®

Review
OPEN

The Role of Metformin in Treating Preeclampsia

Decui Cheng, Xuexin Zhou, Xianming Xu∗

Abstract
Preeclampsia (PE) is a principal cause of maternal and newborn mortality that poses financial and physical burdens to tens of
thousands of families each year. Unfortunately, there is no effective management to arrest the progression of this disease unless
delivery. Therefore, standardized management or preventive treatments are needed urgently. PE is closely associated with placental
hypoxia, which increases the secretion of soluble fms-like tyrosine kinase 1 (sFlt-1) as well as soluble endoglin (sEng) into the maternal
circulation. Metformin has been found to inhibit those anti-angiogenic factors so it might be a candidate to prevent or treat PE.
Women who are diagnosed with gestational diabetes mellitus (GDM) are more likely to have complications of hypertension or PE, so
this review aims to demonstrate that the application of metformin in GDM might prevent the onset or progression of PE complicated
with GDM.
Keywords: Gestational diabetes; Gestational hypertension; Metformin; Preeclampsia
Downloaded from http://journals.lww.com/mfm by BhDMf5ePHKbH4TTImqenVA+lpWIIBvonhQl60Etgtdnn9T1vLQWJq/+R2O4Kjt58 on 05/14/2022

Introduction insulin sensitivity (enhances peripheral glucose uptake and

Preeclampsia (PE) is a condition during pregnancy where
there is a sudden rise in blood pressure and swelling,
mostly in the face, hands, and feet. It generally develops
during the third trimester and affects about one in 20
pregnancies.1 It can be divided into early-onset preeclamp-
sia and late-onset preeclampsia. It is a principle cause of
maternal and newborn mortality that poses financial and
physical burdens to tens of thousands of families each
year.2 Unfortunately, there is no effective management to
arrest the progression of this disease unless delivery.3
Therefore, standardized management or preventive treat-
ments are needed urgently.
PE is closely associated with placental hypoxia, which
increases the secretion of soluble fms-like tyrosine kinase 1
(sFlt-1) as well as soluble endoglin (sEng) into the maternal
circulation.4 These serum biomarkers, as typical anti-
angiogenic factors, lead to systemic endothelial dysfunc-
tion and lead to hypertension and multisystem organ
dysfunction, which can be observed clinically.5 Metformin
has been found to inhibit those anti-angiogenic factors so
might be a candidate to prevent or treat PE.6
Metformin, the “aspirin of the 21st century”,7 is
commonly used to treat type 2 diabetes. It improves
Department of Obstetrics and Gynecology, Shanghai General Hospital,
Shanghai 201600, China.
∗
Corresponding author: Xianming Xu, Department of Obstetrics and
Gynecology, Shanghai General Hospital, South Hospital of Shanghai
General Hospital, 650 Xinsongjiang Road, Songjiang District, Shanghai
201600, China. E-mail: xuxm11@163.com
Copyright © 2021 The Chinese Medical Association, published by
Wolters Kluwer Health, Inc.
This is an open access article distributed under the terms of the
Creative Commons Attribution-Non Commercial-No Derivatives License
4.0 (CCBY-NC-ND), where it is permissible to download and share the
work provided it is properly cited. The work cannot be changed in any
way or used commercially without permission from the journal.
Maternal-Fetal Medicine (2021) 3:3
Received: 22 September 2020
http://dx.doi.org/10.1097/FM9.0000000000000086
utilization), reduces the intestinal absorption of glucose,
and decreases hepatic glucose production. Surprisingly, its
role has been expanding to—but not limited to—the
treatment of prediabetes, gestational diabetes, polycystic
ovarian disease, congestive heart failure, chronic kidney
disease, prolongation of lifespan, and reduction of breast
and prostate cancer metastasis. Moreover, numerous
experiments have suggested that metformin plays an
important role in the treatment or prevention of PE.
Moreover, women who are diagnosed with gestational
diabetes mellitus (GDM) are more likely to have
complications of hypertension or PE, so we hypothesized
that the application of metformin in such cases might
prevent the onset or progression of PE complicated with
GDM.
Pathophysiology of PE
The definitive causes of PE are still a mystery. It is thought to
be a two-stage disorder. The first phase involves defective
placental trophoblastic invasion of the uterine spiral arteries
at 14–18 weeks of gestation leading to decreased
uteroplacental blood flow and the second phrase is that
the release of antiangiogenic factors from the ischemic
placenta into the maternal circulation that contributes to
endothelial damage.8 The earliest pathological change in
early-onset cases is abnormal remodeling of uterine spiral
arteries. These are important adaptive changes in normal
pregnancy, which serve to reduce vascular resistance and
increase blood flow to ensure adequate placental perfusion.
This process is accompanied with the differentiation of
epithelial into endothelial cells, enabling spiral artery
changes from narrow high-resistance vessels to a large-
caliber blood vessels. In patients with PE, trophoblast cells
show insufficient invasion of the spiral arteries, which have
poor remodeling, maintaining the original narrow diameter
and high resistance, leading to placental ischemia or
hypoxia. To achieve normal vascular function during
pregnancy, the placenta and vascular endothelium secrete

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many molecules, including vasoactive substances, growth
factors, adhesion molecules and proteases, among which the
most typical include vascular endothelial growth factor
(VEGF), sFlt-1, placental growth factor (PlGF) and
endothelin. These interact with maternal immune cells
(especially natural killer cells of the uterus) and their
corresponding human leukocyte antigen, which is of great
significance for uterine spiral artery remodeling and related
protease activity. These molecules play important roles for
the formation of a uteroplacental interface, as well as
induction of the maternal cardiovascular system and
adaptive renal changes. This multisystem dysfunction then
leads to the clinical manifestations of PE, including low
platelet counts, increased blood pressure, elevated protein-
uria, and abnormal liver function. Additionally, in a
hyperglycemic state, the number of endothelial progenitor
cells, crucial for angiogenesis and vascular protection, are
reduced and hence their function impaired, leading to
vascular complications and endothelial dysfunction.9
PlGF
PlGF is mainly synthesized by syncytiotrophoblast cells
and can bind to tyrosinase receptors located on tropho-
blastic and vascular endothelial cells.10 It is a protein with
an autocrine effect on trophoblastic cells and a paracrine
effect on vascular growth. PlGF is central to regulating the
functions of trophoblastic and endothelial cells, and can
promote angiogenesis. Notably, the level of PlGF in
patients with PE is lower than in normal pregnancy and
these lower levels can be detected at about 9–11 weeks
before the onset of overt clinical symptoms.
sFlt-1
VEGF is an effective angiogenic factor that activates its
receptors VEGFR-1 and VEGFR-2, and combines with the
nitric oxide (NO) synthase needed for angiogenesis. Thus, it is
crucial in maintaining vessel homeostasis and in promoting
placental angiogenesis. sFlt-1 is a splicing variant of the
tyrosinase receptor of vascular endothelial cells, closely
related to the severity of PE. It can inhibit the production of
VEGF and PlGF and prevent them from interacting with
vascular endothelial receptors. It can also strengthen the
sensitivity of maternal vascular endothelial cells to inflam-
matory cytokines, and lead to their dysfunction. These effects
can result in fetal growth restriction and PE. Brownfoot et al.6
obtained omental biopsy specimens at the time of cesarean
delivery, and the omental vessels were dissected into small
explants, and cultured with or without sFlt-1. They found a
significant reduction in angiogenic sprouting from the vessels
in the presence of sFlt-1.6 If administered sFlt-1 and/or sEng,
animals can perform some characteristics of PE.11 For
instance if VEGFR-1 is given to rats using an adenovirus
vector, the animals will develop some symptoms, such as
proteinuria, glomerular endotheliosis, and hypertension.
sFlt-1 is a reliable predictor of PE, as abnormal levels can be
measured 5 weeks before the onset of symptoms.
sEng
sEng is a membrane glycoprotein, similar to sFlt-1, that is
primarily secreted from syncytiotrophoblast cells. It
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participates in formation of the transforming growth
factor-beta–receptor complex in endothelial cells and
mononuclear cell membranes.12 Physically, sEng promotes
angiogenesis and endothelial cell differentiation, as well as
regulating vascular tension through the action of endo-
thelial nitric oxide synthase (eNOs). Pathologically,
vasodilation and vascular permeability can be inhibited
via the action of NO. Moreover, sEng attaches to
transforming growth factor-beta 1 cell surface receptors
and causes the secondary symptoms of PE.
Angiogenic pathways and insulin resistance (IR)
IR means inadequate response of the body to insulin,
meaning that glucose uptake and utilization cannot be
activated effectively. IR is promoted by the disturbed
expression of proteins involved in visceral obesity and
insulin action pathways. A higher metabolic activity was
noted in adipocytes of visceral fatty tissue, which are less
sensitive to insulin.13 IR inhibits the lipolysis induced by
insulin, leading to increased levels of free fatty acids. Uptake
of these is reduced, resulting in disturbances in insulin
signaling, which may explain why sensitivity to insulin
declines naturally with progressive gestational age, proba-
bly as a result of higher amounts of visceral fatty tissues,
triacylglycerol deposition in cells, and proinflammatory
factors.14 IR and hyperinsulinemia occur progressively
during normal pregnancy peaking in the third trimester,15
when pregnancy-induced hypertension (PIH) occurs most
often, suggesting an association between IR and PIH, but
this rapidly return to pre-pregnancy levels after delivery.16
Studies have shown that IR also exists in patients with PIH,
so hyperinsulinemia and IR should not be overlooked in the
pathogenesis of PIH through multiple aspects, including the
following: (1) decreased NO production; (2) inhibition of
the actions of prostaglandin I2 and E2 to increase peripheral
vascular resistance and blood pressure; (3) inhibition of the
production of prostaglandins to induce endothelial cell
dysfunction; (4) activation of the sympathetic nervous
system; (5) increased renal sodium retention; and (6)
increased cation transport of cell.
Possible mechanisms of metformin for preventing PE
Kalafat and Sukur17 published a meta-analysis about
metformin including 15 citations. They concluded that the
use of metformin vs. insulin to treat gestational diabetes
was correlated with a reduced risk of PIH (relative risk
(RR): 0.56; 95% confidence interval (CI): 0.37–0.85; n =
1260 women) and a non-significantly declined risk of PE
(RR: 0.83; 95% CI: 0.60–1.14; n = 1724 women).17 In
2013, five randomized clinical trials (RCTs) showed the
safety of metformin as well as its efficiency in dealing with
GDM compared with insulin.18–21 Gui et al. made a
systematic review and meta-analysis, demonstrating that
metformin was a better choice than insulin for reducing the
incidence of PIH.22
Metformin therapy reduces sFlt-1 and sEng levels
An experiment in the year of 2015 measured the effects of
metformin on sFlt-1 secretion, which revealed that with the
highest doses, metformin downgraded endothelial cell
secretion by 53% and placental cell secretion by 63%,
Cheng et al., Maternal-Fetal Medicine (2021) 3:3
respectively.6 Using placental villous explants from four
women who had been diagnosed with preterm PE (delivery
required <34 weeks of gestation) and treated with
metformin, sFlt1 levels were less than in a control group.6
That report also suggested that metformin modulates these
anti-angiogenic factors (sFlt-1 and sEng and so on) through
the function of mitochondria, primarily by inhibiting
mitochondrial electron transport chain activity. Mitochon-
drial electron transport chain activity was upregulated in
preterm preeclamptic placentas,6 which is further persua-
sive evidence that metformin can regulate those anti-
angiogenic factors through mitochondrial activity.
Metformin modulates NO-related pathways
Diabetes is always complicated with hypertension,
suggesting that the two diseases might share some
underlying processes. Thus, eNOS is expressed in villous
endothelial cells, and NO is a critical endogenous
vasodilator of the placental vasculature. Paradoxically,
the progression of vascular disease is closely related with
the bioavailability of NO.23 Kinaan et al. demonstrated
that sirtuin 1 can increase the bioavailability of NO by
eNOS deacetylation, and participate in cell proliferation
and angiogenesis.23 Metformin helps achieve endothelial
cell protection mediated by sirtuin 1 through enhanced
eNOS activity. This causes a reduction in apoptosis and
the promotion of angiogenesis. Furthermore, an experi-
ment involving incubation of maternal blood vessels from
the omentum of patients with PE showed that metformin
could reverse the impairment of vascular relaxation by
incubation with tumor necrosis factor alpha,6 a cytokine
with elevated levels in the circulation of patients diagnosed
with PE.
Anti-inflammation
Metformin is mainly used to inhibit or activate 50
adenosine monophosphate-activated protein kinase to
control the release of inflammatory factors, and blocks the
phosphoinositide 3-kinases/serine-threonine kinase path-
way, inhibits the activation of nuclear factor-kappa B, and
downgrade inflammatory factor levels. Thus, it acts to
inhibit the secretion of adhesion molecules by vascular
endothelial cells, blocks the synthesis of oxygen-derived
free radicals and proteases, and reduces vascular endothe-
lium Injury. In addition, metformin can increase the
activity of H9c2 cells, lower reactive oxygen species levels,
and promote activation of the 50 adenosine mono-
phosphate-activated protein kinase signaling pathway
and inhibit the intracellular oxidative stress response
and alleviate the response of intravascular cells to oxygen
free radicals.
Improvement of IR
It has been reported that PE is associated with IR.24 By
reducing IR and thus reducing compensatory hyper-
insulinemia, metformin helps in delaying the onset of type
2 diabetes and in relieving GDM or preventing PE. At the
molecular level, improving the sensitivity to insulin can be
achieved by enhancing glycogen synthesis, increasing
insulin receptor tyrosine kinase activity, reducing the
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speed of glycogenolysis, decreasing the activity of hepatic
glucose-6-phosphatase, and by enhancing the recruitment
and activity of GLUT4 glucose transporters.25 According
to Scarpello and Howlett, insulin secretion can also be
enhanced by stimulating the release of glucagon-like-
peptide-1.26 Furthermore, adipose tissue can also be
effected by metformin, which promotes its sensitivity to
insulin by reducing lipotoxicity, which is achieved by
inhibition of lipolysis and reduction in triglyceride levels.27
Metformin vs. insulin for treating GDM
RCTs on the use of metformin for treating GDM
More than one RCT and case-control observational studies
have demonstrated that metformin is safe and effective in
pregnancy. The milestone metformin in gestational diabetes
(MIG) trial,21 has had a great influence on many countries
including China. In this trial, women were randomly
allocated into either metformin or usual treatments such as
insulin. A high percentage of women assigned to metformin
required additional insulin (46%) but at lower doses than
women receiving insulin alone. The trial measured
composite results of neonates including hypoglycemia,
premature birth (before 37 weeks), need for phototherapy,
and respiratory distress. However, no differences were
found between the two treatment groups. However, when
asked if they would still take metformin for GDM, the
women treated with metformin agreed. The MIG trial
concluded that mothers treated with metformin for GDM
gained less weight, enjoyed a lower risk of maternal
hypoglycemia, had economic oral therapy and better
compliance. In the light of this trial, there have been many
other studies on the application of metformin for GDM. A
study conducted in 2009 showed that chronic hypertension
and PE are strongly associated with increased body mass
index (BMI) during pregnancy.28 Thus, there is a strong
relationship between the risk of PE among pregnant women
with type 1 or type 2 diabetes, with increased rates of two- to
four-fold.29 Compared with insulin, the absolute and
relative values of metformin needed for treating both PIH
and PE have been confirmed in several RCTs. A study in
2008 on mothers at 20–33 weeks of gestation whose
hospital criteria were to initiate insulin, used as a starting
point a dose of 500 mg of metformin once or twice daily, up
to 2500 mg/d with a primary purpose of reaching normal
glycemic levels. Among the 363 mothers who received
metformin, the incidence of PIH was 3.8% vs. 6.2% among
the 370 pregnant women treated with insulin alone. In the
group treated with metformin plus insulin the values were
5.5% vs. 6.2% in the group treated with insulin alone.30
Another study was conducted in pregnant women with
GDM in 2012, using 500 mg/d as an initial dose from the
third day after entering in the research, and increased to
1000 mg/d. The result shows that while the metformin
group (n = 110) showed rates of 1.8% for PIH and 4.6% for
PE; rates in the control group (n = 107) were 3.7% for PIH
and 9.4% for PE.21 Another study used an initial dose of
500 mg of metformin twice daily for adaptation; after
2 weeks, the dose was changed to 1000 mg/d, increasing up
a maximum of 2500 mg/d if necessary, until reaching the
appropriate glycemic targets for pregnant women. For PIH,
the rate in the metformin group (n = 110) was 1.8%
Cheng et al., Maternal-Fetal Medicine (2021) 3:3
compared with 3.7% in the control group (n = 107) 3.7%,
and for PE the rates were 4.6% vs. 9.4% in the controls.21 In
a meta-analysis by Nascimento, the values were significant
in pregnant women with GDM only for PIH (RR: 0.53;
95% CI: 0.31–0.90; P = 0.018).31 Regrettably, no improve-
ments were demonstrated for PE in the metformin group.
However, at least this drug is clearly safe during pregnancy
and is accepted well by pregnant women when compared
with insulin alone.30
Metformin vs. insulin
Alqudah et al. performed a meta-analysis of studies
assessing the risk of PE in high-risk insulin-resistant
women treated with metformin previous to, or during
pregnancy.32 They showed that metformin was related to
lower gestational weight gain and a smaller rate of PE
compared with insulin. In this meta-analysis of RCTs, the
comparison between metformin and insulin confirmed a
decline in the RR values for PE. Although glycemic control
was no different, weight gain after enrolment was clearly
lower in the metformin groups. It has been reported that
weight gain is linked to a higher risk of PE.33 To further
explore whether insulin itself might increase the risk of PE,
or whether this is just a beneficial effect of metformin,
Lamminpää and Vehviläinen-Julkunen conducted a large
population-based registry study in Finland comparing
pregnancy outcomes in women with GDM who were aged
<35 years or >35 years vs. women without GDM in the
same age groups.34 They calculated that among women
with GDM who were aged <35 years, compared with
dietary treatment alone, insulin treatment increased the
risk of pre-eclampsia (RR: 1.19; CI: 1.04–1.36; P =
0.0092); though no difference was found in the groups in
women with GDM who were aged >35 years. In their
meta-analysis, most women (>90%) were aged <35 years,
suggesting that metformin might only have a slight effect
on reducing the risk of PE; however, they concluded that
the application of metformin with or without insulin is still
a better option than insulin alone for reducing the risk of
PE and, possibly, other complications (macrosomia and
neonatal hypoglycemia and so on) of pregnancy.
Potential impact for children after in utero
exposure to metformin
A definitive answer of whether the use of metformin in
pregnancy exerts any long-term influences on the offspring
cannot be provided. Numerous studies have shown that
exposure to a hyperglycemic environment in utero is linked
with obesity in childhood and higher risks of diabetes in later
life, which is more than any risk attributable to genetic
factors.35 These infants are resistant to insulin,36 so it has
been assumed that this is the consequence of epigenetic
changes and that metformin reverses such programming in
fetuses. Another study in the MIG trial examined infants at 2
years of age, which suggested that this might indeed be the
case.37 Infants exposed to metformin had a higher proportion
of subcutaneous fat by measuring subscapular and biceps
skinfold thickness when compared with infants not exposed
to metformin in utero; nonetheless, the total body fat contents
of both groups were similar. On the basis of this result, the
investigators assumed that this was actually a healthier fat
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distribution because these children had less visceral fat so
increased insulin sensitivity would be expected. Clearly,
longer term studies are needed. In another study,38 the body
composition and metabolic profile of 12 infants were
measured 8 years after their mothers with polycystic ovarian
syndrome were treated metformin during pregnancy. These
children had higher fasting blood glucose levels and systolic
blood pressure, and lower low density lipoprotein cholesterol
compared with those exposed to placebo treatment. The
MIG trial included another follow up study with more
samples, and followed up the body composition and
metabolism at 7–9 years of age. Women randomly allocated
to the metformin treatment group, compared with an insulin
treatment group, had increased glycemia (P = 0.00) and more
of their infants were large for gestational age (20.7% vs.
5.9%; P = 0.03), however, no differences was found in
offspring measures at 7 years. In another study from another
country (Auckland), women at enrollment were divided into
two groups randomly, and a higher BMI was noted in the
metformin group (P = 0.08) but weight gain was less in the
period of treatment (P = 0.07). The infants had similar birth
measures. Measures of weight, height (P < 0.05), BMI, arm
and waist circumferences, abdominal fat volume (P = 0.05),
triceps skinfold thickness (P = 0.05), and fat and lean mass
(P = 0.07) were found to be larger after 9 years in the
offspring exposed to metformin in utero. Using dual-X-ray
absorptiometry and bioelectrical impedance analysis they
found that the treatment groups had similar body fat
distributions and abdominal fat percentages, as measured by
magnetic resonance imaging. No differences were found in
the levels of triglycerides, IR cholesterol, leptin, adiponectin,
fasting glucose, insulin, or glycated hemoglobin.39 Thus,
using metformin vs. insulin to treat GDM, the percentages of
abdominal and total fat of the progeny were similar at 7 to 9.
Children exposed to metformin in utero were larger at 9
years. Clearly, metformin treatment influences offspring
outcomes by interacting with their environment.
Conclusions
This review has focused on the incidence of PE in pregnant
women taking metformin and elucidates possible mecha-
nisms for its potential to prevent or to cure this disorder.
For women with GDM treated with metformin, there is no
risk of maternal glucopenia. This treatment option is cost-
effective, minimizes maternal weight gain, involves oral
therapy with favorable compliance, and has a lower risk of
hypertensive disorders. For neonates, the risk of hypogly-
cemia and neonatal intensive care admission will definitely
decline. Pregnant women with GDM have a high incidence
of complications with hypertensive disorders, so there is a
prospect that the first line treatment for gestational
diabetes should involve metformin. In particular, for
those women whose blood glucose cannot be controlled
adequately with insulin alone, metformin can be added
safely and effectively. However, dosages and treatment
times need more precise evaluation.
Acknowledgments
The work was supported by the Shanghai General
Hospital Obstetrics Department affiliated to Shanghai
Jiaotong University.
Cheng et al., Maternal-Fetal Medicine (2021) 3:3 www.maternal-fetalmedicine.org

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