Effect of Resveratrol on Pregnancy, Prenatal Complications and Pregnancy-Associated Structure Alterations

Abstract

Adverse pregnancy outcomes are considered significant health risks for pregnant women and their offspring during pregnancy and throughout their lifespan. These outcomes lead to a perturbated in-utero environment that impacts critical phases of the fetus’s life and correlates to an increased risk of chronic pathological conditions, such as diabetes, obesity, and cardiovascular diseases, in both the mother’s and adult offspring’s life. The dietary intake of naturally occurring antioxidants promotes health benefits and disease prevention. In this regard, maternal dietary intake of polyphenolic antioxidants is linked to a reduced risk of maternal obesity and cardio-metabolic disorders, positively affecting both the fetus and offspring. In this work, we will gather and critically appraise the current literature highlighting the effect/s of the naturally occurring polyphenol antioxidant resveratrol on oxidative stress, inflammation, and other molecular and physiological phenomena associated with pregnancy and pregnancy conditions, such as gestational diabetes, preeclampsia, and preterm labor. The resveratrol impact on prenatal complications and pregnancy-associated structures, such as the fetus and placenta, will also be discussed. Finally, we will draw conclusions from the current knowledge and provide future perspectives on potentially exploiting resveratrol as a therapeutic tool in pregnancy-associated conditions.

Full text

Citation: Ramli, I.; Posadino, A.M.;
Giordo, R.; Fenu, G.; Fardoun, M.;
Iratni, R.; Eid, A.H.; Zayed, H.;
Pintus, G. Effect of Resveratrol on
Pregnancy, Prenatal Complications
and Pregnancy-Associated Structure
Alterations. Antioxidants 2023,12, 341.
https://doi.org/10.3390/
antiox12020341
Academic Editors: Miguel Ortega,
Julia Bujan, Natalio
García-Honduvilla, Melchor
Álvarez de Mon, Miguel
Ángel Alvarez de Mon, Coral Bravo,
Miguel A. Saez and Juan Antonio De
León-Luis
Received: 13 December 2022
Revised: 24 January 2023
Accepted: 28 January 2023
Published: 31 January 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
antioxidants
Review
Effect of Resveratrol on Pregnancy, Prenatal Complications
and Pregnancy-Associated Structure Alterations
Iman Ramli 1, Anna Maria Posadino 2, Roberta Giordo 3, Grazia Fenu 2, Manal Fardoun 4, Rabah Iratni 5,
Ali H. Eid 6, Hatem Zayed 7and Gianfranco Pintus 2, *
1
Departement de Biologie Animale, Universitédes Frères Mentouri Constantine 1, Constantine 25000, Algeria
2Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy
3College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences,
Dubai 505055, United Arab Emirates
4Department of Pharmacology and Toxicology, American University of Beirut, Beirut 11-0236, Lebanon
5Department of Biology, United Arab Emirates University, Al-Ain 15551, United Arab Emirates
6Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha 2713, Qatar
7Department of Biomedical Sciences, College of Health Sciences, QU Health, Qatar University,
Doha 2713, Qatar
*Correspondence: gpintus@uniss.it
Abstract:
Adverse pregnancy outcomes are considered significant health risks for pregnant women
and their offspring during pregnancy and throughout their lifespan. These outcomes lead to a
perturbated in-utero environment that impacts critical phases of the fetus’s life and correlates to
an increased risk of chronic pathological conditions, such as diabetes, obesity, and cardiovascular
diseases, in both the mother’s and adult offspring’s life. The dietary intake of naturally occurring
antioxidants promotes health benefits and disease prevention. In this regard, maternal dietary
intake of polyphenolic antioxidants is linked to a reduced risk of maternal obesity and cardio-
metabolic disorders, positively affecting both the fetus and offspring. In this work, we will gather
and critically appraise the current literature highlighting the effect/s of the naturally occurring
polyphenol antioxidant resveratrol on oxidative stress, inflammation, and other molecular and
physiological phenomena associated with pregnancy and pregnancy conditions, such as gestational
diabetes, preeclampsia, and preterm labor. The resveratrol impact on prenatal complications and
pregnancy-associated structures, such as the fetus and placenta, will also be discussed. Finally, we
will draw conclusions from the current knowledge and provide future perspectives on potentially
exploiting resveratrol as a therapeutic tool in pregnancy-associated conditions.
Keywords:
resveratrol; pregnancy; prenatal; preterm; fetus; pre-eclampsia; placenta; gestationaldiabetes
1. Introduction
Adverse pregnancy outcomes are considered major health risks for pregnant women
and their offspring during pregnancy and throughout their lifespan, with several disorders
recognized, including gestational diabetes, preterm birth, fetal-growth restriction, and
hypertensive disorders of pregnancy such as gestational hypertension, pre-eclampsia, and
related conditions [
1
,
2
]. These outcomes lead to a perturbated in-utero environment that im-
pacts critical phases of fetus development. An increased risk of chronic non-communicable
metabolic diseases, such as cardiovascular disease, diabetes, and obesity, is often related to
detrimental structural changes of major functional systems during fetal life and persists
through the adult offspring’s life [3].
Dietary intake of naturally occurring antioxidants has been linked to disease preven-
tion and health benefits [
4
–
7
]. Indeed, natural products, such as curcumin, resveratrol, and
epigallocatechin-3-gallate, have been shown to exhibit a plethora of biological functions
that eventually provide prevention or protection against several pathological conditions,
Antioxidants 2023,12, 341. https://doi.org/10.3390/antiox12020341 https://www.mdpi.com/journal/antioxidants

Antioxidants 2023,12, 341 2 of 28
including cancer, diabetes, obesity, cardiovascular, and neurodegenerative [
8
–
12
]. Among
the above-mentioned natural phytonutrients, resveratrol (3,5,4
0
-trihydroxy-trans-stilbene),
an antioxidant polyphenolic compound found in various plants and foods including grapes,
berries, peanuts, apples, cacao, and soybeans, has been proven to possess a wide spec-
trum of biological properties including antioxidant, anti-inflammatory, neuroprotective,
cardioprotective, immunomodulatory, antiplatelet, and anticancer [
13
–
18
]. In this regard,
a great body of literature evidence also suggested that maternal dietary intake of antioxi-
dants polyphenols is linked to reduced risk of maternal obesity [
19
] and cardio-metabolic
disorders [20], positively impacting both the fetus and offspring.
This literature review will gather and discuss the current experimental evidence high-
lighting the effect/s of resveratrol on inflammation, oxidative stress, and other molecular
and physiological phenomena associated with pregnancy and pregnancy-associated com-
plications, including preeclampsia, gestational diabetes, and preterm labor. The effect of
resveratrol on prenatal issues and pregnancy-associated structures such as the placenta
and fetus will also be discussed. Finally, conclusions on the current knowledge and future
directions on potentially exploiting resveratrol as a therapeutic tool in pregnancy-associated
conditions are provided to the readers.
2. Bioavailability, Toxicity, and Hormetic Effect of Resveratrol
Due to its numerous pharmacological activities, resveratrol’s effects on humans are
widely studied. Nonetheless, results from the available human clinical trials are so far
contradictory concerning the protective effects of resveratrol against diseases and their
sequelae [
3
]. Similarly, resveratrol intake effects during human pregnancy and the inter-
pretation of its supplementation’s effectiveness are poorly understood due to variations in
species, differences in the characteristics of the enrolled patients, dosage, administration
routes, duration of resveratrol, supplementation and in some cases, pregnancy models
complication [
3
]. Although resveratrol’s high absorbance and rapid metabolization without
pronounced toxicity characterized its beneficial effects in several pregnant women stud-
ies [
21
–
23
], few reports raised doubts about possible toxicity and adverse effects following
its consumption. Hence, the adequate ranges of dosage capable of inducing remarkable
long-term health benefits without raising toxicity issues remain controversial [
3
]. Indeed,
resveratrol dosage ranges differently
in vitro
experimental models (micromolar range in
cell culture media) and
in vivo
experimental models (nanomolar range in the blood); hence,
it is difficult to precise the optimal concentrations for a maximum beneficial effect of
resveratrol in human subjects. However, concerning this aspect, studies
in vivo
indicate
that resveratrol can reach concentration levels similar to those found to exert biological
effects
in vitro
. Indeed, resveratrol can accumulate at relatively high concentrations (up
to
32 µM
) in plasma [
24
,
25
], while concentrations of resveratrol around (~10–30
µ
M) have
been detected in other tissues like the heart, liver, and kidney [
26
,
27
]. Such a resveratrol
characteristic may be of particular relevance, given its ability to cross the placental bar-
rier and directly interact with the fetus [
28
]. Another challenging issue that may affect
resveratrol therapeutic effects making their interpretation difficult, is its poor oral bioavail-
ability [
8
]. Resveratrol’s rapid elimination from the body complicates the maintenance of
the bloodstream’s acceptable therapeutic levels [
29
]; moreover, resveratrol is metabolized
to phenolic metabolites in the liver and intestinal epithelial cells [
30
–
32
], and these phase
II metabolites can be transformed into the aglycone forming a systemic reservoir of bio-
logically active molecules [
8
]. In this light, improving resveratrol oral bioavailability by
establishing new formulations that are more bioavailable and less degradable with clear
pharmacokinetic routes is a crucial future research goal [33].
In human clinical trials, resveratrol was proven to be generally tolerated, yet some ad-
verse effects, including nephrotoxicity and gastrointestinal problems, were reported [
34
,
35
].
For instance, a resveratrol dose of 450 mg/day was shown to be safe for a 60 kg individ-
ual [36]. In contrast, doses of 1000 mg/day or higher were reported to inhibit cytochrome
P450 isoenzymes such as CYP3A4, CYP2C9, and CYP2D6, while activating CYP1A2 lead-

Antioxidants 2023,12, 341 3 of 28
ing to interference with the pharmacokinetics of concomitantly administered drugs [
37
].
Moreover, adverse effects linked to resveratrol intake have been reported on different
parameters, including the metabolic status of type 2 diabetes patients and the endothelial
health, inflammation, and cardiovascular markers of human patients [
38
]. Concerning this
specific topic, a comprehensive analysis of resveratrol’s adverse effects has been reported
elsewhere [
8
]. On pregnancy, a study conducted on a Japanese macaque experimental
model indicated that pregnancy resveratrol intake might cause abnormalities in the fetus,
an adverse effect clearly associated with high resveratrol supplementation. The findings of
this study showed that resveratrol intake (0.2, 0.5, and 1.0 mg in 5 mL administered via
intravenous infusion) managed to reduce the maternal weight, improve glucose tolerance,
increase uterine artery volume blood flow, and decrease placental inflammation and liver
triglyceride deposition. However, resveratrol intake parallelly affected the fetal pancre-
atic mass (enlarged by 42%), demonstrating that pregnancy resveratrol supplementation
delivers beneficial effects on maternal, placental phenotype, and fetal liver but also an
unexplained and concerning alteration of the fetal pancreatic development [
39
]. In this
regard, Cottart et al. [
21
] highlighted that, despite the extensive amount of data concerning
the benefits derived from resveratrol intake, there is scarce research aimed at assessing its
harmful effects, and human clinical studies in this regard are limited [21].
Both
in vitro
and
in vivo
resveratrol’s biological effects are associated with its hermetic
behavior, where low resveratrol doses induce beneficial effects while higher doses usually
have a harmful effect [
40
]. Evidence suggests that such a phenomenon is linked to the bipha-
sic resveratrol effect on the cellular redox state, antioxidant at low doses and pro-oxidant at
high ones [
15
,
40
,
41
]. As such, many of the controversial results in the literature might be
due to this hormetic aspect, besides other elements related to enrolled patients, doses, and
duration of resveratrol supplementation. To summarize, face to the numerous human and
animal studies that support the beneficial and protective properties of resveratrol, clinical
studies that report on resveratrol’s harmful effects are few and controverted. Additionally,
mechanisms underlying resveratrol’s molecular action need more investigation, walling
for a more uniform design of clinical trials to properly investigate resveratrol’s therapeutic
and preventive properties during pregnancy and related complications.
3. Resveratrol’s Mechanism of Action during Pregnancy Complications
Interestingly, maternal resveratrol intake has been reported to have potential benefi-
cial effects in adverse human pregnancies [
3
] and has been intensively studied in rodent
models as a potential therapeutic agent in several pregnancy-related disorders, including
pre-eclampsia (PE) [
42
], gestational diabetes mellitus (GDM) [
22
], fetal-growth restriction
(FGR) [
43
], insulin resistance, and dyslipidemia [
23
,
44
]. However, the molecular mecha-
nisms underlying its efficiency are not entirely understood [
45
]. Studies suggested that
resveratrol’s potential protective mechanisms in adverse pregnancy outcomes are related
to its pleiotropic properties, including antioxidant, anti-inflammatory, anti-obesogenic,
anti-atherosclerotic, and anti-diabetic, which evidently associate its consumption with
the prevention of several non-communicable diseases [
20
,
46
]. Figure 1schematizes the
potential molecular mechanisms that may underpin the protective effects of resveratrol
intake in mothers and their offspring in different models.
A systematic data analysis across different species and dosages indicated that resver-
atrol consumption could decrease inflammation and oxidative stress in placental and
embryonic tissues [
3
]. Oxidative stress is a phenomenon caused by increased levels of
reactive oxygen species (ROS) resulting in disturbance of the cellular redox balance, which
causes the impairment of cellular functions and eventually initiates pathological pathways
leading to disease development [
47
,
48
]. It is now evident that oxidative stress is signifi-
cantly higher during normal pregnancy compared to non-pregnancy periods in women [
49
].
In fact, the gestational and prenatal changes of the maternal body, as well as the high oxy-
gen and energy required for fetal development, favor ROS overproduction [
50
]. These
elevated ROS levels appear to be implicated in pregnancy-related disorders such as PE,

Antioxidants 2023,12, 341 4 of 28
intrauterine growth restriction (IUGR), and fetal death [
51
,
52
]. Thus, evaluating the redox
status during pregnancy in order to find adequate strategies to counteract it appears to be
an issue of utmost importance.
Antioxidants 2023, 12, x FOR PEER REVIEW 4 of 30
[20,46]. Figure 1 schematizes the potential molecular mechanisms that may underpin the
protective effects of resveratrol intake in mothers and their offspring in different models.
Figure 1. Potential molecular mechanisms underpinning the effects of resveratrol intake in mothers
and their offspring in different models.
A systematic data analysis across different species and dosages indicated that
resveratrol consumption could decrease inflammation and oxidative stress in placental
and embryonic tissues [3]. Oxidative stress is a phenomenon caused by increased levels
of reactive oxygen species (ROS) resulting in disturbance of the cellular redox balance,
which causes the impairment of cellular functions and eventually initiates pathological
pathways leading to disease development [47,48]. It is now evident that oxidative stress
is significantly higher during normal pregnancy compared to non-pregnancy periods in
women [49]. In fact, the gestational and prenatal changes of the maternal body, as well as
the high oxygen and energy required for fetal development, favor ROS overproduction
[50]. These elevated ROS levels appear to be implicated in pregnancy-related disorders
such as PE, intrauterine growth restriction (IUGR), and fetal death [51,52]. Thus,
evaluating the redox status during pregnancy in order to find adequate strategies to
counteract it appears to be an issue of utmost importance.
In this regard, studies in murine models have shown that oxidative stress biomarkers
and metabolic dysfunction caused by a low-protein diet in the mother, placenta and
offspring could be improved by a resveratrol-rich diet in pregnant individuals [53]. Anti-
atherogenic activities, low fetal oxidative stress, and reduced apoptosis were also detected
in rodent streptozotocin-induced diabetic models treated with resveratrol [54,55].
Moreover, increased risk of infertility is often linked to advanced maternal age, where the
major oxidative stress-associated causative factors encompass decreased oocyte quality,
low fertilization rate, poor embryonic development, low pregnancy rate, and a high rate
of chromosomal aberrations, telomerase shortening, and apoptosis [56,57]. In this regard,
by delaying cells’ aging process and preventing age-related diseases through ameliorating
mitochondrial function and reducing ROS generation, several studies have reported that
resveratrol supplementation can improve in vitro oocyte maturation and embryonic
developmental competence in different species [58–61]. A study realized in a pregnant-
Figure 1.
Potential molecular mechanisms underpinning the effects of resveratrol intake in mothers
and their offspring in different models.
In this regard, studies in murine models have shown that oxidative stress biomark-
ers and metabolic dysfunction caused by a low-protein diet in the mother, placenta and
offspring could be improved by a resveratrol-rich diet in pregnant individuals [
53
]. Anti-
atherogenic activities, low fetal oxidative stress, and reduced apoptosis were also detected
in rodent streptozotocin-induced diabetic models treated with resveratrol [
54
,
55
]. More-
over, increased risk of infertility is often linked to advanced maternal age, where the
major oxidative stress-associated causative factors encompass decreased oocyte quality,
low fertilization rate, poor embryonic development, low pregnancy rate, and a high rate
of chromosomal aberrations, telomerase shortening, and apoptosis [
56
,
57
]. In this regard,
by delaying cells’ aging process and preventing age-related diseases through ameliorating
mitochondrial function and reducing ROS generation, several studies have reported that
resveratrol supplementation can improve
in vitro
oocyte maturation and embryonic de-
velopmental competence in different species [
58
–
61
]. A study realized in a pregnant-aged
mice model demonstrated that resveratrol intake increases blastocyst development, ame-
liorates pregnancy and implantation rates, and parallelly decreases ROS production with
a significant increase in mitochondrial membrane potential, suggesting that resveratrol
supplementation may improve pregnancy oxidative stress-mediated outcomes in women
with advanced maternal age [
62
]. In this regard, Liu et al. [
63
] have also suggested that
resveratrol can induce oocyte maturation and subsequent embryonic development in aged
mice [
63
]. Indeed, aging-associated reproductive pathologies are frequently associated
with impaired DNA repair, metabolic disorders, genomic instability, telomeric shortening,
apoptosis, and mitochondrial dysfunction [
58
,
64
,
65
], which are the molecular target of
resveratrol action.

Antioxidants 2023,12, 341 5 of 28
Epigenetic regulation represents another potential mechanism related to the maternal
resveratrol intake effects and modulates methylation and acetylation processes affect gene
expression [
66
]. Among the main epigenetic changes exerted by resveratrol in the zygotic
pronuclei are the methylation and acetylation of histone H3 on lysine 9 (H3K9). Gesta-
tional resveratrol supplementation was demonstrated to induce breast cancer-1 promoter
(BRCA-1) hypermethylation and to decrease BRCA-1 expression in the mammary tissue of
rat offspring [
20
]. Another mechanism through which resveratrol’s maternal intake may
improve pregnancy outcomes is by relieving oxidative stress-related mitophagy [
67
,
68
]. Mi-
tophagy is defined as the selective removal of dysfunctional mitochondria by autophagy, a
process aberrantly affected by ROS increase and physiologically restored by oxidative stress
balance [
69
]. Consonantly, a study by Zha et al. [
70
] demonstrated that resveratrol supple-
mentation in pregnant mice might promote mammary gland proliferation and antioxidant
activity through mitophagy activation [
70
]. Pregnancy-related metabolic disorders, such as
GDM, occur when ROS prevents insulin from facilitating cellular glucose uptake, subse-
quently leading to insulin resistance [
71
]. Hypertensive disorders of pregnancy comprising
chronic, white, mask and gestational hypertension, PE, hemolysis, elevated liver enzymes,
and low platelet count were also found to be tightly related to altered pro-inflammatory
and oxidative stress signals and be responsible for the increased risk of chronic diseases
such as obesity, type 2 diabetes, and cardiovascular diseases in adult life [20,72–74].
Resveratrol is also recognized as a Sirtuin 1 (SIRT1) activator. The Sirtuin proteins
family has a beneficial impact on longevity mainly linked to their effects on metabolic
control since they are substantially contributing to lipid and glucose regulation via the
deacetylation of crucial metabolic signals relevant to the activated.
The Sirtuin proteins family has a beneficial impact on longevity primarily related
to their effects on metabolic control as they substantially contribute to lipid and glucose
regulation through the deacetylation of crucial metabolic signals related to the activated
protein kinase-SIRT1-PPARG coactivator-1
α
axis [
75
,
76
]. In this context, a study realized
on rats exposed to a maternal high-fat diet during pregnancy, resveratrol supplementation
(10 mg/kg) managed to restore the impaired expression of SIRT1, phosphor-extracellular
regulated kinases1/2, (p-ERK1/2) and phospho-peroxisome proliferator-activated receptor
γ
(PPAR
γ
), adiponectin and Brain-Derived Neurotrophic Factor (BDNF), all molecules
involved in insulin resistance and mild cognitive dysfunction [
77
]. These previous data un-
derline resveratrol’s ability to improve many maternal-associated complications including
PE, FGR, diabetes, insulin resistance (IR), obesity, and metabolic syndrome [77].
4. Maternal Pregnancy-Related Disorders
4.1. Resveratrol Effect in Pre-Eclampsia and Related Disorders
Pregnancy is known to cause increased levels of oxidative stress, as an aspect of the
systemic inflammatory response, resulting in high-circulated amounts of ROS, with the
placenta representing the main source [
78
]. PE is a pregnancy-specific clinical syndrome
characterized by a multifactorial physiopathology [
79
,
80
], that includes both new-onset
of hypertension and new-onset proteinuria
≥
300 mg/24 h after 20 weeks of gestation,
most often near-term. However, when proteinuria registers normal levels, PE is considered
thrombocytopenia-related hypertension, with altered liver function, renal insufficiency,
pulmonary oedema, and new-onset cerebral or visual disturbances [
81
]. One condition that
features oxidative stress during pregnancy is hypoxia, a common form of intrauterine stress
defined as an abnormal exposure to low oxygen levels, resulting in an excessive generation
of ROS [
82
]. Accordingly, increased placental hypoxia and uterine vascular resistance were
revealed to be associated with PE and fetal/intrauterine growth restriction (FGR/IUGR) in
several animal and human studies [
83
]. Gestational hypoxia induces ROS overproduction
in uteroplacental cells’ mitochondria leading to oxidative stress [
83
]. In contrast, excessive
ROS production causes uteroplacental dysfunction by altering cellular macromolecules,
which underlies PE and FGR pathogenesis [
83
]. Resveratrol has been recently shown to
exert a protective effect against prenatal hypoxia-induced programming of the metabolic

Antioxidants 2023,12, 341 6 of 28
syndrome when offspring-initiated treatment at weaning [
84
]. In a recent study, resveratrol
intake (4 g/kg) managed to ameliorate adverse fetal outcomes in a rat model of severe
prenatal hypoxia [28].
PE-associate oxidative stress originates from the placental impairment caused by
hypoxia-reoxygenation imbalance, lower efficiency of both free radical scavengers and
antioxidant enzymes, impaired angiogenesis, decreased nitric oxide (NO) bioavailability
vascular endothelial dysfunction, cardiovascular complications, and exaggerated inflam-
matory response [
85
–
89
]. A poorly perfused fetoplacental unit releases free radicals and
initiates oxidative stress impairment in placental cells [
88
,
90
,
91
]. Resveratrol was demon-
strated to activate endothelial nitric oxide synthase (eNOS) and increase NO and nuclear
factor-erythroid-derived 2-related factor-2 (Nrf2) production [
92
]. In response to resveratrol,
Nrf2 binds to the antioxidant response element (ARE) promoter upregulating the expres-
sion of antioxidant proteins, including heme oxygenase-1 (HO-1) and glutathione reductase
(GSR), thus counteracting oxidative stress and balancing the cellular redox state [
93
,
94
].
Indeed, in an
in vitro
PE model, resveratrol increased ARE activity and reduced ROS in
endothelial cells exposed to plasma from PE patients compared to cells exposed to plasma
from healthy pregnancies. Noteworthy, plasma from PE patients obtained 1 hr after the
ingestion of polyphenol-rich whole red grapefruit juice (rich in resveratrol) significantly
increased NO production and reduced antioxidant markers in the exposed cells compared
with the serum before juice intake [94].
PE etiology is not fully understood, however, this condition is believed to be asso-
ciated with impaired uterine artery blood flow [
95
]. In this context, recent studies have
shown that resveratrol can induce uterine arteries relaxation during PE pathological events.
Interestingly, resveratrol supplementation with a dose of 4 g/kg was demonstrated to ame-
liorate the PE-like phenotype by significantly increasing uterine artery blood flow velocity
and fetal weight in pregnant C57BL/6J, eNOS
−
/
−
, and COMT
−
/
−
mice murine models,
suggesting resveratrol consumption as a potential therapeutic strategy for
PE disorder [95].
It has been recently shown that circulating SIRT1 is reduced during PE [
96
]. In this
regard, a group of researchers investigated the effects of resveratrol as a SIRT1 activator
using the previously reported
in vitro
/clinical PE model compared to gestational hyperten-
sive (GH) and healthy pregnant (HP) women. The authors showed that resveratrol-elicited
SIRT1 activation alone did not exert any effect and may not be beneficial to women with PE,
suggesting that pregnant women with PE may have different responsive mechanisms to this
molecule [
96
]. Furthermore, aberrant trophoblast invasion is among the factors involved in
PE occurrence and development since it contributes to the progression of multiple condi-
tions and is characterized by impaired spiral artery remodeling [
97
], cell-matrix restruc-
turing, and cytoskeleton dynamics [
98
], during which epithelial-mesenchymal transition
(EMT) occurs leading to the breakdown of cell–cell adhesion, the loss of epithelial pheno-
types, and cell depolarization [
99
,
100
]. During pregnancy, the acquisition of invasive pheno-
types by the extra-villous trophoblast (EVT), was found to be involved in PE pathogenesis
and was suggested to be linked to EMT [
101
]. In this regard, using both
in vitro
(HTR-
8/SVeno cell culture) and
in vivo
(NG-nitro-l-arginine methyl ester mice model) PE models,
Zou et al. [
102
] suggested that resveratrol (100
µ
mol/L
resveratrol /20 mg/kg/day
) might
stimulate the invasive capability of human trophoblasts by promoting a Wnt/
β
-catenin
pathway-mediated EMT transformation, increasing trophoblasts migration and the in-
vasion in the cell model, and markedly ameliorating hypertension and proteinuria in
mice [
102
]. Molecularly, resveratrol-mediated EMT activation occurred through the reg-
ulation of E-cadherin,
β
-catenin, N-cadherin, and vimentin expression, and altered the
WNT-related gene expression, including WNT1, WNT3, and WNT5B [102].
Several studies suggested that the resveratrol-associated anti-hypertensive effect is
mainly related to its capacity to attenuate blood pressure and hypertension symptoms.
Interestingly, a clinical trial with 400 PE patients investigated the outcome of a nifedip-
ine/resveratrol combined treatment against PE, revealing that resveratrol supplementation
significantly reduced the time needed to control blood pressure with a better result in the

Antioxidants 2023,12, 341 7 of 28
group treated with both nifedipine (10mg, up to 5 dosages) and resveratrol, which also
had a significantly delayed time between the hypertensive crises intercourse (50mg, up to
5 dosages) [
23
]. In contrast, resveratrol did not produce any apparent effect on rats in the
study by Moraloglu et al. [
42
], where a Desoxycorticosterone acetate (DOCA) hypertension
PE model was used to test the potential hypotensive effect of resveratrol on the blood
flow. Interestingly, DOCA managed to increase blood pressure and placental and renal
blood flow levels, whereas, no significant differences for the same parameters were rated
in groups treated with resveratrol (20 mg/kg per day) [42].
Consistent with this, other studies indicated that resveratrol anti-hypertensive proper-
ties are also related to its ability to inhibit the release of endothelial dysfunction-associated
anti-angiogenic factors and that their elevation is a main player in placental oxidative
stress and inflammation during the maternal endothelial dysfunction in PE [
103
]. For
instance, serum soluble fms-like tyrosine kinase-1 (sFlt-1), also known as a soluble re-
ceptor for vascular endothelial factors (VEGF), is a protein that binds and decreases the
concentrations of circulating VEGF and placental growth factor (PlGF) [
104
,
105
]. While
Endoglin (Eng) is a transmembrane glycoprotein and is considered another factor playing
a role in PE etiology and an accessory receptor for the transforming growth factor-beta
(TGF-
β
). Eng is highly expressed in syncytiotrophoblast and proliferating endothelial
cells [
106
], it influences the TGF-
β
and eNOS signaling pathways resulting in a significant
angiogenesis modulation [
107
]. In this regard, a study carried out
in vitro
by Hannan
et al. [
108
] demonstrated that resveratrol (0–100
µ
M) decreases sFlt-1 and soluble Eng
secretion from primary trophoblasts and human umbilical vein endothelial cells (HU-
VECs), a phenomenon that positively correlated with increased mRNA expression of the
pro-inflammatory molecules NF
κ
B, IL-6, and IL-1
β
in the trophoblast and decreased of
IL-6, IL-1
β
, and TNF-
α
[
108
]. Additionally, resveratrol significantly increased the mRNA
expression of several antioxidant enzymes including HO-1, NADPH Quinone Dehydro-
genase (1NQO1), Glutamate-Cysteine Ligase Catalytic (GCLC) subunit and thioredoxin
(TXN) in HUVECs, while reducing HO-1 protein levels in trophoblast cells. Expression of
the cell adhesion molecule VCAM-1 and the adhesion of peripheral blood mononuclear
cells were also increased by resveratrol supplementation [
108
]. Further, TNF-
α
-induced
endothelial dysfunction in HUVECs was significantly ameliorated by resveratrol through
i) the reduction in TNF-
α
-induced Endothelin-1 (a vasoconstrictor) expression and ii) the
increase in endothelial eNOS phosphorylation [
108
]. Resveratrol (20 mg/kg/day) has also
been reported to prevent cells from p53- and ROS-dependent apoptosis induced by IL-1
β
in
an NG-Nitro-l-arginine methyl ester-induced PE rats model via the increase in superoxide
dismutase (SOD) suggesting that resveratrol significantly opposes oxidative stress effects
in vivo
[
109
]. Overall, resveratrol can be suggested to alleviate PE symptoms and decrease
its effects in pregnant individuals and their offspring in different models via multiple
pathways mainly related to the attenuation of vascular injury, placental dysfunction, hyper-
tension symptoms, anti-angiogenic factors, oxidative stress and inflammatory responses
Table 1Taken together, the reported data suggests resveratrol as a potential therapeutic tool
in PE.
Table 1. Studies using resveratrol in the treatment of models of pre-eclampsia in pregnancy.
Reference Type of the Study PE Experimental Model Dose Mechanism of Action
Outcomes of
Supplementation in the
Experimental Model
[94] In vitro/Clinical trial -ECs
-Human
200 mL of polyphenol
rich-grape fruit/1 µM
of trans-resveratrol
NO, HO-1, miRNA expression,
GSH, ARE, ROS levels
↑ARE, NO, HO-1, GSH, ARE
↓ROS, oxidative stress
No studied effect in offspring
[96] In vitro/Clinical trial -ECs
-Human
200 mL of polyphenol
rich-grape fruit/1µM of
trans-resveratrol SIRT1 expression No significant effect
No studied effect in offspring

Antioxidants 2023,12, 341 8 of 28
Table 1. Cont.
Reference Type of the Study PE Experimental Model Dose Mechanism of Action
Outcomes of
Supplementation in the
Experimental Model
[102] In vitro/In vivo
-HTR-8/SVeno cell
culture/
-NG-nitro-l-arginine
methyl ester mice
model (L-NAME)
100 µmol/L resveratrol
20 mg/kg/day
Expression of genes regulating
migration, invasion,
angiogenesis and EMT-related
factors in trophoblasts
Hypertension and proteinuria
measurement.
Endothelial dysfunction/
injury
↑E-cadherin, β-catenin,
N-cadherin, and vimentin
expression,
↓Alteration of WNT-related
gene expression, including
WNT1, WNT3 and WNT5B.
↓Hypertension and
proteinuria
No studied effect in offspring
[108] In vitro primary trophoblasts
and HUVECs 0–100 µM
-Angiogenesis activation
(sFlt-1) (sEng) secretion
Anti-inflammatory effect
-NFκB
, IL-6 and IL-1β
-Antioxidant effect
HO-1, NQO1, GCLC, (TXN)
Endothelial dysfunction,
VCAM Endothelin-1 eNOS
↓sFlt-1, sEng
↓IL-6, IL-1βand TNF-α.‘
↑, NQO1, GCLC TXN
↓HO-1 protein in trophoblast.
↑VCAM-1
↓Endotelin-1, ↑eNOS
No studied effect in offspring
[109] In vivo NG-nitro-l-arginine
methyl ester mice
model (L-NAME) 20 mg/kg/day -Antioxidant effect, Apoptosis
SOD, MDA ↑SOD, MDA
No studied effect in offspring
Ecs: Endothelial cells, NO: Nitric oxide, HO-1: Heme oxygenase-1, miRNA: microRNA, GSH: Gluthatione, ARE:
antioxidant response element, ROS: Reactive oxygen species, SIRT1: sirtuin1, WNT: WNT genes, sFlt-1: soluble
fms-like tyrosine kinase-1, sEng: soluble endoglin, NF
κ
B: nuclear factor-kappa B, IL-6: Interleukin-6, IL-1
β
:
Interleukin-1
β
, TXN: thioredoxin, NADPH, NQO1: NADPH Quinone Dehydrogenase 1, TNF-
α
: Tumor necrosis
factor-alpha, GCLC: Glutamate-Cysteine Ligase Catalytic Subunit, VCAM-1: Vascular cell adhesion molecule-1,
eNOS: endothelial nitric oxide synthase, SOD: Superoxide dismutase, MDA: malondialdehyde.
4.2. Resveratrol Effect in Gestational Diabetes and Related Metabolic Disorders
GDM is a type of diabetes characterized by an impaired glucose tolerance that occurs
during pregnancy [
110
]. Although GDM is a reversible pathology and the impaired
metabolism returns to normal after delivery, the risk of developing type 2 diabetes later is
high [
111
]. GDM is extremely harmful to mothers and their offspring and may induce PE,
premature rupture of membranes, and premature delivery [
112
]. The main features of GDM
during pregnancy include increased glucose demand, increased insulin resistance, and
relative insufficiency in insulin secretion [
113
]. Recent studies emphasized the protective
effects of resveratrol in diabetes and its related-cardiovascular complications, involving the
regulation of multiple signaling pathways, inhibition of oxidative stress and inflammation,
enhancement of insulin sensitivity, induction of autophagy, regulation of lipid metabolism,
promotion of GLUT4 expression, translocation, and activation of SIRT1/AMPK signaling
axis [
114
]. Several studies have demonstrated that resveratrol lowers maternal blood
sugar levels, ameliorates the maternal lipid profile [
115
], and prevents delays in embryo
development in rat diabetic dams models [
54
]. In a recent study performed in streptozotocin
GDM pregnant rat model, the ability of resveratrol to lower blood glucose and blood lipids
was tested. Resveratrol supplementation demonstrated a dose-dependent effect (120
and 240 mg/kg), which positively correlates with a decrease in both insulin and blood
glucose levels in comparison with the control group; remarkedly demonstrating a stronger
effect than metformin hydrochloride in improving GDM outcomes [
116
]. Using the same
previous model, it was reported that the resveratrol-zinc oxide complex encapsulated with
chitosan (CS-ZnO-RS) (an encapsulated form of resveratrol to increase the stability and
effectiveness of substances in gestational diabetes management), significantly decreased
the blood glucose levels and maintained the lipid content similar to control group levels,
while simultaneously reducing the level of pro-inflammatory factors (IL-6 and MCP-1)
and significantly decreasing endoplasmic reticulum stress components (GRP78, p-IRE1
α
,
p-eIF2
α
, and p-PERK), and further inhibiting
α
-glucosidase and
α
-amylase activity in a
dose-dependent fashion [117].
Studies also demonstrated that GDM is often related to adverse metabolic health
outcomes in offspring as a common pregnancy complication. In a GDM model of fe-

Antioxidants 2023,12, 341 9 of 28
male Sprague Dawley rats fed with a high-fat and sucrose diet, Brawerman et al. [
118
]
showed that maternal resveratrol supplementation (147 mg/kg/day) protects against
GDM-induced glucose intolerance and offspring islet dysfunction by restoring glucose
tolerance and normoglycemia and improving insulin secretion. At 15 weeks of age, hepatic
steatosis, IR, glucose intolerance, and dysregulated gluconeogenesis were attenuated in off-
spring of resveratrol-treated dams [
118
]. Moreover, the dysregulation of several metabolic
genes (e.g., lpl: lipoprotein lipase; ppara: peroxisome proliferator-activated receptor
α
; g6p:
glucose-6-phosphatase) were also attenuated whilst glucose-stimulated insulin secretion
was improved in the offspring islets of resveratrol-treated dams [118].
It is well known that insulin resistance (IR) caused by insufficient insulin secretion
during pregnancy, may lead to metabolic disorders, mainly GDM and related patholo-
gies [
119
]. Attention was recently given to the role of resveratrol in ameliorating IR in
pregnancy-related metabolic disorders. Consistently, recent studies have shown that resver-
atrol may improve glucose uptake in adipocytes with IR, ameliorate IR in mice fed with
a high-fat diet, and enhances glucose metabolism and insulin tolerance in GDM mice
(
100 mg/kg
) [
120
,
121
]. MicroRNAs (miRNAs), a type of short-chain non-coding endoge-
nous RNAs existing in eukaryotic organisms, are known to exert regulatory effects on
several cell functions and play a different role in many diseases [
122
–
126
]. Recent studies
confirmed the resveratrol’s capacity to regulate their expression [
16
], especially that of MiR-
23a-3p, which was reported to be low-expressed in adipose tissues of obese and diabetic
patients; in fact, its over-expression can reduce TNF-
α
-induced IR in adipocytes [
127
]. In
a study realized on a high-fat diet GDM mice model, resveratrol supplementation (0.2%)
managed to ameliorate glucose uptake and lipid metabolism, regulating the miR-23a-
3p/NOV axis through the increase in Adiponectin, Leptin, Phosphoinositide 3-kinase
(p-PI3K), and phosphorylated Akt (p-Akt) in adipocytes with IR and parallelly decreasing
the nephroblastoma (NOV) overexpression [
128
]. In diabetic embryopathy-murine models,
resveratrol (50mg, up to 5 dosages) significantly ameliorates the embryonic outcome in
terms of diminishing developmental abnormalities, a phenomenon likely associated with
its antioxidative potential, anti-diabetic action, and anti-dyslipidemic nature [23].
Maternal obesity is also a metabolic complication that rates high maternal and fetal
oxidative stress and inflammation. Hypothetically, offspring of obese mothers are at greater
risk of developing obesity, diabetes, and cardiovascular disorders in adult life [
129
], with
risk factors that include variations in both maternal glucose and lipid metabolism (predis-
position to GDM in particular), abnormal pregnancy hormone concentrations
[130–132]
,
stillbirth, premature birth, and macrosomia [132,133].
A recent study conducted in obesity murine models revealed that maternal resver-
atrol supplementation (20 mg/kg/day) improves maternal metabolism and reduces the
placental and liver oxidative stress of mothers and fetuses in a sex-dependent manner [
134
].
Compared to the untreated group, resveratrol supplementation in pregnant animals was
able to lower adipocytes number, triglycerides serum concentrations, insulin resistance,
liver fat accumulation, expression of genes related to insulin resistance, inflammatory
processes, and lowered oxidative stress in mothers, placentas, and female fetal liver [
134
].
Resveratrol treatment (5 mg/kg/day) was shown to improve some of the altered metabolic
symptoms in a programmed prenatal and postnatal high-fat exposure in the progeny of
Sprague Dawley dams’ experimental model, including peripheral leptin resistance, and
related dysbiosis of the gut [
135
,
136
]. Another study suggested that resveratrol’s protective
effects during pregnancy and lactation are diet dependent, where resveratrol supplemen-
tation (2.0 to 2.5 mg/kg/d/dam) decreased body weight and adipose tissue content in
offspring of dams on a high-fat diet but did not affect offspring from the low-fat diet-fed
dams [
137
]. In addition, resveratrol supplementation (300 mg/kg) was demonstrated to
increase high-density lipoprotein cholesterol and low-density lipoprotein cholesterol in
the plasma and partially improved the fat metabolism in the adipose tissue in piglets’
experimental model [
138
]. Intrahepatic cholestasis of pregnancy (ICP), is a pregnancy-
specific liver disease characterized by raised serum bile acids and adverse fetal outcomes

Antioxidants 2023,12, 341 10 of 28
partially related to SIRT1 dysregulation [
139
]. Liao et al. [
139
] studied the molecular
and biochemical mechanism underpinning resveratrol’s regulation of the SIRT1- nuclear
factor-
κ
B (SIRT1-NF-
κ
B) signaling pathway and bile acid biosynthesis in ICP. Resvera-
trol (
30–120 mg/kg/day
) was demonstrated to decrease bile acid levels in the ICP rat
model and was suggested to protect syncytiotrophoblast against trichloroanisole (TCA)-
induced inflammatory injury through the upregulation of SIRT1 and the downregulation
of RelA/p65, a subunit of NF-
κ
B recognized as an activator of SIRT1 [
139
]. In a related
study, it was shown that resveratrol ameliorates ICP conditions by downregulating the
overexpression of matrix metalloproteinases (MMPs) [
140
]. Indeed, in the ethinylestradiol-
induced ICP rat model, resveratrol-diet (15 mg/kg/day) was able to inhibit the elevation of
both MMP-2 and MMP-9, and exhibited better outcomes in restoring bile flow rate, serum
enzymatic activities, and total bile acids (TBA) concentration compared to the ICP known
drug ursodeoxycholic acid [140].
On the other hand, diabetes-associated lipid profile disruption may indirectly af-
fect embryogenesis and organogenesis [
141
], and the impairment of the couple glucose
levels/lipid status may simultaneously alter the fetal and neonatal growth; which may
later impact offspring life and contribute to adult obesity. Using the same previous GDM
model, Singh et al. [
22
] evaluated the effect of resveratrol on lipidic profile variations.
Compared with the untreated GDM group, resveratrol supplementation demonstrated
a dose-dependent effect (120 and 240 mg/kg), which significantly increased both HDL
and adiponectin levels and inversely correlated with the levels of leptin, resistin, TNF-
α
,
IL-6 levels, the body weight, total cholesterol (TC), triglycerides (TG), and low-density
lipoprotein (LDL) [
22
]. Parallelly, resveratrol was shown to reduce mRNA levels of 3-
hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase), the rate-limiting enzyme
of cholesterol synthesis and the statin drugs target in high-fat fed hamster model [
142
].
Statin is an active drug that is used to lower human cholesterol and triglycerides but may
be harmful to pregnant or nursing women [
143
]; therefore, in light of these findings, the
authors suggested resveratrol as a potential therapy for an altered lipidic profile during
pregnancy-associated metabolic disorders.
Overall, the above-mentioned studies evaluated the short-term effects of maternal
resveratrol intake in diabetic and related-metabolic disorders experimental models Table 2.
Resveratrol showed favorable results on metabolic homeostasis and redox state. Never-
theless, the mother and offspring’s longer-term outcomes remain poorly specified. Not to
mention the variations of experimental models, range of doses, routes of administration
and therapeutic periods that may contribute to inconclusive results regarding the potential
metabolic benefits of maternal resveratrol supplementation during pregnancy and lactation.
In this light, extended studies with well-established experimental models are needed.
Table 2.
Studies using resveratrol in the treatment of models of gestational diabetes miletus (GDM)
in pregnancy.
Reference Type of the Study GDM Experimental
Model Dose Mechanism of Action
Outcomes of
Supplementation in the
Experimental Model
[116] In vivo Streptozotocin GDM
pregnant rats model 120 and 240 mg/kg Amelioration of blood glucose
and blood lipids levels
↑Insulin levels,
↓blood glucose levels
Amelioration of lipidic profile
No studied effect in offspring
[117] In vivo Streptozotocin GDM
pregnant rats model 500 µg/mL
(CS-ZnO-RS) Anti-diabetic effect
Anti-inflammatory effect
↓blood glucose levels
lipid content reduced the level
of
↓IL-6 and MCP-1, GRP78,
p-IRE1α, p-eIF2α, and p-PERK
Inhibition of α-glucosidase
and α-amylase
No studied effect in offspring

Antioxidants 2023,12, 341 11 of 28
Table 2. Cont.
Reference Type of the Study GDM Experimental
Model Dose Mechanism of Action
Outcomes of
Supplementation in the
Experimental Model
[22] In vivo Streptozotocin GDM
pregnant rats model 120 and 240 mg/kg Amelioration of the lipids
metabolic profile
↑HDL-C and adiponectin
↓leptin, resistin, TNF-α, IL-6
levels, the body weight, TC,
TG, and LDL-C
No studied effect in offspring
[142] In vivo high-fat fed hamster
model 0.025% Amelioration of the lipids
metabolic profile
-HMG-CoA reductase
expression
No studied effect in offspring
[128] In vivo
high-fat diet GDM mice
model
IR adipocyte model was
established by
dexamethasone-
inducing
0.2%
Amelioration of glucose and
lipids metabolic profile
Amelioration of IR in
adipocytes
↓The bodyweight, serum
glucose
↑serum insulin
Upregulations of
miR-23a-3p/NOV axis
↑Adiponectin, Leptin, p-PI3K,
and p-Akt
No studied effect in offspring
[118] In vivo
female Sprague-Dawley
rat model, fed with a
high-fat and sucrose
diet
147 mg/kg/day
Protection against gestational
diabetes-induced glucose
intolerance and islet
dysfunction
-Restored glucose tolerance,
normoglycaemia and
improved insulin secretion in
offspring
-Attenuation of hepatic
steatosis, insulin resistance,
glucose intolerance and
dysregulated gluconeogenesis
in offspring
-Downregulation of lpl, ppara,
g6p genes
[144] In vivo C57BL/KsJ-Lep (db/+)
(db/+) genetic GDM
pregnant mouse model 10 mg/kg/day
Amelioration of glucose
metabolic profile via
SIRT1/AMPK pathway
Amelioration of IR
↑Glucose metabolism, insulin
tolerance and reproductive
outcome of the pregnant db/+
females
AMPK activation
↓glucose-6-phosphatase in
both pregnant db/+ females
and their offspring
GDM: Gestational diabetes miletus, CS-ZnO-RS: resveratrol-zinc oxide complex encapsulated with chitosan,
IL-6: Interleukin-6, MCP-1: Monocyte Chemoattractant Protein-1, GRP78, p-IRE1
α
, p-eIF2
α
, and p-PERK: en-
doplasmic reticulum stress components, TNF-
α
: Tumor necrosis factor-alpha, TC: Total cholesterol, TG: Triglyc-
erides, LDL-C: low-density lipoprotein-C, IR: Insulin resistance, miR-23a-3p/NOV axis: microRNA-23a-3p,
p-Akt: phosphorylated-AKT, p-PI3K: Phosphoinositide 3-kinase, lpl: lipoprotein lipase gene, ppara: Peroxisome
proliferator-activated receptor alpha, g6p: glucose-6 phosphatase. AMPK: AMP-activated protein kinase.
5. Fetus-Related Abnormalities and Resveratrol
5.1. Prenatal and Resveratrol
Several studies supported resveratrol’s protective and therapeutic effects at the pre-
natal stage. In fact, offspring may show increased susceptibility to certain diseases due
to prenatal or intrauterine conditions, which may be efficiently reversed by resveratrol.
In this section, we present several examples of disease susceptibility due to intrauterine
modifications and the potential role of resveratrol in reversing this susceptibility. These
include susceptibility to metabolic, cardiovascular, and neurological disorders.
Non-alcoholic fatty liver disease (NAFLD) is a hepatic metabolic disorder [
145
] associ-
ated with IUGR [
146
]. A study showed that prenatal ethanol exposure (PEE) increases the
susceptibility to NAFLD in female IUGR rat offspring by inducing intrauterine metabolic
alterations [
147
]. These alterations enhance fetal hepatic lipogenesis and reduce lipid out-
put in utero; moreover, the fetuses of PEE pregnant rats showed decreased weight and
low levels of serum glucose and triglycerides, in addition to hepatocellular ultra-structure
modifications [
147
]. Further analyses also showed attenuated SIRT1 expression and activity
associated with the upregulation of SREBP1c and other downstream lipogenic genes, such
as fatty acid synthase (FASN), acetyl-coenzyme A carboxylase
α
(ACC
α
), and stearyl-
coenzyme A desaturase 1 (SCD1) [
147
]. Interestingly, the hepatic SIRT1-SREBP1c signaling
pathway has been reported to play a crucial role in controlling hepatic lipid metabolism
and thus promoting liver protection against NAFLD [
148
]. Accordingly, by targeting the

Antioxidants 2023,12, 341 12 of 28
hepatic SIRT1-SREBP1c pathway, the SIRT1 chemical activator resveratrol (50 mg/kg/day)
was able to reduce the increased susceptibility to diet-induced NAFLD by reversing the
intrauterine programming of hepatic lipogenesis after birth in PEE offspring rats [
149
].
Another study showed that a maternal high-fat (HF) diet affects the offspring of Sprague
Dawley and may lead to metabolic dysregulation [
136
]. Results showed that offspring
dams with maternal HF exposure have decreased acetate propionate and butyrate levels in
plasma. In addition, the gut microbiota metagenome of these offspring was altered, thus
altering their metabolic homeostasis. The study also suggested that this metabolic dysregu-
lation in offspring was programmed intrauterine by the maternal HF diets and is related to
their gut microbiota [
136
]. In the same study, resveratrol treatment (10 mg/kg/day) was
able to reverse the effects induced by maternal HF diet exposure and ameliorate plasma
propionate levels. In addition, resveratrol relieved metabolic syndrome dysregulation and
related dysbiosis of gut microbiota [136].
Offspring susceptibility to hypertension may originate at the prenatal stage due to
maternal conditions. A study showed that the HF diet exacerbated maternal L-NAME
treatment-induced programmed hypertension of rat offspring [
150
]. This was associated
with increased oxidative stress, attenuated AMP-activated protein kinase (AMPK)/ per-
oxisome proliferator-activated receptor
γ
co-activator 1
α
(PGC-1
α
) pathway and altered
gut microbiota [
150
]. These alterations were initiated at the prenatal stage by induced
hypertensive maternal condition, sustained till adulthood, and exacerbated by the HF
diet. Resveratrol (50 mg/L in drinking water) reversed the increase in Firmicutes to Bac-
teroidetes ratio in the gut microbiota species while amplifying the abundance of phylum
Verrucomicrobia and genus Akkermansia [150]. The overall data indicate resveratrol may
attenuate hypertension of developmental origin by regulating the microbiota.
It is accepted that prenatal hypoxia increases offspring susceptibility to cardiovascular
disease and metabolic disorders [
151
,
152
] such as altered cardiac morphology and dysfunc-
tion and metabolic complications in adulthood [
153
–
155
]. Furthermore, prenatal exposure
to hypoxia was reported to set the stage for ischemia/reperfusion (I/R) injury [
156
,
157
] and
metabolic syndrome in response to a secondary insult such as the HF diet [
84
]. Interestingly,
prenatal hypoxia is able to compromise metabolic and cardiac function in a sex-specific man-
ner [
158
]. Accordingly, prenatal hypoxia and the HF diet impaired metabolic function in the
male but not in female offspring rat [
158
]. In addition, prenatal hypoxia compromised I/R
injury recovery more profoundly in the male compared to female HF diet rat offspring [
158
].
These prenatally-programmed effects were alleviated by resveratrol administration. Indeed,
resveratrol (4 g/kg diet) improved cardiac recovery and attenuated oxidative stress in both
male and female rat offspring, thus, impeding their increased susceptibility to cardiovascu-
lar diseases [
84
]. In addition, resveratrol (D120020402 4 g kg
−1
; Research Diet) improved
their metabolic function prenatally challenged by hypoxia and postnatally by HF diet [
158
].
Molecularly, resveratrol enhanced cardiovascular and metabolic function by mitigating
oxidative stress and activating the AMP-activated protein kinase (AMPK)–acetyl CoA
carboxylase (ACC) and AMPK/perioxysome proliferator-activated receptor-
γ
coactivator
(PGC)-1
α
pathways, resulting in improved fatty acid oxidation, mitochondrial biogenesis,
and metabolic and cardiac health [158].
Prenatal stress may predispose neurological complications in offspring. In a study re-
alized on rat offspring, prenatal gestational stress increased lipid peroxidation and protein
oxidation and decreased antioxidant activity and NO levels [
159
]. In addition, their dentate
gyrus and CA3 hippocampal neurons were severely affected [
159
]. Resveratrol adminis-
tration (10 mg/kg) alleviated prenatal stress-induced oxidative stress and the recovering
neurons of the dentate gyrus [
159
]. Thus, resveratrol antioxidant potential is suggested
to dispose of a neuroprotective role against prenatal stress-induced oxidative damage in
neonatal rat brains [
159
]. In another study conducted by Sahu et al. [
160
], resveratrol
prenatal-intake effect against cognitive deficit in rat offspring was investigated. Prena-
tal stress exposure managed to deteriorated spatial learning and memory and reduced
Na(+), K(+)-ATPase activity in the rats’ offspring brains, while resveratrol administration

Antioxidants 2023,12, 341 13 of 28
(
10 mg/kg
) did not affect ATPase levels and it improved their spatial learning and mem-
ory, suggesting a neuroprotective efficacy of resveratrol against prenatal stress-induced
cognitive impairment [160].
Autism spectrum disorder (ASD) is a neurological disorder characterized by de-
creased social communication and interaction [
161
]. While little is known about ASD
causes, recent evidence supported its association with estrogen receptor
β
(ER
β
) dysreg-
ulation [
162
,
163
]. In fact, maternal hormonal exposure to ER
β
inhibitors such as natural
progesterone and synthetic progestin impairs cognitive flexibility and contributes to ASD
development [
164
,
165
]. A study showed that prenatal exposure of rat offspring to pro-
gestins leads to decreased ER
β
expression in the amygdala [
166
]. This downregulation
was concomitant with an autism-like behavior in the offspring. These prenatal progestin-
induced biochemical and behavioral alterations were shown to be reversed by resveratrol
administration (20 mg/kg) [
166
]. Resveratrol supplementation also reduced progestin-
induced oxidative stress, mitochondrial dysfunction, and lipid dysregulation in the brain,
through the activation of ER
β
and its target genes leading to the amelioration of progestin-
induced ASD-like behavior effects [
166
]. These results are promising for the protective
effect of resveratrol against progestin intake, be it clinical such as oral contraceptives, or
dietary such as in contaminated water and seafood, suggesting that resveratrol may limit
the risk of ASD; however, more clinical studies are needed to determine the resveratrol
doses and duration of treatment in pregnant women. Collectively, these data support the
protective role of resveratrol against a prenatally-induced predisposition to cardiovascular,
neuronal, and metabolic pathological conditions. This protective effect appears to be mainly
associated with resveratrol antioxidative properties.
5.2. Placenta and Resveratrol
The placenta is a large organ that develops in the uterus during pregnancy. It provides
oxygen and nutrients to the fetus and removes waste products from its blood. It plays a
crucial role in fetal organ development and fetal growth [
167
]. In addition, the umbilical
cord of the fetus arises from the placenta [
168
]. Assessing placenta oxidative status as
oxidative stress indication during pregnancy is important due to two main reasons. First,
the placenta is the interface between the mother and fetus [
167
]. Changes in oxygen
levels in the placenta to support increased metabolic rate are associated with increased
circulating ROS [
169
]. This redox imbalance in the placenta may have a direct effect
on fetal development. The second reason is that the placenta exacerbates pregnancy
inflammation by producing inflammatory factors [
170
–
173
]. Thus, it is an important site
for the propagation of maternal inflammation.
Noteworthy resveratrol administration during pregnancy ameliorates placental oxida-
tive status, which is achieved through a plethora of biological effects [
167
,
174
–
176
]. These
resveratrol-initiated effects have been particularly shown to alleviate chemical, microbial,
heavy metal, and high-fat diet (HFD)-induced inflammation in the placenta. Consistently
with that, resveratrol suppressed cadmium (Cd)-induced expression of inflammatory cy-
tokines and chemokines in the placenta of pregnant CD-1 mice and JEG-3 cells (0.2%) [
177
].
These include tumor necrosis factor-
α
(TNF-
α
), interferon-gamma (IFN-
γ
), monocyte
chemoattractant protein 1 (MCP-1), macrophage inflammatory protein-2 (MIP-2), and
chemokine (C–X–C motif) ligand 1 (KC) [
177
]. In contrast, a study conducted on unchal-
lenged pregnant sows failed to report any influences of dietary resveratrol (300 mg/kg)
on pro-inflammatory cytokine levels such as interleukin 1
β
(IL-1
β
), IL-6, IL-8 and tumor
necrosis factor
α
(TNF-
α
) [
167
]. This discrepancy may be due to the dose variation and
duration of resveratrol and stimulus administration (Cd versus no stimulus). It is also
worth mentioning that in the latter study, resveratrol played an antioxidative rather than an
anti-inflammatory role. In another study realized in the human placenta, resveratrol treat-
ment (200
µ
M) significantly attenuated IL-1
α
, IL-1
β
, IL-6, and IL-8 mRNA expression and
reduced the release of IL-6, IL-8, and MCP-1 [
173
]. Interestingly, these anti-inflammatory
effects were observed when the human placenta was stimulated with TNF-
α
, IL-1
β
, or

Antioxidants 2023,12, 341 14 of 28
the synthetic viral dsRNA analogue polyinosinic: polycytidylic acid (poly (I:C)) [
173
].
Effectively, several studies support the resveratrol antioxidant effect at a placental level.
For example, a study showed that resveratrol treatment (0.2 %) attenuated Cd-induced
upregulation of endoplasmic reticulum (ER) stress markers in the placenta of pregnant
mice [
177
]. A similar antioxidant effect of resveratrol (300 mg/kg) was reported in the
placenta of pregnant sows [
167
] where resveratrol was able to increase the expression of
Nrf2 and decreased the expression of Kelch-like ECH-associated protein-1 (Keap1) [
167
]. In
addition, resveratrol increased the mRNA expression of antioxidant enzyme genes includ-
ing catalase (CAT), glutathione peroxidase 1 (GPX1), SOD1 and HO-1. Furthermore, phase
2 detoxification genes, including glutamate-cysteine ligase modifier (GCLM), microsomal
glutathione S-transferase 1(MGST1) and UDP glucuronosyltransferase family 1 member
A1 (UGT1A1) were upregulated by resveratrol administration (300 mg/kg) [167].
The placenta favors the flow toward the fetus of epigenetic alterations induced by the
mother’s conditions, such as GDM and obesity [
178
,
179
]. These epigenetic alterations may
induce pregnancy complications, affect fetal and neonatal phenotype and induce offspring
disease susceptibility [
178
,
179
]. In this regard, resveratrol elicits an anti-epigenetic activity
by regulating epigenetic enzymes. For instance, resveratrol attenuated both DNA methyl-
transferase (DNMT) activity and DNMT3B expression in the placenta of Cd-challenged
pregnant mice (0.2 %) [
177
]. In addition, resveratrol administration enhanced the activity
and expression of the nuclear deacetylase, Sirtuin 1 (SIRT1), and inhibited Cd-induced
PI3K/Akt signaling pathway [
177
]. A similar activating effect was elicited by resveratrol
on the Sirt1 protein in the placenta of pregnant sows (300mg/kg) [
167
]. Furthermore,
resveratrol (100
µ
moL/L) has been shown able to prevent the up-regulation of the placental
early growth response protein-1 (Egr-1), which is a protein that regulates DNA demethyla-
tion [
180
]. Although maternal nutritional epigenetics is an intriguing topic under intense
investigation [
181
], further studies are necessary to better understand the role of resveratrol
in modulating maternal epigenetics.
Studies on non-human primates have also shown that resveratrol reduced placental
inflammation and improved glucose metabolism [
39
,
144
]. A study by Tran et al. [
173
]
showed that resveratrol (200
µ
M) restored insulin signaling and glucose uptake aberrantly
altered by the pro-inflammatory cytokines TNF-
α
and IL-1
β
, the bacterial lipopolysaccha-
rides LPS and polyinosinic-polycytidylic acid (poly(I:C) in human placenta tissue [
173
].
Not only did resveratrol alleviate placental inflammation, but it also reduced insulin resis-
tance in the human placenta tissue [
173
]. As previously stated, the release of endothelial
dysfunction-associated anti-angiogenic factors such as sFlt-1 is one of the main features
in placental oxidative stress and inflammation during PE [
103
,
180
]. In humans, resver-
atrol (100
µ
moL/L) abolished cytokine-induced release of sFlt-1 from normal and from
pre-eclamptic placental explants [
180
]. A similar inhibitory effect on sFlt-1 was observed in
resveratrol-treated HUVEC or HTR-8/SVneo [
180
]. In these cells, resveratrol also increased
the expression of HO-1, an enzyme found to be dysfunctional in preeclampsia [
180
]. These
latest studies indicate that resveratrol plays anti-inflammatory, antioxidative, and growth
factor-regulating roles at the level of the placenta by modulating oxidative/antioxidative
enzymes expression, counteracting proinflammatory cytokines release and modulating the
expression of growth factors concentration such as VEGF and PlGF through sFlt-1 [
104
,
105
].
Overall, the presented data indicate that dietary resveratrol supplementation during
pregnancy improves the placental status, which is beneficial for reproductive performance
and the offspring’s well-being. However, long-term clinical trials on pregnant women
are warranted to reinforce resveratrol’s beneficial effects on the placenta and placenta-
associated functions.
5.3. Preterm and Resveratrol
Preterm birth (PTB) (<37 weeks of gestation) is considered a leading cause of newborn
death and a risk factor for short and long-term adverse health outcomes. Although the etiol-
ogy of PTB remains unclear, it is thought that an inappropriate increase in net inflammatory

Antioxidants 2023,12, 341 15 of 28
load seems to be a pivotal key [
182
]. Genital tract infections by Gram-negative bacteria
are a common complication in human pregnancy and have been shown to increase the
risk of preterm delivery. Several studies demonstrated that bacterial Lipopolysaccharide
(LPS) elicits a strong maternal inflammatory response that often results in preterm delivery
and fetal death in the murine model endotoxin-induced preterm labor [
183
]. Such a phe-
nomenon has been reported to occur via the induction of cytokine/chemokine production
and infiltration of uterine, placental, and fetal tissues with leukocytes, leading to the re-
lease of prostaglandins, endocannabinoids, nitrogen, ROS, and MMPs [
184
]. Interestingly,
prostaglandins, NO and TNF-
α
components were demonstrated to trigger preterm labor in
both animal models [
185
–
187
] and humans [
188
]. The endocannabinoid system (ECS) is
a cell-signaling system found in multiple organ systems and is integral to sustaining the
microenvironment necessary for early pregnancy success and maintenance. A great body
of literature suggests that in addition to early pregnancy events, the ECS plays a major
role in regulating pregnancy maintenance and labor timing [
189
]. Through the ECS and
PPAR-
α
systems modulation, resveratrol pre-treatment was found to prevent oxidative
stress and inflammation by increasing the tissue levels of palmitoylethanolamide (PEA)
and cannabinoid receptors type 1 CB1 and type 2 CB2 in sham animals. In the same
model, resveratrol also induces a general increase in PPAR-
α
and COX-2 protein levels,
thus attenuating inflammation and oxidative stress and leading to PTB prevention [190].
Despite the immensity of research into PTB pathophysiology, the resveratrol admin-
istration effect on this disorder remains unclear, although few studies suggested that
resveratrol decreases PTB rate mainly via the suppression of inflammation and infection
complications. Regarding the studies included in this review, only a few investigated
the correlation between resveratrol consumption and PTB. In a study realized by Bariani
et al. [
183
],
in vivo
treatment of 15-day pregnant BALB/c mice with resveratrol (
3 mg/kg
)
prevented the LPS-induced PTB in 64% of the cases, whereas only 15% of mice in the
LPS treated group had normal term birth. Resveratrol’s treatment resulted in a reduced
NOS activity (p< 0.05) in the uterus of LPS-treated mice and parallelly reduced the expres-
sion of LPS-induced pro-inflammatory agents, such as iNOS (p< 0.05), COX-2 (
p< 0.05
),
prostaglandin E2 (PGE2) (p< 0.05), and anandamide (AEA) (p< 0.05). Interestingly,
resveratrol administration also prompted ameliorative changes in the LPS-altered uterine
endocannabinoid profile [
183
]. In addition, spontaneous PTB is tightly linked with under-
lying intrauterine inflammation and infection that evokes an immune response involving
the release of cytokines such as IL-1
β
, TNF-
α
, [
191
–
194
], cyclooxygenase (COX)-induced
PGs [
195
], and matrix-degrading enzymes [
196
], which trigger uterine contractions, mem-
brane rupture, and cervical ripening [
197
], leading to the infant preterm delivery. In
Furuya et al.’s research [
198
], resveratrol administration (20 to 40 mg/kg) significantly de-
creased the PTB rate in an LPS-induced preterm mouse model and LPS-exposed peritoneal
macrophages by suppressing the increased proinflammatory cytokines and consequent
elevation of macrophages COX-2 [
198
]. Moreover, resveratrol uptake abolished TNF-
α
and interleukin IL-1
β
activity by downregulating their expression without any apparent
effect on IL-6 levels. Parallelly, resveratrol treatment suppressed the elevation of TNF-
α
and IL-1
β
levels in LPS-exposed peritoneal macrophages and significantly eradicated the
proinflammatory cytokine-mediated elevation of COX-2 in peritoneal macrophages [198].
It is well established that SIRT1 is mainly localized in the nucleus to exert its antiapop-
totic effects during oxidative stress or toxic substance-induced damage, and its amount
increases in the nucleus to protect the cell from apoptosis. In a tentative to identify the
protective role of SIRT1 in PTB and the role of resveratrol to ameliorate its dysregulation,
a study realized on PBMCs cells sampled from an established hyperoxia model of pre-
mature infants administered with different amounts of oxygen at birth, demonstrated
a concentration-dependent increase in SIRT1 translocation rates, ROS and MDA levels.
Interestingly, resveratrol (6
µ
mol/L) treatment managed to attenuate hyperoxia-associated
outcomes resulting in opposite effects [199].

Antioxidants 2023,12, 341 16 of 28
Overall, the effects of resveratrol in PTB complications appear to be based on its
capacity to counteract infections, inflammation, and oxidative stress-related outcomes.
Nevertheless, further investigations including clinical trials are needed to better elucidate
the molecular underlying mechanisms of action related to the beneficial effect of resveratrol
intake on PTB.
5.4. Fetus and Resveratrol
The “fetal basis of adult disease” hypothesis is now considered a keystone in the
development of important diseases in adult/advanced age, such as cardiovascular and
metabolic diseases. These events are associated with epigenetic dysregulations, and they are
mainly supported by alterations in the fetus development during pregnancy and caused by
non-optimal conditions in the uterus, such as GDM, maternal malnutrition, and functional
placental deficit [200,201].
Resveratrol pregnancy intake appears to be able to reverse the negative effects on
the fetus caused by in-utero adverse conditions and induce a positive impact on adult life
health. Although studies have been carried out on different species and with different
dosages and routes of administration, the overall data indicate that resveratrol is capable of
providing positive effects on fetal development in different gestational phases [3].
Prenatal exposure to environmental stress can also lead to greater susceptibility
to clinical disorders in adulthood. This is the case of fetal exposure in utero to 2,3,7,8-
tetrachlorodibenzo-p-dioxin (TCDD) leading to alterations in the differentiation of T cells
in the thymus and to a great susceptibility to autoimmune diseases [
202
]. TCDD can
trigger toxicity through activation of the aryl hydrocarbon receptor and severely affects
maternal and fetal immune systems during pregnancy [
203
]. A study performed in mice
by
Singh et al.
[
204
] evaluated whether resveratrol administration (100 mg/kg of body
weight) inhibited TCDD-induced immunotoxicity during pregnancy in the mother and
fetus. Resveratrol was observed to protect not only normal non-pregnant mice, but also
pregnant mothers and their fetuses from TCDD-induced thymic atrophy, apoptosis, al-
terations in T cell receptor, molecule expression, and T cells differentiation stimulatory.
Furthermore, Cytochrome P450 Family 1 Subfamily A Member 1 (CYP1A1) expression
in the thymus of both mother and fetus is significantly reduced when resveratrol is used
in vivo
after exposure to TCDD. Taken together the results demonstrate that resveratrol
consumption, during pregnancy, is able to protect the mother and the fetus from toxicity
induced by environmental pollutants such as TCDD [204].
Mothers exposure to ethanol during pregnancy may also induce various disorders in
their offspring, known as fetal alcohol spectrum disorders (FASD), which mainly affect the
cerebellum from developing. A study by Kumar et al. [
205
] demonstrated that resveratrol
exhibited neuroprotective and antioxidant effects in the cerebellum of a rat pups model
exposed to ethanol by acting on redox regulatory proteins. In particular, resveratrol
administration managed to inhibit apoptosis and increase cerebellar granule cell survival.
On a molecular level, resveratrol was able to restore ethanol-induced Nrf2 variation levels
and parallelly maintained physiological levels of the expression and the activity of its
downstream gene targets, such as NADPH quinone oxidoreductase 1 and superoxide
dismutase in the same experimental model [205].
Several benefits of resveratrol administration (1 g total trans-resveratrol was implanted
subcutaneously into the animal) during pregnancy and fetal development were notable
in the study by Darby et al. [
206
], where they showed its crucial role in increasing uterine
artery blood flow in pregnant sheep, leading to increased fetal growth, optimal regulation
of blood pressure and oxygenation. The authors also analyzed the direct resveratrol effects
on the fetal heart in chronically catheterized pregnant sheep showing that resveratrol
induced a significant increase in arterial blood oxygen saturation (SaO2), and fetal arterial
oxygen partial pressure (PAO2). Parallelly, resveratrol supplementation did not affect
SIRT1 mRNA levels or the activity of the AKT/mTOR or CAMKII signaling pathway in
this model [
206
]. The authors concluded that maternal resveratrol supplementation could

Antioxidants 2023,12, 341 17 of 28
increase oxygenation and fetal growth in this animal model that mimics the fetal cardiac de-
velopment conditions in humans and propose resveratrol as a possible candidate to restore
fetal substrate supply in pregnancies with placental insufficiency [
206
]. Subsequently, the
same authors reported the ability of resveratrol to increase body volume and fetal weight
without affecting brain weight and volume and to optimize uterine artery blood flow,
umbilical vein oxygen saturation, and fetal oxygen release. The authors concluded that
increasing fetal weight might be beneficial to ameliorate fetal growth and oxygen supply
impairment during pregnancy [
207
]. Employing a rat model, Bourque et al. [
28
] demon-
strated that resveratrol could improve fetal outcomes associated with prenatal hypoxia,
a common complication in pregnancy [
28
]. Indeed, resveratrol maternal intake during
the gestational period (GD7 - GD21) was able to almost completely nullify fetal death in
hypoxic pregnancies [28].
Another positive effect of resveratrol on fetal outcomes is its ability to increase fetal
hemoglobin levels (HbF) [
208
]. Among the hemoglobinopathies, beta-thalassemia is char-
acterized by a reduced synthesis of the beta-globin chain, with an unbalanced production
of the globin chain, ineffective erythropoiesis, and anemia. This imbalance can be reduced
by inducing an increase in gamma-globin gene expression, which combines with excess
alpha-globin chains and produces HbF. Other events related to this disease lead to sec-
ondary tissue damage due to excess ROS production. [
208
]. In a study performed in human
K562 cell line and erythroid precursors derived from normal donors and patients with
beta-thalassemia, Fibach et al. [
209
] demonstrated that resveratrol (0–100
µ
M) exhibited
antioxidant activity and stimulated the expression of gamma-globin genes leading to HbF
accumulation [
209
]. A later study by Theodorou et al. [
210
] reported that resveratrol and
one of its semi-synthetic derivatives act as (0–100
µ
M) therapeutic molecules carrying
out an antioxidant effect and an inductive effect on HbF synthesis in primary erythroid
progenitor cells from healthy donors. It is worth noting that the association of resveratrol
and the drug decitabine caused a significant increase in hemoglobin induction activity
above the level induced by the stilbene alone [210].
Moreover, a recent work by Bosquesi et al. [
211
] reported that both resveratrol and
its synthetic derivatives (100
µ
mol/Kg) possess a potential positive effect in the treatment
of sickle cell anemia (SCD) symptoms via the induction of gamma-globin. In CD34+ stem
cells, resveratrol and one of its semi-synthetic compounds were able to induce twice the pro-
duction of gamma-globin chains (
γ
G +
γ
A), compared to the vehicle. This semi-synthetic
compound emerges as a new molecule in the gamma-globin inducers group. Aside from
this property, anti-inflammatory and analgesic activities were also proven for these com-
pounds suggesting them as an alternative in the treatment of SCD symptoms [211].
Resveratrol owns multiple positive health effects on different metabolic parameters,
but it also possesses many different negative activities on the cellular life of various tis-
sues/organs in different animal species [
212
–
215
]. In this context, the study [
216
] evaluated
resveratrol’s effects on human fetal adrenocortical steroidogenesis during the 9–12th gesta-
tional weeks
in vitro
using human primary culture of fetal adrenocortical cells (HFAC) from
glands of aborted fetuses. The authors showed that resveratrol (10
µ
M/24 h) significantly
suppressed the synthesis of dehydroepiandrosterone, androstenedione, and 11- deoxycorti-
sol in cells stimulated with adrenocorticotropic hormone (ACTH), an event associated with
the inhibition of the activities and expression of cytochromes 17
α
-hydroxylase/17,20 lyase
(CYP17) and 21-hydroxylase (CYP21). Based on the data obtained in this model, the authors
advise against resveratrol intake by women who are in the early stages of pregnancy.
6. Conclusions and Future Directions
Resveratrol has been reported to possess numerous benefits against complicated preg-
nancies, with its activity elicited by regulating different physiological and cellular functions
and modulating multiple intracellular signaling pathways implicated in pregnancy and
pregnancy-associated conditions. Resveratrol demonstrated potent antioxidant activities by
blocking DNA damage, regulating antioxidant enzymes, and modulating redox-regulated

Antioxidants 2023,12, 341 18 of 28
intracellular signals. Resveratrol also showed anti-inflammatory properties by inhibiting
pro-inflammatory signaling pathways and the secretions of pro-inflammatory cytokines
and growth factors. Resveratrol has the capability to cross the placenta, improve its oxida-
tive status and directly affect the fetus during the gestational period producing beneficial
effects for the reproductive performance and the offspring’s well-being. Resveratrol may
offer potential therapeutic benefits for PE due to its antioxidative stress/anti-inflammatory
properties that prevent cells from undergoing apoptosis and mediates a protective ef-
fect by decreasing blood pressure and attenuating vascular endothelial injury. Interest-
ingly, resveratrol mediates a positive response in blood glucose regulation and attenuates
GDM-related complications.
Despite the multiple reported benefits, the use of resveratrol in pregnancy needs to be
better investigated to dissolve the high-dose-related toxicity issues highlighted by some
papers and the intricate information derived from the available literature analysis. Indeed,
although clinical trials indicate resveratrol safety for human consumption, results from the
same studies are inconclusive regarding resveratrol’s protective effects against diseases
and their complications. In particular, due to the vast difference in experimental models
employed, duration of treatments, dosages, routes of administration, and formulations,
the final interpretation of resveratrol effects on pregnancy and associated complications
remains to be extrapolated.
Particular attention should be directed to performing systematic long-term clinical
trials on pregnant women using determined resveratrol dosages to possibly reinforce
and ultimately demonstrate resveratrol’s protective and therapeutic role. Specifically, the
optimal resveratrol dosages to be employed in humans remains to be clarified. Indeed,
ranges of biologically active resveratrol concentrations
in vitro
and
in vivo
experimental
models differ enormously; hence, based on the currently available data, it is difficult to
extrapolate the resveratrol concentration/s that provide the maximum beneficial effect
in human subjects without provoking toxicity. This aspect is even more critical consider-
ing the resveratrol hormetic properties that tightly associate its final biological outcomes
to the employed concentrations. Not to mention the interaction of resveratrol with the
cellular and body redox state, which also influences its final effect in being beneficial or
harmful. Furthermore, due to its poor bioavailability, as performed for other natural com-
pounds [
217
–
219
], new resveratrol formulations that provide better molecule absorption
and pharmacodynamics need to be developed and commercialized. In this light, many of
the controversial resveratrol results in the literature might be due to the aforementioned
aspects, which warrant more profound and systematic investigations to reach a final word
on resveratrol therapeutic potentials.
Overall, the data presented in our review indicates that resveratrol pregnancy con-
sumption has numerous benefits on metabolic health for pregnant women and their off-
spring therapeutic approach in pregnancy-related pathological conditions such as elevated
inflammation, preeclampsia, and GDM (Figure 2). Therefore, although some adverse effects
have been highlighted at high dosages, clinical trials proved resveratrol safe for human
consumption, making its recommendation by physicians to pregnant women conceivable.
If that ever happens, the final validation of resveratrol therapeutic employment in preg-
nancy by evidence-based research would have massive consequences both on the mother
and the fetus, allowing for early intervention and ensuring healthy mothers and children.

Antioxidants 2023,12, 341 19 of 28
Antioxidants 2023, 12, x FOR PEER REVIEW 20 of 30
the resveratrol hormetic properties that tightly associate its final biological outcomes to
the employed concentrations. Not to mention the interaction of resveratrol with the cellu-
lar and body redox state, which also influences its final effect in being beneficial or harm-
ful. Furthermore, due to its poor bioavailability, as performed for other natural com-
pounds [217–219], new resveratrol formulations that provide better molecule absorption
and pharmacodynamics need to be developed and commercialized. In this light, many of
the controversial resveratrol results in the literature might be due to the aforementioned
aspects, which warrant more profound and systematic investigations to reach a final word
on resveratrol therapeutic potentials.
Overall, the data presented in our review indicates that resveratrol pregnancy con-
sumption has numerous benefits on metabolic health for pregnant women and their off-
spring therapeutic approach in pregnancy-related pathological conditions such as ele-
vated inflammation, preeclampsia, and GDM (Figure 2). Therefore, although some ad-
verse effects have been highlighted at high dosages, clinical trials proved resveratrol safe
for human consumption, making its recommendation by physicians to pregnant women
conceivable. If that ever happens, the final validation of resveratrol therapeutic employ-
ment in pregnancy by evidence-based research would have massive consequences both
on the mother and the fetus, allowing for early intervention and ensuring healthy mothers
and children.
Figure 2. Maternal resveratrol supplementation decreases the risk of adverse pregnancy outcomes
by ameliorating the in-utero conditions. Schematic representation of the resveratrol-impacted cross-
talk between abnormal in-utero conditions and adverse pregnancy risk.
Author Contributions: Conceptualization, R.G. and G.P.; writing—original draft preparation, I.R.,
A.M.P., R.G., G.F., M.F., R.I., A.H.E., and H.Z.; writing—review and editing, G.P.; visualization, I.R.,
R.G., and G.P.; supervision, G.P.; project administration, G.P.; funding acquisition, G.P. All authors
have read and agreed to the published version of the manuscript.
Funding: This work has been m ade p ossi ble t hanks to grants from Progetto Fondazione di Sardegna
-bando 2022–2023 and FAR2020-Pintus.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Figure 2.
Maternal resveratrol supplementation decreases the risk of adverse pregnancy outcomes by
ameliorating the in-utero conditions. Schematic representation of the resveratrol-impacted crosstalk
between abnormal in-utero conditions and adverse pregnancy risk.
Author Contributions:
Conceptualization, R.G. and G.P.; writing—original draft preparation, I.R.,
A.M.P., R.G., G.F., M.F., R.I., A.H.E. and H.Z.; writing—review and editing, G.P.; visualization, I.R.,
R.G. and G.P.; supervision, G.P.; project administration, G.P.; funding acquisition, G.P. All authors
have read and agreed to the published version of the manuscript.
Funding:
This work has been made possible thanks to grants from Progetto Fondazione di Sardegna
-bando 2022–2023 and FAR2020-Pintus.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
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