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