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Pravastatin, proton pump inhibitors, metformin,

micronutrients and biological products: new
horizons for the prevention or treatment of
preeclampsia
Stephen Tong, Ph.D., FRANZCOG; Tu'uhevaha J. Kaitu'u-Lino, PhD; Roxanne Hastie, PhD;
Fiona Brownfoot, PhD, FRANZCOG; Catalina Clover, Ph.D.; Dr. Natalie Hannan

Introduction
Preeclampsia complicates about 3% to 5% of
pregnancies.1,2 Unlike most
major complications of pregnancy
endanger women and fetuses,3and their
side effects may persist for
decades in the mother (increases the
risk of major cardiovascular diseases4,5) and
the child (increases the risk of chronic
disabilities and developmental delays resulting
from fetal growth restriction and prematurity).
There is a shortage of drugs to treat
the pathophysiological progression of preeclampsia. definitively determine whether pravastatin can prevent pre-eclampsia. pump inhibitors
Only 1 drug, aspirin, clearly prevents the
condition, and none have been conclusively
shown to improve
From the Translational Obstetrics
Group, Department of Obstetrics and
Gynaecology, University of Melbourne,
There has been a growing research drive to identify new therapeutic agents for
prevention or treatment of pre-eclampsia, drugs that may affect the pathophysiology of pre-eclampsia
underlying disease. Molecular targets of candidate treatments include stress
oxidative, antiangiogenic factors, and angiotensin, nitric oxide, and proinflammatory pathways. I know
believes that the proposed treatments that are being evaluated in preclinical and clinical trials
they act on placental or endothelial disease, or on both. Most have adopted the pragmatic strategy of
reusing medicines. Of all the proposed therapeutic agents, pravastatin has
received the most interest. There are preclinical studies showing that it has pleiotropic actions that
favorably impact multiple molecular targets and can resolve a preeclampsia phenotype in
many animal models. An early-stage clinical trial suggests it may have therapeutic activity.
Several large prevention trials are planned or underway and, when completed, could
protons, metformin and sulfasalazine are other drugs with preclinical evidence of multiple actions
molecules that could resolve the pathophysiology of preeclampsia. These agents are also
currently being evaluated in clinical trials. There have been many recent preclinical studies identifying
the potential of numerous natural compounds to treat preeclampsia, such as plant extracts and
micronutrients that have potent anti-inflammatory or antioxidant activity. Recent studies
Preclinical studies have also proposed new strategies targeting molecules, such as monoclonal antibodies
targeting tumor necrosis factor alpha, placental growth factor, and RNA technology from

Melbourne, Australia (Drs Tong, Kaitu'u-
Lino, Hastie, Brownfoot, Cluver, and Hannan);
Mercy Perinatal, Mercy Hospital for Women,
Heidelberg, Victoria, Australia (Drs Tong,
Kaitu'u-Lino, Hastie, Brownfoot, Cluver, and
Hannan); and Department of Obstetrics and
short interference, to silence gene expression of fmslike soluble tyrosine kinase-1 or
angiotensinogen. Other treatment approaches that have transitioned to human trials (which
range from single-arm trials to phase III trials that have been completed or are ongoing)
include folic acid, nitric oxide donors (such as L-arginine), recombinant antithrombin III, antigen
Digoxin immune-binding fragment and melatonin. There have been case series showing that

Gynaecology, Stellenbosch University, Cape removal of circulating soluble fms-like tyrosine kinase-1 may help stabilize the
Town, South Africa (Dr. Cluver). disease and prolong pregnancy. Interestingly, there are case reports suggesting that the antibody
Received on May 30, 2020; revised August 25, 2020; accepted monoclonal eculizumab (complement inhibitor) may have therapeutic potential. if they are discovered
on September 10, 2020.
new agents that have been shown to be effective in preventing or treating pre-eclampsia,
Australia's National Health and Medical
Research Council provides salary support
to ST (#1136418), TJK-L. (#1159261), RH
(#1176922), FB (#1142363), and NH (#1146128). Keywords:antioxidants, antithrombin III, apheresis, immune antigen-binding fragment of
Mercy Health Foundation Provides
digoxin, esomeprazole, L-arginine, melatonin, metformin, nitric oxide, pravastatin,
Salary Support to CC
preeclampsia, short interfering RNAs, soluble fms-like tyrosine kinase-1, treatment
The authors report no conflict of interest. East

document is part of a supplement.

Corresponding author: Stephen Tong,
PhD, FRANZCOG.fuerte@unimelb.edu.au
0002-9378/$36.00
crown copyright2020 Published by Elsevier Inc. All
All rights reserved.
https://doi.org/10.1016/j.ajog.2020.09.014
illness. A Cochrane systematic review
A high-quality study synthesizing data from 60
trials (36,716 participants) concluded that aspirin
modestly reduces proteinuric pre-eclampsia by
about 18% (risk
relative [RR] 0.82; confidence interval [CI] of the
95%, 0.77m10.88).6 Although the RR reduction
for preterm preeclampsia is
greater than,7,8 this subtype represents
only a small fraction of cases. Furthermore,
although the Cochrane review shows
encouraging trends, it is not clear whether
calcium prevents pre-eclampsia.9,10
Therefore, there is a pressing need to
identify new therapeutic agents to decrease
the global burden of disease.

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we will review research efforts to develop myometrium This creates a supply of Here, disease (experiment).22,23 Consequently, sFlt-1
new prevention and treatment strategies for high-flow, low-resistance blood has been an important target for
preeclampsia. An over-maternal compartment that many who strive to identify new therapies
view of the pathogenesis of preeclampsia adequately perfuse the placenta and tic agents

will be presented first. Then we will maintain the pregnancy. Poor cytodiscuss The presence of an
several therapeutic candidates Trophoblast invasion leading to poor increased proinflammatory response
agents, summarizing at which steps of placental implantation is the initial (both in the placenta and in the
the pathophysiologic pathway they are pathogenic event leading to preeclampsia.11 [systemic] vasculature) and oxidative
thought to act and presenting the stress in preeclampsia is well established.24
preclinical and clinical evidence. Figure Poor placentation early in the Normal pregnancy evokes a
1 provides a broad overview of the pregnancy causes persistent placental proinflammatory state, which is
classes of candidate therapeutic agents thathypoxia, ischemia-reperfusion injury, and exaggerated in preeclampsia.25
be discussed as the scope of this review, placental oxidative stress (Figure 2).12 monocytes and large ulocytes are activated an
The preeclamptic placenta reacts emerging therapeutic agents , we will not cover an imbalance of circulating pro-
aspirin, releasing excessive amounts of calcium, or low molecular weight heparin. inflammatory and anti-inflammatory
soluble factors that enter the cytokines occurs, including an increase in
maternal circulation and cause tumor necrosis factor alpha (TNF-a) and interleukin-6
search strategy endothelial dysfunction, maternal 26This proinflammatory state in blood
To prepare this review, we conducted a vascular injury, and hypertension. vessels results in endothelial activation,
systematic search using the National Library Soluble factors derived from the placenta local endothelial secretion of
of Medicine, the National Center for include antiangiogenic factors, such as inflammatory cytokines.

Biotechnological information. Soluble fms-like tyrosine kinase-1 and adhesion molecules were used, and a narrowing
of the following search terms: “pre-(sFlt-1)13,14 and soluble endoglin in the vasodilators nitric oxide and eclampsia or pre-
eclampsia” and “treat- (sEng).15 These factors bind and prostaglandins.
ment or drug or prevention or neutralize the actions of proangiogenic The initial events of therapeutic malplacenta.”
There were 17,557 hits with factors, such as vascular endothelial implantation and perfusion, in years from 1914 to
2020. growth factor (VEGF) and growth factor it is believed to give rise to oxidative
Examining the breakdown of beta transforming growth. There are others stress and tissue damage by free
published articles by year, there was soluble factors derived from the placenta, such radicals, which accumulate in placental insufficiency
a spike in published manuscripts spanning as proinflammatory cytokines and placental This is evidenced in the placenta
the years 2015 to 2019 (with 2020 tracking debris.16 by an increase in xanthine oxidase
similar to 2019). Given the number of total Soluble factors in the placenta and nicotinamide adenine
articles and the intention of can reduce the production of important dinucleotide phosphate oxidase (important
we provide a contemporary update, vasoactive molecules (including superoxide sources), increase our systematic search focused
on studies vasodilator, nitric oxide) and cause the lipid peroxidation and activation of
published since 2015. We identified 5,075 local release of factors derived apoptotic pathways.28mi30Due to
articles published between 2015 and 2020. of the endothelium that further placental oxidative stress and
We examined these articles by reviewing the exacerbate endothelial dysfunction. endothelial activation, oxidative stress
title and abstract. The relevant articles were These include thromboxane and is also present in the maternal
then scrutinized in depth and, if they were still endothelin-1 (ET-1) (both induce vasculature, with elevated markers of
relevant, were discussed in this review. vasoconstriction) and proinflammatory cytokines.
lipid peroxidation and decreased
We also search for references manually Although clearly not the main antioxidant capacity.31
before 2015. In addition, we also look for the event that triggers the disease, sFlt-1 is In addition to inflammation
the US, Africa, Europe and Australia. likely to be a central driver of the disease and oxidative stress, exacerbated
lian clinical trial registries. For this review, pre-eclampsia, as it meets most criteria hypercoagulation also results from
we prioritize drugs with pre-in vivo to establish a causal process of the disease. endothelial activation.32 Injury to
clinical data and only trials proposed by Sir Bradford Hill were included.17 Circulating endothelium results in an increase that had
been previously recorded. sFlt-1 reliably increases in most platelet adhesion, reduced fibrinolysis
of preeclampsia cases (consistency)18,19; the and activation of the coagulation
Steps in the pathogenesis levels rise before clinical disease cascade.32 This is evident among women
of preeclampsia that are (temporary)20,21; levels correlate with with preeclampsia due to reduced
pursued as therapeutic targets the severity of the disease (strength and antithrombin III33 and elevated platelet
During embryo implantation in early biological gradient)14; the link is biologically counts and fibronectin34 and is
pregnancy, the placental extravillous plausible (plausibility); and overexpression of especially evident among women who
cytotrophoblast invades and remodels the sFlt-1 in animal models may recapitulate the develop HELLP syndrome (hemolysis,
uterine spiral arteries in the clinical features of elevated liver enzymes Y

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low platelet count) and disseminated intravascular

FIGURE 1
coagulation.
Classes of Therapeutic Interventions Being Evaluated to Treat Preeclampsia
Consequently, the identification of
drugs that dampen the inflammatory
response or resolve oxidative stress has
been another common therapeutic
Type of therapy c Description examples
strategy.
intervene in
Candidates for drugs to treat or prevent
reused drugs The most popular approach North Pravasta
preeclampsia
Pravastatin
Proton-pump inhibitor esomeprazole
Pravastatin is a widely used lipid-lowering Advantage:some drug safety

drug to reduce the risk of the information will be known, I ormin

I ormin
cardiovascular events.35 During the last which will allow the efficacy trials to be accelerated
A thrombin III
decade, it has received the most attention of
Disadvantage:Limits preclinical
all drug candidates (other than aspirin and Sulfasalazine
discovery to drugs that are already
calcium) for its potential to treat or prevent formulated
melatonin
preeclampsia. Sulfasalazine (see comments section)

Preclinical studies suggest that

plasma apheresis blood filtration
pravastatin may have beneficial actions on apheresis using
to remove lipids or excess an-
maternal and placental vascular diseases. In columns that are
angiogenic factors.
vitro, administration of pravastatin to placental designed to
tissues or cells increases antioxidant pathways remove sFlt-1
Advantage: Small trials have
and may promote a favorable angiogenic profile sFlt1
it is shown that you can remove the sFlt-1
elimination
by decreasing sFlt-1 and sEng secretion.36 circulating (albeit temporarily)
There is also in vitro experimental evidence that
Disadvantage: Invader
resolves endothelial dysfunction in several

experimental tests (reduces the expression of monoclonal bodies Monoclonal anbodies are
etenercept
vascular cell adhesion molecule 1 highly specific and can be

mAb orientation designed to limit the transfer (a -TNFÿ)

[VCAM-1] and ET-1 and leukocyte adhesion
protein of interest placental
on endothelial cells and increases migration and
Advantage:exquisitely specific eculizumab
endothelial cell adhesion).36,37This
Disadvantage: Expensive, and (complement
This means that it could act beneficially on
still needs more pregnancy inhibitor)
maternal and placental vascular diseases
safety data
(Figure 1).

gene silencing
Several groups have reported that siRNAs are short strands of RNA.
siRNA target siRNAs
pravastatin can resolve the preeclampsia that exploit intracellular
machinery to reduce
phenotype in various animal models (such as sFlt-1 either

Expression of genes and target

hypertension and proteinuria).22,23,38mi angiotensinogen
proteins.
40 In these animal models, there is also evidence siRNA binds to target mRNA

Advantage:exquisitely specific
that pravastatin can reduce circulating sFlt-1,
decrease inflammation, and upregulate nitric Disadvantage: Still requires phase trials
mRNA degradation
oxide synthase (the enzyme in the endothelium I 'firsts in humans'

that produces nitric acid).

rust).22,23,38mi40
Pravastatin treatment during pregnancy
may even improve long-term outcomes after
Of the examples listed, only siRNA technologies have not been tested in pregnant women.
mab, monoclonal antibody; mRNA, messenger RNA; SFlt-1, soluble fms-like tyrosine kinase-1; siRNA, short interfering RNA; TNF-a,
tumor necrosis factor alpha.
Tong. Pravastatin, proton pump inhibitors, metformin, micronutrients, and biologics as prevention or treatment of preeclampsia. I am J
Obstet Gynecol 2022.

pregnancy. Pravastatin Administered During

Pregnancy in a Mouse Model of Preeclampsia
(Complement Inactivation Model) Resolved Left maternal renal remodeling and childbirth in a rat model of preeclampsia (human

Ventricular Hypertension injury.41 Pravastatin administered angiotensinogen gene incorporated) resolved

during pregnancy and 28 days after cardiovascular problems

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FIGURE 2
Pathogenesis of preeclampsia: a 2-stage process

STAGE 1 – Placental Disease

Pro
oxidize-ve
EITHER EITHER
-inflammatory
two two
- stress
EITHER
O2 cytokines
two

ROS TNFa

IL-6
ROS
sFlt-1 sFlt-1

SENG sFlt-1 sFlt-1

PlGF
SENG
An - angiogenic sFlt-1
factors

STAGE 2 – Maternal Vascular Disease

TNFa

SENG sFlt-1

sFlt-1
SENG IL-6 angiotensin
ROS sFlt-1
Less nitric oxide TNFÿ ROS
SENG
sFlt-1
SENG sFlt-1
sFlt-1 IL-6
TNFa

End Organ Injury

IL-6,interleukin-6;PlGF,placental growth factor;pink,reactive oxygen species;sing,soluble endoglin;SFlt-1,soluble fms-like tyrosine kinase-1;TNF-a, tumor necrosis factor alpha. Tong.

Pravastatin, proton pump inhibitors, metformin, micronutrients, and biologics as prevention or treatment of preeclampsia. I am J Obstet Gynecol 2022.

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dysfunction detected by echocardiography Pravastatin was originally assigned There is no registered treatment trial
and histologically (less cardiac a category X rating, suggesting it should be for pravastatin.
hypertrophy and interstitial fibrosis).42 avoided during pregnancy. However, a
There have also been early phase trials of systematic review concluded Proton-pump inhibitor

pravastatin. Costantine et al.43 that there is no association between fetal proton pump inhibitors are systemic abnormalities and
reported a small randomized trial where pravastatin antenatal pravastatin taken to relieve gastric acid reflux administration
10 mg or placebo daily (although the number of symptomatic by decreasing acid secretion,
(started at 12e16 weeks gestation) pregnancies where pravastatin was included during pregnancy. We have been
administered to 20 participants with administered was only 500mi600, which means that the published preclinical evidence49 suggesting
history of premature preeclampsia. The half-life was studies conducted to date may not have the that, like pravastatin, proton pump inhibitors
2 to 3 hours, and pravastatin appeared safe. Also, 4 sufficient power to detect an increased risk of (lansoprazole, rabeprazole, and esomeprazole)
out of 10 structural abnormalities ).46 Reassuringly, may decrease
Participants who received placebo animal toxicology studies suggested that placental release of sFlt-1 and sEng developed preeclampsia, but none for
Although the drug is safe,46 pravastatin is in vitro (at lower concentrations than
those who received pravastatin. not detectable43 or in very low concentrations45 pravastatin36). Using primary tissues, the
Circulating levels of sFlt-1 tended to in the umbilical cord at birth, and placental report also demonstrated that proton pump
a non-significant reduction. perfusion studies suggest that there may be inhibitors reduce placental and vascular pro-
Lefkou et al.44 reported an unblinded, an active output of the drug inflammatories.
uncontrolled study of 11 participants returned to the maternal compartment.47 cytokine production and mitigate
with antiphospholipid syndrome However, since the developing fetal endothelial dysfunction (reducing
who received 20 mg pravastatin daily and brain may be sensitive to expression of VCAM-1 and ET-1, reducing
compared them with 10 participants who did not receive the drug.
there are in vitro studies showing that pravastatin endothelial cell proliferation and endothelial tube
Differences in clinical outcomes were may increase neural stem cell death formation). The report also provided evidence
surprising: only 6 of 11 newborns in pla mouse fetal cells48), large trials of that esomeprazole
bait survived, while the 11 partici- pravastatin ideally should monitor can facilitate favorable vascular dypants in pravastatin had a healthy life
neonatal and child health. namics, as it upregulates nitric oxide
term births. There were also ultrasound tests that Ongoing trials offer hope phosphorylated synthase in endothelial cells

showed that pravastatin that there will be a clear answer as to (an enzyme that produces powerful nitros).
improves uterine blood flow (where it se- if pravastatin prevents pre- tric oxide) and vasodilates human rial ultrasounds
performed at least one eclampsia (laMesaresumes all trials omental blood vessels ex vivo (obtained
a week apart showed a ongoing randomized studies discussed in this review). during cesarean delivery).49
improvement in mean uterine artery pulsatility A large multicenter trial in Europe Furthermore, esomeprazole has been shown to
index for the 11 participants who received (EudraCT 2016-005206-19) aims to randomize resolve the hypertensive phenotype in 2 animal
pravastatin). Although encouraging, the 1,120 participants identified as being at high models of preeclampsia.49,50
findings require validation. risk of developing pre-eclampsia between 35 and Therefore, pump inhibitors

There has been 1 randomized 36 weeks of gestation (according to a screening protons may have the potential to treat or
treatment trial. The Statins to Improve algorithm) to 20 mg pravastatin or placebo. A prevent pre-eclampsia.
Early-Onset Pre-eclampsia (StAmP) trial was a phase I safety and pharmacokinetic trial in the Proton pump inhibitors are well tolerated. In
multicentre trial in the UK, in which pravastatin United States will randomly assign 48 participants addition, there are safety data from very large
40 mg or placebo was administered daily at with cohorts that conclude that there is no teratogenic
background of risk, even
62 participants with preeclampsia at term preeclampsia at 12 to 16 weeks after first trimester exposure.51,52 A meta-
analysis diagnosed between 24 and 31 weeks of gestation with placebo,10,20 has reported an association of gestation.45
There was no change in the or 40 mg pravastatin daily between prenatal exposure and the child's primary outcome, which
was a reduction. (NCT01717586). Excitingly, a sFlt-1 bell asthma,53 but it is unclear whether
plasma tion 3 days after the large trial also inNeither
the United
doesStates
pravastatin
randomization. the link is causal or whether
will randomly assign 1550 participants with a confounding variables can explain the
affect perinatal outcomes. However, history of finding preeclampsia. this little essay was
almost certain (requiring delivery before 34 weeks' gestation) to Saleh et al54 examined a cohort of
insufficient to definitively rule out the potential of pravastatin 20 mg or placebo (NCT03944512). An women with confirmed or suspected
pravastatin to treat pre-eclampsia. In a case series of unblinded trial in Indonesia will randomly assign preeclampsia and found that those who
4 women with premature preeclampsia, pravastatin 280 women at 10 to 20 weeks' gestation to receive concurrently taking inhibitors

(40 mg daily) may have 40 mg proton pump daily pravastatin or no drug.

favorable (decreased sFlt-1, sEng and
stabilized circulating levels of sFlt-1.36 (INOVASIA trial; NCT03648970). ET-1) compared to those who do

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No. Epidemiological data from a Metformin and sulfasalazine Swedish (PACTR20168001752102; trial results
cohort of 157,720 pregnancies provided a mixed picture55:
Metformin women
is an oral hypoglycemic agent that not yet reported) (Mesa).
It is used to treat type II diabetes and pregnancy. 64In the light of our experience from that
coinciding with the international proton pump diabetes. Similar to the meprazole pravastatin trial,56 we started with farhibitors did, in fact,
have a higher risk and proton pump inhibitors, also macrokinetic studies (prior to preeclampsia (adjusted
odds ratio [aOR], 1.17; 95% CI, reduces antiangiogenicpreeclampsia
factor secretion
in a embark
dose -dependent
on randomized
manner
trial)
in aincohort
1.04mi1.
of 15
32),women
but a reduced
preeclampsia with premature
riskbefore
diagnosed of placental
37 weeks .
can also mitigate
premature and confirmed that there were good
endothelial gestation dysfunction (reduces circulating levels of the drug.60 and fiveThere are

(aOR, 0.63; 95% CI, 0.41mI, 0.96) or in VCAM-1 expression) and may promote <34 weeks of gestation (aOR, 0.41; 95%
vasodilation throughout the maternal omental for preterm preeclampsia than CI, 0.20mL0.82).
of blood vessels.57 You can also have We report will
a clinical
compare
trialthe
conducted
combination
on
esomeprazole (40 mg) and metformin (1000 angiogenic
promotingproperties, as it from
vessel growth can Cape Town, South
120 participants Africa,
diagnosed
with where
placebo we assign mg)(Mesa).
with(NCT03717701)
A North American open-label
trial of premature preeclampsia between 26 and 32 metformin
median will recruit
A randomized 60by
trial women at 40 et
Syngelaki mgal.pregnant women with
esomeprazole type 1 diabetes
or placebo daily.56 (The
either
aortic rings obtained from mice.57 In addition,
there is evidence that it resolves the preeclampsia
phenotype in animal models.58,59
Main outcome is the rate of disorders of
gestation prolongation (the 60th examining the hypertensive potential of metformin ; NCT03570632).
primary outcome) was 11.4 days (between to reduce maternal health and Sulfasalazine, an anti-inflammatory
quartile range [IQR] 3.6mi19.7) in fetal weight gain in women who are drug used to treat the inflammatory arm
esomeprazole and 8.3 days (IQR, obese reported a remarkable 76% bowel disease, a 2.8mi19.6) has also been
shown among those who received the reduction in rates of pre-eclampsia stratified to reduce placental secretion of
placebo, a nonsignificant increase of 3 (OR, 0.24; 95% CI, 0.10mL, 0.61; sFlt-1, increase in placental growth factor
days (95% CI, 2.9mL8.8; PAGES¼.31).P<.001). A meta-analysis of trials (PlGF) and endothelial shrinkage Although it is
a likely explanation for our evaluation of metformin versus insulin dysfunction.66 Its potential advantage findings is that 40
mg of esomeprazole concluded that the rates of hypertension is that its potent anti-inflammatory cannot resolve the
Premature preeclampsia, disorders between those properties may help resolve the disorders are reduced, the study may
have been underestimated. administered metformin (n = 836; RR, 0.68; Placental and systemic inflammation
motorized. We followed the randomized trial 95%with
CI, 0.48m,
pharmacokinetic
0.95),61 butstudies
a meta-analysis
and found of present in preeclampsia. However,
trials in which women received that circulating concentrations
not find an esomeprazole
of metformin
were
or placebo
minimaldid
7 it is not clear how much drug is absorbed
into the circulation. given this
difference in hypertensive disease. information, we have started a
hours after administration.56 Therefore, an order61(n=609; RR, 0.86; 95% CI, macrokinetic trial of sulfasalazine in among women with
daily, or 0.33mi2.26;P¼.76). This is despite the preeclampsia higher doses, doses twice
intravenous administration may be effective, inclusion of the trial by Syngelaki et premature (ACTRN12617000226303).
although this would require evaluation. al.60 where the treatment effect It has also been reported that there are other molecules

Reassuringly, the levels of that meprazole were it was significant. Although there are some small cells that decrease sFlt-1 secretion
undetectable in the promising prospects, it should be noted that (such as the umbilical cord at birth, suggesting as sofa cone, YC1, and
that no metformin prevention trial has evaluated uabaín),67mi69but may be distant
there is no significant the risk of developing pre-eclampsia as a from the translation since their
transplacental passage with this oral dose.56 primary outcome. security remains uncertain.
There are more large trials evaluating 40 mg A large cohort that evaluated the results
of registered daily esomeprazole (Mesa). A trial of infancy (growth, emotional, and Mechanisms of action by which
in Australia aims to randomize 480 participants developmental) concluded that prenatal pravastatin, proton pump inhibitors,
identified as high risk from a first-trimester administration of metformin is safe.62 metformin, and sulfasalazine decrease soluble
screening algorithm (the primary outcome is a However, there are also preclinical data and fms-like tyrosine kinase-1 The question arises
difference in blood clinical trials that raise safety concerns.63A as to how drugs with such disparate actions-
drawback of metformin is that it has a from lipids
pressure at 36 weeks of gestation; high prevalence of gastrointestinal side descent, proton pump inhibition to ANZCTR12618001755224). a placebo effects,
which may decrease compliance. glycemic control: converge to reduce the
controlled prevention trial in Egypt has We just completed recruitment aiming to randomize 1000 sFlt-1 secretion. Target identification

participants of 180 participants in a randomized study common intracellular is not just a matter of

(NCT03717740), and an Extended Scientific Curiosity 3000mg placebo treatment trial: If found, aims to randomize 390
women with release metformin or placebo given in strengthens biological plausibility and can
premature preeclampsia (NCT03213639). divided doses, in South Africa discover new drug targets. We have

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TABLE

Ongoing randomized placebo-controlled treatment and prevention trials for pre-eclampsia that are registered

Description
Primary outcome of prevention trials: rates of pre-eclampsia; Primary outcome for
treatment trials: Prolongation of pregnancy (unless
Drug Registry number Location otherwise stated) expected completion date

Prevention

Pravastatin (20mg EudraCT 2016-005206-19 Europe 1120 participants, randomized at 35m36 weeks of gestation, identified at Recruitment; final date
daily) increased risk based on a screening algorithmb It does not indicate

NCT03944512 USA 1550 randomized participants at 12-16 weeks' gestation. Expected period of
Identified at increased risk based on a history of preeclampsia June recruitment
preterm requiring delivery < 34 weeks' gestation 2026mJune 2031

esomeprazole (40mg ANZCTR12618001755224 Australia 480 randomized participants at <16 weeks' gestation, identified with Recruitment; final date
daily) increased risk based on a first-trimester screening algorithmC It does not indicate

The primary outcome is blood pressure at 36 weeks' gestation.

NCT03717740 Egypt 1000 participants, identified at increased risk based on clinical factors (NICE January 2022

guidelines)

Treatment

Metformin (3000mg PACTR20168001752102 South Africa 180 participants with premature preeclampsia (PI2 trial), randomized August 2020
daily, in divided doses) at 26m to 32 weeks' gestation (recruitment is now

complete)

esomeprazole (40 mg NCT03213639 Egypt 390 participants with premature preeclampsia (ESOPE trial), randomized October 2020

daily) at 28m to 32 weeks' gestation

Metformin (1000mg) NCT03717701 Egypt 120 participants with premature preeclampsia, randomized to esomeprazole November 2020

and esomeprazole (40 and metformin or placebo at 28-32 weeks' gestation

milligrams)

Sprout Extract Tablet ACTRN12618000216213 Australia 180 participants with premature preeclampsia, randomized at 24 min Not yet started; no date of

of broccoli (8 mg twice a day) 34 weeks gestation set completion

Digoxin immune Fab NCT03008616 USA 200 participants with premature preeclampsia, randomized at 23-32 weeks March 2020

(AMAG-423) gestation
(intravenous infusion) The primary outcome is the proportion of infants who have intraventricular
haemorrhage and necrotizing enterocolitis or who have died by 36 weeks' gestation
(gestational age corrected).

recombinant NCT04182373 Japan 200 participants with premature preeclampsia, randomized at 24 mi May 2022
antithrombin III (KW 32 weeks gestation
3357) (intravenous
infusion)

ESOPE, esomeprazole in the treatment of early-onset preeclampsia; BONITO, National Institute of Health and Care Excellence; PlGF, placental growth factor.

a Expected end date, declared as part of clinical trial registry; b Third trimester screening algorithm combines mean arterial pressure, maternal history, clinical characteristics, and circulating levels of PlGF and soluble fms-like tyrosine kinase-1; CThe first
The quarterly screening algorithm combines mean arterial pressure, maternal history, clinical features, ultrasound-measured uterine artery pulsatility index, and circulating levels of PlGF and pregnancy-associated plasma protein A.

Tong. Pravastatin, proton pump inhibitors, metformin, micronutrients, and biologics as prevention or treatment of preeclampsia. I am J Obstet Gynecol 2022.
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identified 2 molecular targets where they are Antioxidants, plant extracts and that resveratrol resolves the
acting some of these drugs. micronutrients hypertensive phenotype in a pregnant rat model.81
studies We have shown that the inhibition of role
Given the which they report
of oxidative that
stress Now
in a series there have
of micro been
electron many
transport
produces energy) dedrugs with antioxidant actions have
the pathogenesis been nutrients
of preeclampsia, or plant
many chain
extracts
of the mitochondria
that increase the
(which
placental secretion of sFlt-1, evaluated for its potential to prevent (including polyphenols and flavonoids)
suggesting that mitochondria may actively regulate sFlt-1 secretion.57
or treat pre-eclampsia. A very large clinical can resolve preeclampsia in animal models.82mi86A
trial76(n=10.154; RR for preeclampsia in the treatment trial
We have also shown that metformin vitamin arm, 1.07; 95% CI, 0.93m1.24; P=.33) randomized broccoli sprouts

57and esomeprazole70decrease sFlt-1 dashed hope stemming from an earlier trial77 that (enriched in the antioxidant sulforaphane87)
production by inhibiting mitochondrial function. Though
the antioxidants, vitamin C and E, prevents (ANZCTR12618000216213)
You've been register
this identifies mitochondria as a preeclampsia. (Table).88
theoretical pharmacological objective, the With respect to other micronutrients,
deliberate search for other drugs that disturb Melatonin is a natural compound High-dose folic acid supplementation
the function of this subcellular organ should released by the pineal gland that had been proposed as a preventive treatment,
be done with care given its function regulates the circadian rhythm. It is well but unfortunately a large phase III trial found no
essential in power generation known for its antioxidant properties. In benefit (n=2464; RR of pre-eclampsia
intracellular. preclinical studies, melatonin reduced
Placental and epidermal growth factor receptor oxidative stress among women receiving 4 mg folic acid pathway (EGFR) is an important cellular
signal regulated molecules involved in the it was 1.10; 95% CI, 0.90m1.34; P¼.37).89
pathway that promotes cell survival and coordinates antioxidant response.78 In a single-arm phase I Nicotinamide (vitamin B3) has been shown
many intracellular processes.70 trial, the team reported that 10 mg of oral to antagonize vasoconstriction and resolve the
We have shown that the EGFR pathway also melatonin (given 3 times daily) to 20 women with preeclampsia phenotype in 2 animal models.90 A
positively regulates the secretion of sFlt-170 and premature preeclampsia prolonged gestation by a small single-arm trial of nicotinamide administered
that statins, esomeprazole,70 median of 6 to 2.3 days and reduced the to 25 women with preeclampsia is reported
and sulfasalazine71 can inhibit EGFR signaling
to reduce sFlt-1 secretion. need for antihypertensive agents (NCT3419364).
Gefitinib is a molecularly targeted drug compared to 48 with trolls.78 No other trials of Therefore, micronutrients and
designed to inhibit EGFR to treat lung cancer. Plant extracts may merit testing in clinical
We have shown that gefitinib is potentially the melatonin. trials given that they are widely consumed and
most potent inhibitor of sFlt-1 of any small MitoQ is a small molecule available as a well tolerated. However, since preclinical studies
molecule drug where very low drug nutritional supplement that targets mitochondrial
concentrations are required to decrease sFlt-1 oxidative stress (an important source of reactive have identified so many candidates with

secretion in vitro.70 However, because EGFR oxygen species that cause intracellular oxidative therapeutic potential, the challenge is sorting out
signaling plays an important role in the biology stress). yang et al79 recently showed that MitoQ which ones should be tested in clinical trials.
of the placenta, any proposed human trial of reduced placental oxidative stress and resolved Perhaps a systematic preclinical evaluation
gefitinib would need to be carefully designed preeclampsia in a mouse model alone comparing candidates in similar models could be a
with fetal safety as the primary outcome. if given later in pregnancy. pragmatic approach to choosing which ones are
Interestingly, it exacerbated the preeclampsia prioritized for human trials.
phenotype if it started early in pregnancy, and
It is likely that there are other they reasonably hypothesize that it was due to stress
molecular circuits that regulate sFlt-1 oxidative plays an important role. Drugs targeting the nitric
secretion in addition to mitochondria and EGFR. For oxide synthase pathway
For example, we36 and others72 have a positive role in early placental enhancing elements of the nitric oxide synthase
showed that direct inhibition of developing. pathway has been a focus of
the 3-hydroxy-methylglutaryl coenzyme Polyphenols are micronutrients with antioxidant properties strategies since
A reductase pathway (the direct target of therapeutics found in food, increased circulating levels of oxide

statins) may decrease sFlt-1 secretion. such as berries, beans, vegetables, tea, nitric acid (produced by nitric oxide synthase)
Furthermore, the inhibition of hypoxia nuts, and red wine. Flavonoids are anti can resolve maternal vascular disease.
inducible factor-1 alpha (HIF-1a) oxidants conferring fruits and vegetables Considerable optimism was generated pathway also
reduces secretion of sFlt-1.68 its vivid colors. We have shown that from a randomized trial comparing oral sildenafil
Since proton pump inhibitors49 adding the polyphenol resveratrol to the 50 mg given 3 times daily (enhancing nitric oxide
and metformin73mi75inhibit HIF-1a placental cytotrophoblast increases the action) with placebo given to 100 participants with
expression, this may be another mechanism by whichintracellular molecules involved in the antioxidant premature pre-eclampsia. The length of pregnancy
which these drugs inhibit the release of response and reduces the secretion of sFlt-1.80 , while
was significantly
sFlt-1. others have shown

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ajog.org expert review

was prolonged by 4 days among and 2006101 based on the premise that it constant portion (Fc) of the
those who received sildenafil (14.4 days [95% CI, 12.5
eliminated the lipids that cause cardiovascular immunoglobulin G antibody. The
mi16.6] vs. 10.4 days [95% CI, 8.4mi diseases. Since those periods, the focus of TNF receptor on etanercept binds
12.3];P¼.008), and there was evidence treating preeclampsia with apheresis has shifted to TNF a and neutralizes its activity.
of reduced resistance to blood flow of the to its potential to remove sFlt-1 from the Two teams have shown that etanercept can re
uterine and umbilical arteries (measured by circulation. thadhani the preeclampsia phenotype in rat
ultrasound).91 Unfortunately, since that trial, et al.102 dextran sulfate columns models.105,106
concerns have been raised regarding a used for apheresis to preferentially Preeclampsia is associated with
possible association between exposure remove sFlt-1 and conducted a pilot study in complement activation, and disruption of this
prenatal sil denafil and neonatal death from women with preterm labor system in a mouse model can produce
preeclampsia. There were 15% to 28% clinical features of preeclampsia.107
pulmonary hypertension.92 Given reduction in circulating levels of sFlt-1 There has been a case report where doses

this information, it is difficult to predict what might happen after a single series of the complement inhibitor
apheresis treatment. have enthusiasm to pursue In addition, 3 more women underwent eculizumab (a humanized recombinant
sue sildenafil as a treatment for serial apheresis treatments: circulating monoclonal antibody (maB) used for pre-
eclampsia. sFlt-1 was transiently reduced after each hemolytic uraemic syndrome) was used for
treatment
Vadillo-Ortega et al.93published a trial treating a patient of 26and pregnancies
3/7 weeks lasted from
of randomized 15 to
blinded prevention (n=222 per
syndrome. pregnancy
After with
arm), which HELLP
found that food
23 days.102
bars treatment, her biochemistry (including tests for L-arginine They oxide
(a nitric subsequently
substrate)reported
significantly altered liver
with function
a history of and administered
low platelet to women
counts)
theof
normalized and preeclampsia resulted in a gain 17 days results of 11
gestation moregiving
before women with
birth to marked reduction in preeclampsia
gestation.108 rates
Also ha at 0.17;
(RR, 29 2/795%
weeks'
CI, 0.12).
There have been 2 case reports in which a preventionpremature pre-eclampsia
trial concluded who received
that eculizumab was administered shortly after the similar,94 and there are preclinical
apheresis treatment (once or several times),
103 and the group had pregnancies
that potentially lasted longer than a
contemporary pre-eclamptic cohort that did
not receive the treatment. 103 There is a single-
arm trial of apheresis treatment birth to treat acute infants.
support that L-arginine could prevent ment in 23 participants recorded kidney injury and poor kidney function preeclampsia.
(healthy
95,96 These clues make Larginine a promising volunteers
concept. and women
It is therefore disappointing that
largethere
clinical
do not
trialsappear
derivedtofrom
be any
pre-
eclampsia after that . with pre-eclampsia) where safety is they responded to dialysis.109,110 Both cases
the main outcome (NCT02923296). fully recovered. Although eculizumab may merit
Apheresis is invasive and it will be further investigation for its potential to treat
A small trial of S-nitrosoglutathione challenging to conduct large clinical trials. preeclampsia, one downside is that it is
intravenously (a nitric oxide donor) in 6 Even without such trials, it could arguably exceptionally expensive.
participants with premature preeclampsia play a role in treating diseases that occur at
demonstrated a decrease in blood pressure. very early gestations, Digoxin binding to immune antigen
safe and showed trends toward where options are limited and the fragment (Fab), immunoglobulin
fragment improving several indices reflecting
The prognosis is bleak (the analogy may be derived from sheep and used to treat digoxin
severity of disease) .97 In contrast, abdominal cerclage,
preterm
offered
births
to women
in a blinded
who have
randomized
had recurrent toxicity, has been proposed as a treatment.
prevention trial of 100 in participants who compared mononitrate
The evidencefrom
supporting
very early
thisgestations,
technique although
comes The reason is that digitalis-like endogenous
from factors block the
oral isosorbide (nitric oxide donor) with intracellular sodium pumps in the endothelium
placebo did find a difference in the case series only).104). leading to vasoconstriction. Digoxin immune
incidence of pre-eclampsia, but it is likely Fab blocks these factors. There is a randomized
underpowered.98 Monoclonal antibodies trial that aims to administer either the Digoxin
Relaxin is an endogenous peptide Monoclonal antibodies may be an attractive class of Immune Fab (NCT03008616) (Mesa) or placebo
hormone that increases nitric oxide drugs to treat pre-eclampsia, as they are to 200 women with premature preeclampsia. It
and can reduce endothelial dysfunction. highly specific and, in theory, can be follows a pilot trial suggesting that it is safe and
99A phase I trial of recombinant designed not to cross the placenta. TNF-ÿ is possibly improved renal blood flow (improved
human relaxin administered to a cytokine that is increased in preeclampsia26 creatinine clearance), but did not affect the use
women with premature preeclampsia and is postulated to play an important role in of antihypertensive medications.111
was discontinued without reporting the proinflammatory response associated
results (NCT00333307). with the disease. Etanercept is a fusion
protein (used clinically to treat rheumatoid
Aphaeresis arthritis) in which a part of the TNF- ÿ receptor Antithrombin III
Apheresis was initially proposed as a is fused with the Recombinant antithrombin III has been
treatment for preeclampsia in 2003100 proposed as a treatment for

FEBRUARY 2022American Journal of Obstetrics and GynecologyS1165

Machine Translated by Google

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preeclampsia as its anti-inflammatory and preeclampsia116). This is a smart limited in time (since women generally
anticoagulant properties are postulated to be beneficial. strategy given that most siRNAs give birth soon after diagnosis), preeclampsia
Unfortunately, a multicenter placebo administered into the venous circulation are with severe features can still occur, which

absorbed by the liver, which turns out to be results in a significant maternal loss.

controlled treatment trial in which circulating angiotensinogen is morbidity. There is potentially an America unsatisfied with preterm
women synthesized. This means that siRNAs demand for a drug that can temporize the

preeclampsia did not find a difference in can simply be administered intravenously, disease at term of pregnancy.
median age increase with most reaching the liver. Interestingly, some prevention trials

gestational age (5.0 days [range, 0mi75] siRNA treatments can be produced have taken the novel approach of a

in the treatment group and 6.0 days [range, 0mi at scale and can be a biomarker strategy to identify people at risk of

85] in the placebo group; P¼.95).112 exciting development if they translate into preeclampsia. For example, a phase II trial of

A randomized treatment trial in Japan of clinical trials. esomeprazole is randomizing those identified at

another recombinant antithrombin increased risk of preeclampsia based on a first-

Drug III, KW-3357, is registered Other novel approaches trimester screening algorithm
(NCT04182373) (Table). Other scientifically sophisticated
preclinical approaches that have been shown to(combines
solve a maternal characteristics
placental growth factor preeclampsia phenotype in animal characteristics, sonographic findings and
PlGF administration may help to overcome patterns (but may still be far from circulating levels of PlGF and loss of VEGF that is
neutralized by translation) include stem cells,117 pregnancy-associated plasma protein A;
circulating sFlt-1. This can restore delivery of siRNA nanoparticles,118 and a ANZCTR12618001755224)
homeostasis of blood vessels and be a form of drug-carrying biopolymer that can (Mesa) and a phase III trial of treatment retain an active drug (a pre-disease fragment. Makris et
al.113 showed the administration of PlGF to a model of preeclampsia
vastatininisaidentifying
baboon (produced by ligating
women peptide thatainhibits
NF-kB, a master regulator on the basis of a pro-inflammatory response screening test ) in the

35 to 36 weeks of gestation (combines

uterine artery to induce maternal hypoplacental vascular compartment to characteristics and circulating levels oxia)
resolved clinical parameters, inhibits maternal systemic inflammation of sFlt-1 and PlGF; EudraCT 2016- including
hypertension. Despite (but prevent potentially harmful placental 005206-19) (Table). Since the detection
Encouragingly, it is enormously transfer).119 based solely on clinical history alone

expensive and challenging to improve has a modest positive predictive value (meaning that
the manufacture of whole proteins, Considerations in the design of futures most who are
such as PlGF, for human administration. clinical trials randomized are not intended to develop

Almost all randomized treatment trials disease) and low sensitivity,120incor

short interfering RNAs completed56,112or ongoing (Mesa) porar biomarkers to identify have been
Recently, Turanov et al.114 published for premature preeclampsia, women at higher risk may be a valuable
the use of RNA interference technology where the primary result has been short- approach for designing large prevention
focused (siRNA) targeting sFlt-1. These are mainly
strands
in prolonging
of RNA taking
gestation
advantage
(the short
of the trials.
StAmP assay that evaluated existing intracellular exception,
machinery where
for oral
the
pravastatin
primary outcome
was an
was reduced expression of target proteins. The team
was agenerated
differencesiRNAs
in sFlt -1
targeting
circulating45).
sFlt-1, Comment

Winning Pregnancy appears to be a chemically appropriate

engineered result
for most
so current
that it may
treatment
be There has been an encouraging escalation in the

trials trying to identify drugs that resist degradation

showed
andthey
survive
canlonger
mitigate
in pathophysiology
circulation, and research activity focused on identifying new treatment

de la reduced the expression of sFlt-1 in mice. The

reported
disease
to date
(since
also
no reduced
siRNA has
circulating
been strategies for preeclampsia. The increase in the number

sFlt-1 and identified none). For anyone who lowered their blood pressure and of preclinical reports in recent years has been quite

pronounced. In fact, there is now a rather bewildering

number of candidates

find out, you may need to be more which seem to solve several problems.

tinuria in a baboon model evaluated in subsequent large phase III plications in animal models. It's more preeclampsia.
trials to see if its administration can improve encouraging that there has also
Haase et al.115also used technology of clinically relevant endpoints, such as maternal outcomes been an increase in clinical trials
siRNA and showed that silencing and published in the last decade45,56,91,112
neonatal. and others that are ongoing (Mesa).
angiotensinogen resolved the preeclamptic
phenotype in animal models, including There have been no trials of treatment of Here, we wish to discuss some points that

proteinuria, hypertension, and fetal growth Medications that can mitigate the progression of can help refine the translation strategy for

restriction (perturbations in the disease in cohorts with preeclampsia. research teams seeking
renin-angiotensin system causing endo- diagnosed at term gestation. Although preclinical concepts or thelial dysfunction
are a likely feature of the disease course, clinical trials are being contemplated.

S1166American Journal of Obstetrics and GynecologyFEBRUARY 2022

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ajog.org expert review

First, it is clear that most agents it would have to be exceptionally secure. The could have a lasting impact,
candidate therapeutics for preeclampsia reason is that all detection devices saving the lives of babies and mothers and
ing examined are reused medications: that approaches to identify women at risk to decrease lifelong sequelae is, medications
-
licensed to treat another drug preeclampsia have modest value in predicting brought by this condition.
lime condition and now identified for its potential precisely preeclampsia; that is, a value
to treat preeclampsia. Drug repurposing is a low positive predictive value.120 This means that GLOSSARY
pragmatic way forward, as it can speed up promising any preventative treatment will be given
results for many months now. ORa: adjusted odds ratio

preclinical concepts to trials since there may be more pregnancies than ever were safety data for the CI: confidence interval

drug. That's why, destined to develop the condition than those that EGFR: growth factor receptor inhibitor

Drug reuse can save a lot were. In contrast, the threshold at which we can epidermal

years of phase I safety and toxicological trials.121 tolerate safety uncertainties may be lower when Fab: antigen-binding fragment HELLP: hemolysis,

It is a strategy worth following. treatments for clinical pre-eclampsia are being elevated liver enzymes, low blood count

However, it should also be noted that a contemplated. This is because for treatment trials, platelets

disadvantage of the reuse strategy is that it limits it is anticipated that the drug will be given to a IL-6: interleukin-6

preclinical discovery to already formulated drugs. select few (all of whom have the disease) for a few IQR: interquartile range
Significant advances have been made in therapeutic weeks, if not days, and NF-kB: kappa light chain enhancer
strategies for oncology through targeted approaches nuclear factor of activated B cells

well away from early pregnancy, when the PlGF: growth factor

molecularly.122,123: generate new compounds teratogenic risk is higher. When considering these placental RR: relative risk

tailored to specific target molecules that are dots, siRNA approaches, antibodies ROS: reactive oxygen species
known disease drivers. it's possible monoclonal and apheresis may be more suitable sEng: soluble endoglin
that reuse can be effective in preventing for treatment trials, while the SFlt-1: fms-like tyrosine kinase-1 siRNA

pre-eclampsia (to modify the disease in drug reuse can be more soluble: short interfering RNA

an early stage of its pathogenesis), but suitable for large prevention trials. TNF-a: tumor necrosis factor alpha VEGF:

will need more molecularly targeted approaches vascular endothelial growth factor

to treat preeclampsia because by the time Our last comment is that although there has
disease is clinically evident, been a welcome increase in maternal vascular
and placental clinical trials of new candidates to treat prevent
or they will be gone. be the
pre-eclampsia, verytotal
advanced.
numberThis to
remains
may mean that only modest approaches will be used compared to other molecularly targeted ones.
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