used for diastolic BP.7 Random urine
samples were tested for albumin at each prenatal visit.
A validation study in which information on BP andurinary albumin was checked against that in the origi-
nal medical records showed remarkable accuracy.7 Inthat study, investigators selected 772 recordings sus-
pected of error because of wide deviations from the
sequence of BPs recorded in that patient during thecourse of pregnancy. The percentage of error for these
BP readings was 1.8%. In a random sample of urinaryalbumin data, the percentage of error was 0.08%. There-
From the Epidemiology Branch, National Institute of Child Health andHuman Development, NIH, Bethesda, Maryland; and the Magee Wom-ens Research Institute and Department of Obstetrics, Gynecology andReproductive Sciences, University of Pittsburgh, Pittsburgh, Pennsyl-vania.
261VOL. 97, NO. 2, FEBRUARY 2001 0029-7844/ 01/ $20.00
PII S0029-7844(00)01125-X
The Gold Standard performs badly in predicting
preeclampsia-related adverse outcomes
Pathogenesis of preeclampsia (PE)
sFlt-1
PlGF
Adapted from: Karumanchi 2009
Initial lesion, localized
in the placenta
1st and early
2nd trimester
Preeclampsia syndrome,
generalized defects
late 2nd and 3rd
trimester
- PE
- IUGR
- Preterm delivery
- Placental abruption
- IUFD
Nuffield Department of Obstetrics & Gynaecology
sFlt1 Soluble FMS Like Tyrosine Kinase 1
Levine et al 2003
PLGF Placental Growth Factor
Levine et al 2003
• 457 women • 409 normal • 48 with PE
Work out who has or hasn’t got the disease at presentation?
Rana S et al. Circulation. 2012;125:911-919
sFlt
1 (
pg/
ml)
• 457 women • 409 normal • 48 with PE
Work out who has or hasn’t got the disease at presentation?
Rana S et al. Circulation. 2012;125:911-919
sFlt
1/P
lGF
Rat
io
Accuracy of prediction of an adverse outcome (<34w)
Rana et al, Circulation 2012
PROGNOSIS: The prediction
of short-term outcome in pregnant women
with suspected preeclampsia
?PREDICTION
PROGNOSIS enrollment
Argentina
Australia
Austria
Belgium
Canada
Chile
Germany
The Netherlands
New Zealand
Norway
Peru
Spain
Sweden
United Kingdom
32 Study
sites
1273 Subjects enrolled
Objective of the study
• Is it possible to RULE-OUT preeclampsia in the following 7 days
• Is it possible to RULE-IN preeclampsia in the following 4 weeks
Ruling out preeclampsia
• Using the sFlt-1/PlGF ratio cut-off of <38, preeclampsia can be ruled out within 1 week with 99.3% negative predictive value (NPV)
Rule out of preeclampsia within 1 week
(95% CI)
Development
cohort
Validation
cohort
NPV 98.9%
(97.3–99.7)
99.3%
(97.9–99.9)
Sensitivity 88.2%
(72.5–96.7)
80.0%
(51.9–95.7)
Specificity 80.0%
(76.1–83.6)
78.3%
(74.6–81.7)
Ruling in preeclampsia
• Using the sFlt-1/PlGF ratio cut-off of ≥38, preeclampsia can be ruled in within 4 weeks with 36.7% positive predictive value (PPV)
Rule in of preeclampsia within 4 weeks
(95% CI)
Development
cohort
Validation
cohort
PPV 40.7%
(31.9–49.9)
36.7%
(28.4–45.7)
Sensitivity 74.6%
(62.5–84.5)
66.2%
(54.0–77.0)
Specificity 83.1%
(79.3–86.5)
83.1%
(79.4–86.3)
1. Zeisler et al (2014). 20th COGI World Congress 2014 2. Verlohren et al (2014). Hypertension 63:346-352
PE: Preeclampsia; PlGF: Placental growth factor; sFlt-1: Soluble fms-like tyrosine kinase-1
85 110 38
Early
onset 20
34
Late
onset
sFlt-1/PlGF ratio
< 38
Patient will not develop PE for at least ONE week
≥ 85
< 38
≥ 38 – < 85
Aid in diagnosis*2
Using gestational age-specific cut-offs, the sFlt-1/PlGF ratio can aid in the diagnosis and short-term prediction of PE
≥ 110
Highly suggestive of PE Patient is likely to develop
PE within 4 weeks
≥ 38 – < 110
Short-term prediction1
* Used in addition to other accepted diagnostic tools and clinical information
What can the sFlt1/PlGF Ratio do?
Summary
• Preeclampsia is a placental disease
• sFlt1 and PLGF are disease related markers
• sFlt1/PLGF ratio can RULE OUT disease with a 99.3% NPV for the following 7 days
• sFlt1/PLGF ratio can RULE IN disease with a 38.6% PPV
• A useful additional clinical tool