Progress in our Understanding of the

Syndrome
But how about progress in the
management of preeclampsia
Prof Gus Dekker
University of Adelaide, Australia
Dr Muhammad Ilham Aldika Akbar
Airlangga University, Surabaya
MFM March 2023 Jakarta
 Preeclampsia – the Syndrome
None of us is as good as all of us…
 CW Redman Lancet 1976
• Fetal outcome in trial of antihypertensive
treatment in pregnancy
• 242 women with moderate treated with
methyldopa (reduced number of midtrimester
abortions)
• No effect preeclampsia, similar birthweights in
treated and control group
• Multivariate analysis showed that hypotensive
treatment had no effect on fetal growth
Roberts JM, Redman CWG

Pre-eclampsia: more than pregnancy-

induced hypertension
Lancet 1993;341: 1447-1451
Prevention of preeclampsia would mean a significant step
forwards in prenatal care. In preventive medicine the general
term prevention may have three different connotations

• Primary prevention means averting the occurrence of a disease

• Secondary prevention implies breaking off the disease process before the
emergence of clinically recognizable disease

• Tertiary prevention means prevention of complications caused by the

disease process, and is thus synonym to treating a disease
 Prevention of Preeclampsia
A Heterogeneous Syndrome

Primary prevention means averting the

occurrence of a disease – is it possible ?
Have enough sex with good partner prior to
conceiving

Olfactory senses (Wedekind and Furi 1997,

Milinski 2013) ?
Despite absence of vomeronasal organ, humans have
the ability to detect and evaluate MHC peptides in body
odor
 Length of Sexual Relationship
Robillard PY et al Lancet 1994
60
Multigravidae
50
N = 104 Total
Primigravidae
40

30 N = 64

20 N = 46

10 N = 743

0
0-4 5-8 9 - 12 12 +
Cohabitation before conception (months) Gus Dekker
19%
 Weight and Age

1. Stay lean

2. Don’t have babies too late

3. Healthy nutrition (avoid Fast Food)

For Women - Check your birthweight
N=33 N=211 N=2061 N=1225
Gus Dekker
Maternal Birthweight
Know your birthweight !
• Your intra-uterine
journey has a major
impact on the risk for
complications – in
particular preeclampsia

• But is this ‘Barker in

action ‘ or shared genes
or both ?

Gus Dekker
 Thrombospondin-1 (TSP-1) is a prothrombotic
and anti-angiogenic glycoprotein; risk factor for
familial premature myocardial infarction

Gus Dekker
Gus Dekker
 Prevention of Preeclampsia
A Heterogeneous Syndrome

Secondary prevention implies breaking off the

disease process before the emergence of
clinically recognizable disease
Acetyl Salicylic Acid – Aspirin
LMWH
Calcium
Metformin
Esomeprazole

PRAVASTATIN
 miR-200 family has been shown to be associated with PE and upregulated in
the plasma and placenta of PE patients
miR-200 family inhibits TB invasion and epithelial-mesenchymal transition (EMT)
process by stimulating epithelial marker expression (Ecadherin and ZO-1) and
repressing mesenchymal marker expression (ZEB1 and TGFβ1)
EMT markers in placenta of PE patients showed higher E-cadherin and lower
ZEB1 and TGF-β1 protein expression.
Aspirin suppresses miR-200 family and the miR-200 family-mediated cell
functions, including cell invasion and EMT changes, are completely reversed.

Conclusion: aspirin fully reverse miR-200-mediated trophoblast biology and

act through the network signaling of TGF-β1/ZEB1/ miR-200.

These results provide a plausible mechanism explaining aspirin’s effect on

preeclampsia prevention and a therapeutic target for disease intervention.
 Serum sFlt-1 and sEng profiles and placental oxidative stress
levels were significantly decreased in PE patients treated
with aspirin compared with untreated patients without it,
whereas serum PLGF and placental SOD profiles were
increased in PE patients with aspirin.

Aspirin attenuated the role of sFlt-1 in oxidative stress and

endothelial dysfunction and reduced apoptosis of
trophoblasts by inactivating the NF-jB signalling pathway in
HTR-8/SVneo trophoblast cells.
Gus Dekker
 ASPRE post hoc analysis
Poon et al AJOG 2017
• Post hoc analysis ASPRE 150 mg Aspirin
nocte
• Ppv 1.8% PE < 32 weeks; 4.3% PE < 37
weeks
• Overall effect preterm PE OR 0.38 (0.2-
0.74)
• No effect in chronic hypertension
• No effect term PE
 WHO Calcium Trial among Low Calcium Intake
Pregnant Women Villar et al , SMFM 2006 Miami
• 8,325 nulliparous pregnant women randomised
• < 20 weeks, populations with Ca intake < 600 mg
• 1.5 g Calcium
• Severe preeclampsia RR 0.76; 0.66-0.89
• Adverse Maternal Outcome RR 0.80; 0.70-0.91
• Neonatal Death RR 0.78; 056-0.88
• Preterm Birth (women < 20yrs) 0.82;0.67-1.01

Gus Dekker
Metformin versus Placebo in
Obese Pregnant Women
without Diabetes Mellitus
• Argyro Syngelaki, Ph.D., Kypros H. Nicolaides, M.D., Jyoti Balani,
M.D., Steve Hyer, M.D., Ranjit Akolekar, M.D., Reena Kotecha, M.D.,
Alice Pastides, M.D., and Hassan Shehata, M.D. N Engl J Med 2016;
374:434-443

•BMI ≥ 35, 3 gram Metformin

Results
 Results

*In seven patients (two patients in the metformin group and five in the placebo
group), the study regimen was stopped because of fetal growth restriction, as
evidenced by an estimated fetal weight below the 5th percentile and abnormal
fetal Doppler studies.

Fetal growth
restriction 2/202 5/195 1.41 0.23
Conclusions Nicolaides 2016
• Prophylactic therapy with a daily dose of 3.0 g of metformin from 12
to 18 weeks of gestation until delivery was not associated with a lower
median neonatal birth weight.
• Treatment was however associated with a lower maternal weight gain
and a decreased risk of PET.
• Current evidence suggests that metformin may be able to reduce both
placental and maternal vascular aspects of PET
Future questions to address
1. Can Metformin prevent PET?
2. Does metformin influence weight and fat distribution in offspring
later on in life?
3. Can metformin reduce post partum weight retention?
2 gram Metformin BMI > 30
EMPOWar – negative
MOP vs. EMPOWaR
• EMPOWaR examined the effect of metformin at a dose of 2.5 g
per day, administered from 16 to 18 weeks of gestation to
delivery, in 449 white women without diabetes who had a BMI
of more than 30
• No significant results
• ?underpowered by including BMI 30-35
• ?underdosing (2.5g vs 3g)
• Lower adherence to an adequate dose of medication

1. Chiswick C, Reynolds RM, Denison F, et al. Effect of metformin on maternal and fetal outcomes in obese pregnant
women (EMPOWaR): a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 2015;3:778-
786
BMI > 27.5, 2 gram Metformin
No effect preeclampsia, no effect GDM
26-32 weeks, 3 gram Metformin
(BMI 26-36 and 25-35)
 Endothelial Protective Role of Statin

STATIN
H
O
Lipid protection
effects NO ↑ CO ↑
Improved
↓ Superoxide anions ↓ sFLT-1 & placental
↓ LDL
↓ Microalbuminuria sENG angiogenesis and
↓ Ox LDL
↓ cell death ↑ VEGF vascular
↑ LOX-1 expression
↓ remodelling
inflammation

Restoration of endothelium derived relaxation

Pleiotropic Effect of Statin

Girardi, 2018
Gus Dekker
Gus Dekker
Gus Dekker
 INOVASIA

Bandung Surabaya Makassar

40 sample 80 sample 53 sample

recruited recruited recruited

Subgroup
biomarkers
study

Clinical Trial.gov identifier: NCT03648970

 SURABAYA ARM
Biomarkers Study sFlt-1
ET-1 PlGF

Biomarkers
NO Measured sEng

IL6 VEGF
 Maternal Characteristics and Preeclampsia Risk Factors
Maternal Characteristics Control Group Pravastatin Group P value
N=86 N=87
Maternal Age (years old)# 31.66+6.11 32.32+5.26 0.448c
Parity
Nullipara 25 (29.1) 13 (14.9%) 0.025*
Multipara 61 (70.9) 74 (85.1)
BMI (kg/m2)$ 25.28 (9.05) 26.67 (9) 0.057d
GA at recruitment (weeks)$ 16 (5) 15 (5) 0.237d
Preeclampsia Risk Factors
Chronic Hypertension 20 (23.5) 17 (19.5) 0.524
Previous Preeclampsia 18 (20.9) 31 (35.6) 0.032
Pre-gestational DM 2 (2.3) 2 (2.3) 0.991
Systolic BP initial (mmHg)$ 120 (20) 120.5 (18.25) 0.025 d*
Diastolic BP initial (mmHg)$ 80 (20) 70 (18) 0.457 d
MAP initial (mmHg)$ 93 (11.5) 97 (13) 0.096d
Abnormal Uterine Artery Doppler 53 (61.6%) 52 (59.8%) 0.802
velocimetry
American Journal of Perinatology, 2022
SURABAYA
ARM
Biomarker
Result

American Journal of Perinatology, 2021

SURABAYA
ARM
Biomarker
Result
 INOVASIA Biomarkers Result Summary
Pro Preeclampsia Markers Anti Preeclampsia
Markers
Control Pravastatin
sFLT-1 ↑ = Control Pravastatin
sFlt-1/PlGF ↑ = PlGF ↓ =
ratio VEGF = =
sENG ↑ = NO ↓ ↑
IL-6 = ↓
ET-1 = ↓
MULTICENTER RESULTS
 Maternal Outcomes
Maternal Outcomes Control Group Pravastatin Group P value
N=86 N=87
Any preeclampsia 37 (43) 28 (32.3) 0.141
GA at diagnosis preeclampsia# 34.89+3.38 36.39+2.32 0.048*
(weeks)
Preterm Preeclampsia 23 (26.7) 12 (13.8) 0.034*
RR: 0.52 (0.27-0.97)
< 37 weeks

Severe preeclampsia 19 (22.1) 16 (18.4) 0.305

HELLP 2 (2.3) 1 (1.1) 0.621b
Stillbirth 4 (4.7) 1 (1.1) 0.211b
SGA (< 10th centile) 7 (8.2) 4 (4.6) 0.330
GA at delivery (weeks)# 36.0 + 4.3 37.4 + 1.9 0.045 d*
Systolic BP at delivery (mmHg)$ 130 (32.5) 120 (20) 0.048 d*

Diastolic BP at delivery (mmHg)$ 90 (20) 80 (10) 0.099 d

MAP at delivery (mmHg)$ 100 (27.75) 97 (17) 0.222 d American Journal of

Length of stay (days)$ 3 (1) 4 (3) 0.674 d Perinatology, 2022
 Perinatal Outcomes
Perinatal Outcomes Control Group Pravastatin Group P value

Preterm delivery < 37 31 (36) 14 (16.1) 0.003*

weeks RR: 0.45
(0.26-0.78)

Birthweight$ (gram) 2900 (1025) 3000 (700) 0.107 b

Birthweight < 2500 gram 35 (40.7) 24 (27.6) 0.069c
Birthweight < 1500 gram 8 (9.3) 3 (3.45) 0.114c
Height$ (cm) 47.5 (4.25) 48 (4) 0.264 b
Apgar score 1 minute < 7 22 (25.6) 5 (5.7) <0.001c*
Apgar score 5 minutes < 7 9 (10.5) 2 (2.3) 0.028 c*

American Journal of Perinatology, 2022

In percentages
 Prevention of Preeclampsia
A Heterogeneous Syndrome

Tertiary prevention means prevention of

complications caused by the disease process,
and is thus synonym to timely recognition and
treating a disease
Good antenatal care
 Maternal mortality from eclampsia and pre-eclampsia
No Magnesium sulphate
No Anti-hypertensive treatment

120

Confidential enquiries, England and Wales

100 Confidential enquiries, United Kingdom
Rate per million maternities

80

60

40

20
Hamlin 1952
Influential Lancet paper
0
1952 1955 1958 1961 1964 1967 1970 1973 1976 1979 1982 1985 1988 1991 1994 1997 2000-
- 54 - 57 - 60 - 63 - 66 - 69 - 72 - 75 - 78 - 81 - 84 - 87 - 90 - 93 - 96 - 99 02

Source: Confidential enquiries into maternal deaths, Figure 3.1. Graph by Alison Macfarlane
 Hamlin 1952 An early revolution in the development of antenatal care

Some basic principles were laid down

which established modern methods of unremittingly regular screening for pre-
eclampsia by measuring the blood pressure and testing the urine at each visit
and arranging admission to hospital if the warning signs developed and inducing
delivery before the problem ran out of control.

Hamlin RHJ. The prevention of eclampsia and pre-eclampsia. Lancet 1952;1:64-

68.
 Hamlin 1952 Continued

for example he identified that missing antenatal visits left

important and sometime dangerous gaps in the screening net
and introduced obsessional methods of seeking out clinic
defaulters:
“......the police were asked to deliver the message that an
immediate visit to the hospital was expected. Excellent results
followed this procedure in most instances.”

These principles were implemented in the UK in the next decade

Failures of antenatal care where highlighted as the major
avoidable factors … including a need (a continuing theme
today) to make contact with women who fail to attend
antenatal clinics

Why Mothers Die 2000-2002

Cemach 2004
Evidence

• Eclampsia or maternal death are regularly associated

with reduced or no antenatal care
• (Obed et al 1994, MacKay et al 2001, Abi Said et al 1995,
Ansari et al 1995)
Optimize GWG (gestational weight gain),
particularly for overweight and obese women
Happy to take questions

Gus Dekker