PREECLAMPSIAAnswers to Questions

and Questions to Answer

Professor Shaun BrenneckeDepartment of Maternal-Fetal Medicine

University of Melbourne Department of Obstetrics GynaecologyRoyal Women’s Hospital

Parkville, Victoria, Australia

Declaration of conflicts of interest

Name: Shaun Brennecke

Preeclampsia research findings from my department described in this presentation have been supported within the past 5 years by:

Roche Diagnostics (Preeclampsia Biomarker Research)

Australian NHMRC (Other Preeclampsia Research)

BIRTHS IN AUSTRALIA

• Population of Australia = 25 million

• Total annual births in Australia = 300,000 +

• 6.5% of babies born are low birthweight (<2,500 g)

• 8.6% of babies are pre-term (< 37 weeks)

• 1:10 women have gestational diabetes

Australian Bureau of Statistics/Australian Institute of Health and Welfare

Melbourne is the capital city of Victoria, a state of 230,000 square kilometresThe border regions of Victoria are up to 550 kilometres from Melbourne

Royal Women’s Hospital, Melbourne

THE ROYAL WOMEN'S HOSPITAL Melbourne

Opened in 1856

First public hospital for women in Australia

Currently - Annual births = 7,600 +

- Primipara = 4,200 +

- Babies born (>20 weeks) = 7,780 +

- Babies admitted to SCN = 2,000 +

RWH Birth outcomes

• Normal birth rate (NVB) = 51%

• Forceps rate = 13.5%

• Vacuum rate = 6.7%

• Vaginal breech rate = 0.7%

• Caesarean rate = 28.5%

• Induction of Labour rate = 36.1%

• Augmentation with oxytocic rate = 26.1%

• PPH > 1500 mls = 2.1%

• Neonatal death rate = 0.5%

PREECLAMPSIA

is the most common serious medical disease of human pregnancy

with an incidence of 1-5% in most parts of the world

PREECLAMPSIA

SIGNIFICANCE

WORLDWIDE …..

A mother dies every 8 minutes

from

complications of pre-eclampsia

CAUSES OF MATERNAL DEATH, AUSTRALIA, 1973-2014

Diagnosis

Prediction

Prevention

Management

Prognosis

PREECLAMPSIAAnswers to Questions

and Questions to Answer

WHAT IS

PREECLAMPSIA?

“Preeclampsia is a disease of theories”

Paul ZweifelGerman Obstetrician

1916

Pregnancy Hypertension 2018, 72(1):24-43

Maternal hypertension (BP > 140/90) developing after 20 weeks gestation

and the co-existence of one or more of the following new onset conditions:

1. Proteinuria2. Other maternal organ dysfunction, including

a) Renal insufficiency (creatinine ≥ 90 umol/L)b) Liver involvement (elevated transaminases and/or

severe right upper quadrant or epigastric pain)a) Neurological complications (eg. hyperreflexia and/or clonus,

eclampsia, visual disturbance, blindness, stroke)a) Haematological complications (thrombocytopenia, DIC,

haemolysis)3. Uteroplacental dysfunction (such as fetal growth restriction,

abnormal umbilical artery Dopplers, still birth)

Pregnancy Hypertension 2018, 72(1):24-43

CONTEMPORARY DEFINITION OF PREECLAMPSIA

PREECLAMPSIA

CONCEPTION

PREECLAMPSIA A CLINICAL SYNDROME

WITH MANY PATHOGENETIC PATHWAYS

SYNDROME

Greek derivation meaning “concurrence”

A set of clinical signs and symptoms that are correlated with each other

A syndrome can be very closely correlated with an aetiology or pathogenesis e.g. Down syndrome,

or it may be not specific to only one disease

WHAT IS THE “GOLD STANDARD” FOR DIAGNOSING PREECLAMPSIA?

PREECLAMPSIA

ABNORMAL PLACENTATION

SPIRAL ARTERIOLES IN NORMAL AND “PREECLAMPTIC” PREGNANCIES

- EXTENT OF TROPHOBLAST INVASION ( ) -

PREECLAMPSIA IS A MULTISYSTEM DISORDER

PREECLAMPSIA IS A SYNDROME

Maynard SE et al. J Clin Invest (2003)

MATERNAL CIRCULATING sFlt-1 IS ABNORMALLY HIGH IN PREECLAMPSIA

SOLUBLE FMS-LIKE TYROSINE KINASE-1 (sFlt1)

• Tyrosine kinase protein that disables proteins that cause blood vessel growth

• Splice variant of the VEGF receptor 1

• Also known as sVEGFR-1

• Binds and reduces free circulating levels of proangiogenic factors VEGF and PlGF

• Blunts beneficial effects of VEGF and PlGF on maternal vascular endothelium

• Expressed in and released from placental tissue

MATERNAL CIRCULATING PLGF IS ABNORMALLY LOW IN PREECLAMPSIA

Levine RJ et al (2004) NEJM 350(7): 672-683

PLACENTAL GROWTH FACTOR (PlGF)

• Key protein in angiogenesis and vasculogenesis

• Member of the vascular endothelial growth factor (VEGF) sub-family

• Main source during pregnancy is the placenta

PREECLAMPSIA IS A PLACENTAL DISORDER

MATERNAL VASCULAR DYSFUNCTION IN PREECLAMPSIA

Benzing T. Nature Reviews Nephrology (2016)

VASCULAR DYSFUNCTION IN PREECLAMPSIA

Ahmed A and Cudmore MJ. Biochemical Society Transactions (2009) 37, 1237-1242

sFLT-1/PlGF RATIO

A Test of Placental Dysfunction

Schoofs K et al. J Perinat Med (2014)

sFlt-1/PlGF RATIO AND PREGNANCY OUTCOME

Can preeclampsia be diagnosed

pathognomonicallyusing the sFlt-1/PlGF ratio test?

QUESTION TO ANSWER

CAN PREECLAMPSIA

BE PREDICTED?

De

tectio

n r

ate

P

E fo

r F

PR

10

%0

10

20

30

40

50

60

70

80

90

100 96%

54%

Early PE <34 wks

All PE<42 wks

FIRST TRIMESTER SCREENING FOR PREECLAMPSIA

Am J Obstet Gynecol (2013) 2018:203.e1.10.

Prof Jon Hyett

Sample 3066

The PROGNOSIS Study

Key Points

Sample size n=1050

A single sFlt/PlGF ratio cut-off value of 38 is appropriate for gestational ages 24-37 weeks

A low sFlt-1/PlGF ratio (≤ 38) rules out preeclampsia within one week (NPV of 99.3%)

and within four weeks (NPV of 94.3%)

A high sFlt-1/PlGF ratio (> 38) predicts preeclampsiawithin four weeks (PPV of 36.7%)

The PROGNOSIS Study

sFLT-1/PlGF

Prediction (Differential) Diagnosis

Progression

sFLT-1/PlGF is a test not a treatment

“ Whether or not patients are better off from undergoing a diagnostic test

will depend on how test information is used to guide subsequent decisions

on starting, stopping or modifying treatment”

Ben Mol et al Semin Reprod Med (2003) 21(1):17-25

Can further studies evaluating the use of biomarkersimprove the ability to predict and manage preeclampsia?

Can the further use of biomarkersminimise observer bias and user error,

and increase clinician confidence in their use?

Can using biomarkers as inclusion criteria for clinical trials assessing preeclampsia interventions

help identify those at highest risk and thereby better target those most likely to benefit?

QUESTIONS TO ANSWER

CAN PREECLAMPSIA

BE PREVENTED?

Combined Multi-Marker Screening and Randomised Patient Treatment with Aspirin for Evidence-Based Preeclampsia Prevention

Am J Obstet Gynecol. (2017) Feb;216(2):110-120.e6.

Am J Obstet Gynecol. (2017) Feb;216(2):121-128.e.2.

LDA DECREASES sFLT1/PlGF RATIO IN PE SERA TREATED BeWo CELLS

QUESTIONS TO ANSWER

Low dose Aspirin…

How much?When?

Mechanism(s)?What time?

DOESANTENATAL

CAREIMPROVE

MORBIDITY AND MORTALITY FROM

PREECLAMPSIA?

DECREASING PREECLAMPSIA MORTALITY

Historical Perspective

Dr John Ballantyne1861-1923

Edinburgh PerinatologistApostle of Antenatal Care

PREECLAMPSIA

Historically, the primary medical justification

for antenatal care

DECREASING PREECLAMPSIA MORTALITY

Historical Perspective

Cause 1935 1950 1950 as a percentage of 1935

Toxaemia 7.8 2.6 33.3

Maternal mortality rates per 10,000 births.

Source: A. Macfarlane and M. Mugford, Birth Counts: Statistics of Pregnancy and Childbirth (London, 1984), ii. 276-7.

DECLINE IN PREECLAMPSIA MATERNAL MORTALITY ENGLAND AND WALES

1935-1950

Nicolaides KH, Prenat Diag (2011): 31: 3-6

Pyramid of prenatal care: past (left) and future (right)

A MODEL FOR A NEW PYRAMID OF PRENATAL CAREBASED ON THE 11 TO 13 WEEKS’ ASSESSMENT

Is there a better pregnancy care model?

Can we reverse the over-medicalisation of pregnancy that has evolved since the start of antenatal care?

QUESTIONS TO ANSWER

Do we now have the potential to provide the right care to the right woman at the right time

by improving risk assignment so as to minimise false positives and false negatives,

by reducing direct and indirect costs to the health system and society

via the more efficient use of expensive resources by optimising patient access to management

that is targeted and ultimately improves outcomes by preventing disease early in its development?

QUESTIONS TO ANSWER

DOES PREECLAMPSIA

IMPACT ON

LATER LIFE MATERNAL

HEALTH?

PREECLAMPSIA AND

LONG TERM MATERNAL MORTALITY

Irgens et al. BMJ (2001) 323, 7323: 1213-7

PREECLAMPSIA AND MATERNAL MORTALITY

"There are very few identified risk factors

for later life heart disease in women;

preeclampsia is one of the few warning signs we'll get and we should take advantage of it"

Eleni Tsigas,

Executive Director,

Pre-eclampsia Foundation

Female Sex and Cardiovascular Disease Risk Factors

LIFE LONG SURVEILLANCE OF CARDIOVASCULAR HEALTH

Weight

Exercise

Diet

Blood Lipids

Blood Pressure

Smoking

Diabetes Screening

Alcohol

Depression and Stress

LINKING PREECLAMPSIA AND SUBSEQUENT INCREASED RISK OF

LATER LIFE CARDIOVASCULAR DISEASE…

PREECLAMPSIA

Genetic Predisposition

Percentage of preeclamptic women among relatives of index women

Daughters 23.8%Daughters-in-law 6.5%

Mothers 15.9%Mothers-in-law 4.4%

Cooper, Brennecke and Wilton (1993) J Hyperten Preg 12(1), 1-23

Can we use the known linkbetween preeclampsia and

long term morbidity and mortality risk to improve health outcomes

for women and their offspring?

QUESTION TO ANSWER

Are we close to a revolutionary opportunity

for a new paradigm of pregnancy care

which will lead to a life time benefit for mothers and their babies

and an improvement in the health of the population as a whole?

IN CONCLUSION….

THANK YOU FOR YOUR ATTENTION!

ANY QUESTIONS?