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It has been widely known that oxidative stress disrupts the balance between reactive oxygen species (ROS) and the antioxidant system in the body. During pregnancy, the physiological generation of ROS is involved in a variety of developmental processes ranging from oocyte maturation to luteolysis and embryo implantation. While abnormal overproduction of ROS disrupts these processes resulting in reproductive failure. In addition, excessive oxidative stress impairs maternal and placental functions and eventually results in fetal loss, IUGR, and gestational diabetes mellitus. Although some oxidative stress is inevitable during pregnancy, a balancing act between oxidant and antioxidant production is necessary at different stages of the pregnancy. The review aims to highlight the importance of maintaining oxidative and antioxidant balance throughout pregnancy. Furthermore, we highlight the role of oxidative stress in pregnancy-related diseases.
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Review Article
The Role of Oxidative Stress and Antioxidant
Balance in Pregnancy
Tarique Hussain ,
1,2
Ghulam Murtaza,
3
Elsayed Metwally,
4
Dildar Hussain Kalhoro,
5
Muhammad Saleem Kalhoro,
6
Baban Ali Rahu,
3
Raja Ghazanfar Ali Sahito,
7
Yulong Yin,
8
Huansheng Yang,
9
Muhammad Ismail Chughtai,
2
and Bie Tan
1
1
College of Animal Science and Technology, Hunan Agricultural University, Changsha, 410128 Hunan, China
2
Animal Science Division, Nuclear Institute for Agriculture and Biology College, Pakistan Institute of Engineering and Applied
Sciences (NIAB-C, PIEAS), Faisalabad 38000, Pakistan
3
Department of Animal Reproduction, Faculty of Animal Husbandry and Veterinary Sciences, Sindh Agriculture University,
Tandojam, Sindh 70050, Pakistan
4
Department of Cytology & Histology, Faculty of Veterinary Medicine, Suez Canal University, Ismailia, Egypt
5
Department of Veterinary Microbiology, Faculty of Animal Husbandry and Veterinary Sciences, Sindh Agriculture University,
Tandojam, Sindh 70050, Pakistan
6
Department of Animal Products Technology, Faculty of Animal Husbandry and Veterinary Sciences, Sindh Agriculture University,
Tandojam, Sindh 70050, Pakistan
7
Institute of Neurophysiology, University of Cologne, Cologne 50931, Germany
8
Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, 410125 Hunan, China
9
Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Laboratory of Animal Nutrition and
Human Health, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China
Correspondence should be addressed to Tarique Hussain; drtariquerahoo@gmail.com and Bie Tan; bietan@hunau.edu.cn
Received 15 March 2021; Revised 16 August 2021; Accepted 4 September 2021; Published 27 September 2021
Academic Editor: Mingliang Jin
Copyright © 2021 Tarique Hussain et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
It has been widely known that oxidative stress disrupts the balance between reactive oxygen species (ROS) and the antioxidant
system in the body. During pregnancy, the physiological generation of ROS is involved in a variety of developmental processes
ranging from oocyte maturation to luteolysis and embryo implantation. While abnormal overproduction of ROS disrupts these
processes resulting in reproductive failure. In addition, excessive oxidative stress impairs maternal and placental functions and
eventually results in fetal loss, IUGR, and gestational diabetes mellitus. Although some oxidative stress is inevitable during
pregnancy, a balancing act between oxidant and antioxidant production is necessary at dierent stages of the pregnancy. The
review aims to highlight the importance of maintaining oxidative and antioxidant balance throughout pregnancy. Furthermore,
we highlight the role of oxidative stress in pregnancy-related diseases.
1. Introduction
Several reproductive problems have been linked to oxidative
stress. Oxidative stress occurs when the bodys antioxidant
system is depleted owing to an excess of reactive oxygen spe-
cies (ROS). ROS are highly reactive molecules that are unsta-
ble and short-lived. These molecules contribute to the control
of signaling pathways, as well as cellular and physiological
processes [1]. However, excess ROS may cause cellular toxic-
ity [2]. Animals have an enzymatic antioxidant defense
mechanism that suppresses the formation of reactive oxygen
species (ROS). It is worth noting that cellular integrity is
maintained by a balance of enzymatic and non-enzymatic
antioxidant systems. When oxidative stress increases, both
Hindawi
Mediators of Inflammation
Volume 2021, Article ID 9962860, 11 pages
https://doi.org/10.1155/2021/9962860
antioxidant systems are depleted resulting in reproductive
problems [3, 4]. Enzymatic antioxidants like glutathione per-
oxidase (GPx) and superoxide dismutase (SOD) are antioxi-
dants to neutralize free radicals. On other hand, the non-
enzymatic antioxidants such as vitamin C, vitamin E, plant
polyphenol, carotenoids, and glutathione interrupt free radi-
cal chain reactions. Importantly, antioxidants may have ther-
apeutic promise in the treatment of reproductive-related
problems [5].
ROS has a biological eect on various reproductive pro-
cesses, such as oocyte maturation, fertilization, embryo
development, pregnancy, as well as oocyte maturation and
fertility. A number of research studies, including animals
and humans, showed that ROS has been implicated with
female reproduction, particularly ovaries [68], fallopian
tubes [9] and embryos [10].
The primary function of the placenta is to exchange
nutrients and oxygen between mother and fetus. Therefore,
interference in these functions leads to hypoxia due to oxida-
tive stress. The disruption in placental function is due to
many factors resulting in pregnancy complications [11]. A
large number of studies reported that pregnancy problems
have been associated with overwhelming oxidative stress
from the placenta and or maternal tissues [12]. Other mech-
anisms are also implicated in the etiology of these complica-
tions; oxidative stress has evolved to regulate the cellular and
molecular pathways such as altered angiogenesis and inam-
mation to mediate disease outcomes [13]. The oxidative sce-
nario develops due to increased ROS and depletion of the
antioxidant system [14]. Though the development of abnor-
mal oxidative stress leads to spontaneous abortion, idio-
pathic recurrent pregnancy loss and embryogenesis defect
[2, 1518].
Oxidative stress has been linked to a number of meta-
bolic processes that aect animal health and performance
[19]. The study of oxidative stress has increased as a result
of its role in adverse pregnancy outcomes. Oxidative stress
exhibits dual functions, it aids in the maintenance of redox
balance and it plays a part in female reproductive processes.
As a result, oxidative stress may aggravate IUGR, endometri-
osis, and other reproductive issues. Oxidative stress also reg-
ulates signaling networks including Kelch-like ECH-
associated protein 1, Nuclear factor erythroid 2-related fac-
tor 2 (Keap1-Nrf2), nuclear factor kappa-B (NF-κB), fork-
head transcription factors of the O class (FOXO) and
Mitogen-activated protein kinase (MAPK). Lastly, targeting
these pathways appears attractive as a potential therapeutic
strategy against pregnancy-related anomalies [5].
2. Oxidative Stress and Its
Regulatory Mechanism
ROS are oxidative metabolic byproducts that play an impor-
tant part in cellular activity. They are also implicated in a
number of pathological diseases, including in-vitro and in-
vivo pregnancy diculties [2025]. The factors responsible
for overproduction of ROS are ultraviolet radiation, cigarette
smoking, alcohol, non-steroidal anti-inammatory medica-
tion, ischemia-reperfusion injury, chronic infections, and
inammatory diseases [26, 27]. The enzyme superoxide dis-
mutase converts the superoxide anion radical to hydrogen
peroxide and oxygen [28], and catalase eliminates hydrogen
peroxide when its quantities in the cell are higher [29]. Glu-
tathione reductase is found throughout the body tissues and
operates similarly to GPx. Using several systems; the GSR
enzyme reduced oxidized glutathione by utilizing NADPH
[30, 31].
The secondary defense is based on the GPx enzyme,
which possesses peroxidase activity and may eliminate lipid
hydroperoxides irrespective phospholipase A2 [32]. There
are also a number of oxido-reductases that catalyse thiol
and other protein reduction processes. Protective enzymes
against free radicals are produced once the cellular compo-
nents have been oxidatively damaged. For example, DNA
nuclear enzymes are known to protect DNA from oxidative
damage induced by free radicals [33]. Vitamin E functions as
a cofactor for glutathione peroxidase enzymes, and its pres-
ence in all cellular membranes suggests that it can protect
lipids from oxidation. The ascorbic acid-GSH redox couple
directly reduces the tocopherol radical. While β-carotene
functions in concert with vitamin E, which is a strong scav-
enger of free radicals, but β-carotene only works at low oxy-
gen pressure. Vitamin E, on the other hand, protects β-
carotene against oxidative damage [34]. In addition, some
antioxidants work as free radical quenchers [35]. Early preg-
nancy deciency in antioxidants has been associated with
the development of maternal-related disorders such as gesta-
tional hypertension, gestational diabetes, and other compli-
cations [36]. Therefore, the generation of ROS molecules
controls several signaling pathways that govern a variety of
cellular functions. The activation of these signals causes a
change in cellular function, which has a pathogenic eect
on the cell [37].
3. Oxidative Stress Scenarios in Pregnancy
In normal pregnancy, the developing tissues and organs of
the fetus require enough nutrition and oxygen. These pro-
cesses generate ROS in both maternal and fetal tissues that
inuence fetal growth development. To provide a suitable
environment for the fetus and maternal body, the balance
between ROS and antioxidants could be maintained [38].
During pregnancy, the body undergoes numerous physio-
logical changes. The evidence of ROS formation in the sec-
ond trimester of pregnancy was assumed by the
researchers. Increased production of ROS occurs due to the
enhanced metabolism, high consumption of oxygen and uti-
lization of fatty acids. During third trimester of pregnancy,
increase insulin resistance, fat catabolism, and release of free
fatty acids resulting in enhanced production of hydrogen
peroxide [39]. Placental cells have a lot of mitochondria,
which are the main source of pro-oxygenates. The superox-
ide anion radical produces more radical species and their
generation rises as the pregnancy continues.
Several studies have found that oxidative stress is linked
to pregnancy complications that may inuence fetal devel-
opment. The major causes are a lack of nutrition and oxygen
for developing fetuses, which causes hypoplasia and disrupts
2 Mediators of Inammation
placental function [39, 40]. The dierence in total plasma
antioxidants status between pregnant and non-pregnant
individuals has been observed, implying a low level in the
rst phase of pregnancy. The total antioxidant capacity of
a pregnant woman increases during the second and third tri-
mesters, and by the last week of pregnancy, it has reached
the level of a non-pregnant woman. TAC activity increases
after the 8
th
week of pregnancy, and these changes are linked
to dierences in plasma uric acid levels [41]. Furthermore,
reduced TAC levels in pregnancy have been linked to low
levels of serum albumin, bilirubin, and vitamin E [42]. As
result, it appears that plasma SOD activity is reduced during
pregnancy [43]. The SOD reduction promoted triglycerides,
total cholesterol, and low-density lipoprotein (LDL) choles-
terol levels in blood plasma. Therefore, SOD refers as indica-
tor of oxidative stress and lipid peroxide activity followed by
25 weeks of pregnancy. As a result, lipid peroxidation levels
in the blood are higher in pregnant women, serving as a
marker of oxidative stress. Previous studies have found that
supplementing pregnant individuals with the dietary vita-
mins, antioxidants, and minerals enhanced TAC activity
[4244].
4. Oxidative Stress in Ovary, Uterus
and Placenta
Almost every stage of pregnancy is aected by ROS. ROS is
known to be the important regulator of ovarian cellular
activity [45]. The ROS positive impact has been already
mentioned. Previous studies showed that the presence of
SOD in ovary, copper-zinc SOD (Cu-Zn SOD) in granulosa
cells of follicles and manganese superoxide dismutase
(MnSOD) in luteal cells of the corpus luteum in rats [46].
The sources of ROS in the follicles are macrophages, leuko-
cytes and cytokines [26]. Ovulation is dependent on concen-
tration of ROS. ROS suppressors have been demonstrated to
interfere with the ovulatory process [47]. Follicles develop-
ment is associated with an increased metabolic function of
granulosa cells, particularly excess amount of cytochrome
P450 and steroidogenesis [48]. The presence of ROS in
pre-ovulatory follicles alters blood ow and nally leads to
follicle rupture [49]. Furthermore, FSH stimulates the syn-
thesis of estrogen, while the overexpression of CAT in devel-
oping follicles protects them from apoptosis, ensuring that
ovarian function is preserved [50]. Depletion of oxygen is
required for follicular angiogenesis [6]. The corpus luteum
contributes to functional luteolysis by producing ROS. Dur-
ing the luteal phase, both the ROS and antioxidants are
linked to progesterone production [51]. The benecial
eects of ROS and antioxidants in female reproductive and
pregnancy outcomes are depicted in Table 1.
The developing fetus has a high energy requirement due
to the placental hyperactive metabolic rate, resulting in oxi-
dative stress [52]. Of note, that superoxide anions produced
by placental mitochondria appear to be the essential source
of ROS and lipid peroxidation in the placenta [53]. As the
pregnancy progresses, mitochondrial synthesis of lipid per-
oxides, free radicals, and vitamin E may also increase [54].
The placenta and large blood arteries mature slowly in the
second phase of the pregnancy. After that, maternal blood
pumps via interstitial space into the mothers spiral artery
[54, 55]. Free radicals are abundant in placental tissues,
and oxidation occurs throughout the process. With the help
of antioxidant activity, the placenta can slowly adapt to the
environment after recovering from stress [40].
SOD activity decreases during the late luteal phase due to
increased amounts of lipid peroxide. Importantly, ROS are
known to have a role in numerous phases of the endometrial
cycle, and may also produce PGF
2
through NF-κB activation
[56]. Estrogen and progesterone levels dropped signicantly
as a result of lower SOD expression. In a consequence, ROS
accumulates in the uterus, leading to implantation failure.
The basal level of ROS controls angiogenic activity in the
endometrium and results in endometrial regeneration dur-
ing each cycle. Thus, appropriate ROS concentration is crit-
ical for normal homeostasis. However, an increased level of
ROS from the placenta has been associated with
pregnancy-related disorders [5759]. The TNF-αcytokine
that inuences endothelial cell dysfunction and the antioxi-
dant Mn-SOD are both disrupted and have protective
eects. The production of cytokines and prostaglandins is
increased by ROS-related poor placental function, producing
endothelial cell injury and contributing to preeclampsia [60].
5. Regulation of Multiple Signaling
Pathways by Oxidative Stress
Oxidative stress has been linked to inuence signaling path-
ways, particularly in reproductive diseases ranging from egg
production to ovulation. It alters immune system of the
uterus resulting in embryonic failure [61, 62]. Oxidative
stress has also been involved in regulating molecular path-
ways in reproductive disorders such as p38 MAPK, Keap1-
Nrf2, the Jun N-terminal kinase (JNK), the FOXO family,
and apoptotic pathways. Therefore, the research on this
aspect may yield new insights that might inuence female
reproductive system.
Nrf2 is a signaling molecule that protects cellular func-
tion by acting as an antioxidant in response to oxidative
stress [63]. Physiologically, Nrf2 binds with Keap1 in the
cytoplasm before being degraded by the proteasome [64].
Once the Nrf2 is activated, it translocate into nucleus, where
it activates several antioxidant genes [65]. In contrast, activa-
tion of antioxidant genes and restoration of vascular redox
homeostasis are required when OS is evident suggesting
the crucial function of Nrf2 [66]. The deciency of Nrf2
induced fetal DNA damage and neurological discrepancies
and inactivation of Nrf2 were also exhibited inammation
triggered trophoblastic apoptosis. Previous evidence showed
that Nrf2 plays an important role in pregnancy and protects
the fetus from OS in-utero [67]. The maternal immune sys-
tem is susceptible to Nrf2. Nrf2 is only decreased once the
full-term foetus is delivered in a normal pregnancy. When
a fetus is infected in utero, the Nrf2 expression is favorably
reduced [68]. In the case of OS-induced metritis, it is
expected that Nrf2 would be considerably decreased, and
Keap1 would bind to Nrf2. Similarly, FOXO3 is essential
in the interaction between Keap1 and Nrf2. In the absence
3Mediators of Inammation
of FOXO3, Nrf2 is activated by AKT and protects cells
against OS [69]. Lastly, we hypothesized that OS causes
inammation in the reproductive system, with FOXO3 play-
ing a role in the interaction between Keap1 and Nrf2, which
may be used as a marker for OS insults.
NF-κB is an inert molecule, its family comprises ve
transcription factors c-Rel, p50, p52, RelB and RelA (p65)
[70]. NF-B is a redox-sensitive transcription factor that is
the primary regulator of the inammatory response [71].
Therefore, the benecial eects of NF-κB are evident in
embryonic stress that activates NF-κB and other diverse
inammatory cytokines which persuades apoptosis within
placenta [72]. Hence, it was concluded that NF-κB plays an
important role in the cell survival by releasing anti-
apoptotic genes. In normal conditions, NF-κB is bound to
inhibitory IκB proteins and remains inactive in the cyto-
plasm. The breakdown of IκB proteins activates NF-B, which
subsequently translocate into the nucleus and generates
desirable genes, whereas IκB proteins are mediated by the
IκB kinase (IKK) complex (IKKαand IKKβ) [73]. Increased
expression of NF-κB in cultured endometrial stromal cells
has been found in reproductive diseases such as endometri-
osis [74]. Altered production of NF-κB production has been
associated with inammation. Endometriosis is a condition
induced by OS which increases the concentration of TNF-
α, resulting in inammation thereby; NF-κB is activated.
Moreover, IL-1βactivates NF-κB, which in turn produces
inammatory cytokines [75], comprising macrophage
migration inhibitory factor (MIF) in endometrial stromal
cells [76] and TNF-αin immortalized epithelial (12Z) cell
line [77]. In summary, OS-mediated reproductive disorders
are caused by NF-κB activation.
FOXO1 and FOXO3 have been contributed to OS and
pregnancy. The FOXO subfamily of Forkhead transcription
factors is a direct downstream target of the PI3K/Akt path-
way [78]. The family of FOXO proteins is involved in dier-
ent biological processes such as proliferation, apoptosis,
autophagy, metabolism, inammation, dierentiation and
stress tolerance [79]. The FOXC1 displays a pivotal role in
reproduction and also mediates cyclic dierentiation and
apoptosis in normal endometrium [80]. Recent studies have
shown that FOXO1 knockdown disrupts the expression of
over 500 genes in decidualized human endometrial stromal
cells [81]. Previous research has shown that FOXO tran-
scription factors can control multiple gene responses to
change hormone levels [82]. Besides, that FOXO1 is also
responsible for the induction of decidual marker genes,
including WNT4, prolactin (PRL) and insulin-like growth
factor-binding protein 1 (IGFBP1) [83].
Three signaling molecules are triggered by the extracel-
lular milieu, including ERK, which is activated by inamma-
tion and growth factors, and JNK and p38 MAPK, which are
mostly activated by stress and inammation [84]. It has been
shown that ERK activation is increased in endometrial tis-
sue, suggesting that ERK may play a role in endometriosis
and phosphorylated ERK is increased in primary eutopic
epithelial cells [85]. ERK activation can also be inuenced
by oxidative stress. In response to normal women, hydrogen
peroxide causes ERK phosphorylation in endometriotic stro-
mal cells [86].
6. Contribution of Oxidative Stress in
Pregnancy Complications
6.1. Intrauterine Growth Restriction. Intrauterine growth
restriction (IUGR) is a pregnancy ailment in which an
underweight/incomplete fetus develops in the uterus [87].
The causes are multifactorial such as maternal, fetal, placen-
tal, infectious, or genetics [88]. About 76% of intrauterine
deaths have been associated with IUGR [89]. The most sig-
nicant cause of IUGR is utero-placental dysfunction occurs
due to the congested maternal utero-placental blood ow
[90]. Proper functioning of the placenta requires greater
energy demand for cell growth, proliferation and metabolic
activity which in turn produce oxidative stress. Oxidative
stress plays an essential role against various stimuli which
inuence placental function [91]. Cellular injury occurs as
a result of lipid peroxidation and fatty acid oxidation, and
Table 1: Positive eect of ROS and antioxidant system in various events of female reproduction and pregnancy outcomes.
Oxidant/antioxidant compounds Functional activity Species References
expression of GSTm2 Preparation of uterus for blastocyst implantation Mouse [130]
GPX and GSR activities Regulator of H
2
0
2
and cell death in placental progression Sheep [131]
Silence the expression of GPX4 Inuencing embryonic brain and heart functions Mouse [132]
hydrogen peroxide and superoxide radical Control uterine contractions Humans [133]
SOD1, GPX and GST activities in early
pregnancy Rescue Corpus luteum form apoptosis Sheep [134]
CAT and GPX and oviduct GSH in estrus
cycle Govern hydrogen peroxide during fertilization Cow [135]
expression of SOD1 in early pregnancy Directions of luteal functions Human [136]
CAT and GPX, and GSH in placenta tissues Regulates hydrogen peroxide and activation of placental
dierentiation Human [137]
CAT, SOD and GPX in placental and fetal
tissues Defense against ROS toxicity in feto-placental system Human [138]
uterine peroxide at blastocyst attachment Defense to negative eects of hydrogen peroxide actions Rat [139]
4 Mediators of Inammation
it is mostly utilised to identify oxidative stress indicators
[92]. Evidence of IUGR in livestock has been raised through
environmental factors and aects goats, sheep, pigs and
other animals. Of note, that signicant evidence of IUGR
exists in multi-fetal animals including pigs. It has been doc-
umented those animals with this condition have reduced
birth weight, postnatal growth, development and liver dys-
function [93]. A detailed description of IUGR occurrences
in clinical and health deviations is well been ascribed in
the previous studies [9496]. More evidence is required to
be revealed the underlying molecular mechanisms.
6.2. Spontaneous Miscarriage and Recurrent Pregnancy Loss.
Spontaneous abortion can be classied as loss of pregnancy
before 20 weeks of gestation. The incidence may range from
8-20% in pregnancies and is due to chromosomal aberration,
which accounts for 50% of all miscarriages. While, the rest
are associated with congenital and uterine malfunctions,
infections, maternal diseases and unknown causes [97].
In early pregnancy losses, elevated levels of MDA and
lipid peroxides were observed in placental tissues in compar-
ison with controls. Previous studies have shown that over-
loading of ROS could lead to the premature and sudden
formation of maternal placental perfusion [2]. Other evi-
dence reported that oxidative stress damage the trophoblast
and ultimately leading to early pregnancy losses. The inci-
dence of oxidative stress occurred due to the depletion of
the antioxidants system and thus unable to scavenge free
radicals [87, 98]. Although there is diversity in previous
studies, it seems to be a relationship between ROS and anti-
oxidants in miscarriage. The abnormal placentation may
arise from syncytiotrophoblasts and may be vulnerable to
idiopathic recurrent pregnancy loss [97]. Oxidative stress
enables the potential to inuence pregnancies due to the
depletion of antioxidant capacity within the body [99]. The
inuence of oxidative stress in pregnancy problems is
depicted in Figure 1. The issue of recurrent pregnancy losses,
research gaps, and their treatment has been thoroughly
reviewed [100, 101].
6.3. Gestational Diabetes Mellitus (GDM). GDM is a type of
diabetes mellitus in which pregnant women develops glucose
intolerance to a dierent degree [102]. It was reported in 2-
5% of pregnancies while; data suggested the incidences
increased up to 18% in all pregnancies [103]. GDM develops
during the second trimester of pregnancy, causing fetal
macrosomia, perinatal mortality, and making mother vul-
nerable for T2DM [102, 104].
The pregnancy has been linked to an imbalance of pro
and anti-inammatory mediators [105]. The levels of T cells
subsets were increased in women with GDM compared to
control healthy subjects whereas; T cells expressing CTLA-
Oxidative
stress
ROS inducers:
mitochondria, immune cells,
inflammation, diabetes,
infections and smoking etc
ROS scavengers:
enzymatic & non-
enzymatic
antioxidants
First trimester Second trimester Third trimester
Early pregnancy loss,
recurrent miscarriage,
preterm birth and
IUGR
IUGR
Preterm birth, IUGR
and still birth
Improver trophoblastic invasion
results in influence spiral arteries
development
(ii)
Presence of oxygenated blood results
in rise of oxygen tension and OS
(i)
Enhanced vascular resistance in
placenta & decreased uteroplacental
perfusion
(iii)
Ischemia perfusion injury.(iv)
Enhanced OS leads to damage
lipids, proteins and DNA
(i)
Induced DNA damage results in
fetal anomalies
(ii)
Triggers advanced aging leads to
placental insufficiency
(iii)
Sudden rise in oxygen tension,
overwhelmed ROS & oxidative stress
(i)
Influence uterine perfusion
(ii)
Continuous accelerated OS leads to
declining antioxidants
(iii)
Depletion of antioxidant as well as
reducing system
(iv)
Figure 1: The Impact of Oxidative Stress on Pregnancy Outcomes.
5Mediators of Inammation
4, a downregulation of the immune system which lightly
expressed in Tregs were suppressed [106]. Changes in the
Treg population suggest that the Treg pool in GDM is
becoming less active [76]. Thus, it suggests that the lack of
immune down-regulation helps maternal-fetal tolerance.
Although, the toll-like receptors TLR-2 and TLR-4 stimulate
inammatory cytokines which were enhanced in peripheral
blood mononuclear cells of women with GDM [107]. Previ-
ous literature revealed the ambiguous results of TNF-αin
GDM condition [79, 82], but more descriptive role of
GDM is well-highlighted somewhere else [108]. An evidence
of oxidative stress-related problems during pregnancy is
well-reviewed by others [12, 109].
7. Antioxidant Approaches in Pregnancy
The detrimental eects of oxidative stress and ROS on
female reproduction system have been well illustrated for
since long [110]. It was suggested that the generation of
ROS is impaired by cytochrome P450 and corpus luteum,
which itself is considered a key source. The initiation of
oocyte maturation and others processes are mostly aected
by dierent levels of ROS and antioxidants [6]. Endometri-
osis and unexplained infertility conditions are also linked
to the OS [111].
Antioxidant supplementation possess positive eects
through a variety of pathways, including direct scavenging
of reactive oxygen species (ROS) and damage repair [112].
The protective eects on fertility consisting enhanced blood
circulation in endometrium, reduced hyperandrogenism,
lowered insulin resistance, and positive impact on prosta-
glandin synthesis and steroidogenesis [112114]. A current
systematic review indicates the positive impact of antioxi-
dants in female fertility [115]. Antioxidants were also
involved in enhancing live birth weight and clinical preg-
nancy rates. Though, the evidence is poor with a slight
increase to high heterogeneity due to the trials on enrolled
women oering various kinds of antioxidants. Antioxidants
have shown various responses when they are taken alone
or in combination exerted a positive eect on pregnancy rate
[116]. Moreover, dietary/injectable source of antioxidants
during periparturient period provide benecial eects on
pregnancy outcome and growth performance of suckling
kids of goats [117, 118].
There is evidence that increased antioxidant levels con-
front and scavenge ROS in women who have repeated abor-
tions as a result of ROS overload. Previous research has
found that women with recurrent abortion have higher
levels of lipoperoxides and lower amounts of vitamin A, E,
and beta carotene, suggesting the role of ROS. When com-
pared to healthy subject, glutathione activity was low in
women who had recurrent abortions [44, 119]. Moreover,
selenium concentration from hair samples was also signi-
cantly reduced in recurrent abortion than the healthy preg-
nancies [120]. Increased glucose levels during pregnancy
cause teratogenic consequences due to chemical changes
and DNA rearrangements. Increased glucose causes the for-
mation of glycation products, which aect genomic function
and negatively regulate embryonic development. In diabetic
pregnancy, changes in membrane lipids induce biological
prostaglandin events, and an enhanced level of ROS causes
dysmorphogenesis in the fetus [121]. A reduced level of lipid
peroxidation in women with GDM was reported due to
depletion of antioxidants activity. Hydroperoxide produc-
tion aects prostaglandin synthesis patterns, which may
result in morbidity owing to antioxidant depletion [122].
GDM also triggers oxidative stress in fetus, thus the intake
of antioxidants during pregnancy is essential factor for
improving pregnancy health [123]. Further, a detailed
description on the role of antioxidants in pregnancy is
well-discussed in the previous studies [2, 44, 124129].
8. Conclusion
Antioxidant defense has been established to regulate the
generation of ROS; however the increased amount of ROS
cannot be controlled, resulting in oxidative stress. So, the
potential strategies of antioxidant to decrease ROS levels
are critical. According to a large number of studies, oxidative
stress is the primary contributing factor in a variety of preg-
nancy complications. Overstimulation of ROS can cause
hyperglycemia, IUGR, miscarriage, and spontaneous abor-
tion throughout all stages of pregnancy. Placental oxidative
stress is caused by a number of variables, including maternal
history, genetics, and environmental factors, and can lead to
negative pregnancy outcomes. Future research should focus
on improving the breakdown of intracellular ROS and
enhancing antioxidant bioavailability. Targeting signaling
molecules with natural bioactive compounds will be used
to minimize the occurrence of reproductive problems.
Conflicts of Interest
All authors have no any conict of interest.
Acknowledgments
This project was funded by the National Natural Science
Foundation of China (32072745, 31960666) and Innovation
Province Project (2019RS3021).
References
[1] D. Pereira, N. E. de Long, R. C. Wang, F. T. Yazdi, A. C. Hol-
loway, and S. Raha, Angiogenesis in the placenta: the role of
reactive oxygen species signaling,BioMed Research Interna-
tional, vol. 2015, Article ID 814543, 12 pages, 2015.
[2] L. Poston, N. Igosheva, H. D. Mistry et al., Role of oxidative
stress and antioxidant supplementation in pregnancy disor-
ders,American Journal of Clinical Nutrition, vol. 94, 6 Suppl,
pp. 1980s1985s, 2011.
[3] M. T. Lin and M. F. Beal, Mitochondrial dysfunction and
oxidative stress in neurodegenerative diseases,Nature,
vol. 443, no. 7113, pp. 787795, 2006.
[4] N. Khansari, Y. Shakiba, and M. Mahmoudi, Chronic
inammation and oxidative stress as a major cause of age-
related diseases and cancer,Recent Patents on Inammation
& Allergy Drug Discovery, vol. 3, no. 1, pp. 7380, 2009.
6 Mediators of Inammation
[5] J. Lu, Z. Wang, J. Cao, Y. Chen, and Y. Dong, A novel and
compact review on the role of oxidative stress in female
reproduction,Reproductive Biology and Endocrinology,
vol. 16, no. 1, pp. 118, 2018.
[6] H. R. Behrman, P. H. Kodaman, S. L. Preston, and S. Gao,
Oxidative stress and the ovary,Journal of the Society of
Gynecologic Investigation, vol. 8, 1_suppl, pp. S40S42, 2001.
[7] L. Sabatini, C. Wilson, A. Lower, T. Al-Shawaf, and J. G.
Grudzinskas, Superoxide dismutase activity in human follic-
ular uid after controlled ovarian hyperstimulation in
women undergoing in vitro fertilization,Fertility and Steril-
ity, vol. 72, no. 6, pp. 10271034, 1999.
[8] M. Jozwik, S. Wolczynski, M. Jozwik, and M. Szamatowicz,
Oxidative stress markers in preovulatory follicular uid in
humans,Molecular Human Reproduction, vol. 5, no. 5,
pp. 409413, 1999.
[9] S. El Mouatassim, P. Guerin, and Y. Menezo, Expression of
genes encoding antioxidant enzymes in human and mouse
oocytes during the nal stages of maturation,Molecular
Human Reproduction, vol. 5, no. 8, pp. 720725, 1999.
[10] P. Guerin, S. El Mouatassim, and Y. Menezo, Oxidative
stress and protection against reactive oxygen species in the
pre-implantation embryo and its surroundings,Human
Reproduction Update, vol. 7, no. 2, pp. 175189, 2001.
[11] M. H. Schoots, S. L. Gordijn, S. A. Scherjon, H. van Goor, and
J. L. Hillebrands, Oxidative stress in placental pathology,
Placenta, vol. 69, pp. 153161, 2018.
[12] A. C. Pereira and F. Martel, Oxidative stress in pregnancy
and fertility pathologies,Cell Biology and Toxicology,
vol. 30, no. 5, pp. 301312, 2014.
[13] S. J. Holdsworth-Carson, R. Lim, A. Mitton et al., Peroxi-
some proliferator-activated receptors are altered in patholo-
gies of the human placenta: gestational diabetes mellitus,
intrauterine growth restriction and preeclampsia,Placenta,
vol. 31, no. 3, pp. 222229, 2010.
[14] L. C. Sánchez-Aranguren, C. E. Prada, C. E. Riaño-
Medina, and M. Lopez, Endothelial dysfunction and pre-
eclampsia: role of oxidative stress,Frontiers in Physiology,
vol. 5, p. 372, 2014.
[15] G. J. Burton, H. W. Yung, T. Cindrova-Davies, and D. S.
Charnock-Jones, Placental endoplasmic reticulum stress
and oxidative stress in the pathophysiology of unexplained
intrauterine growth restriction and early onset preeclamp-
sia,Placenta, vol. 30, Suppl A, pp. 4348, 2009.
[16] L. Myatt, Review: Reactive oxygen and nitrogen species and
functional adaptation of the placenta,Placenta, vol. 31,
pp. S66S69, 2010.
[17] M. Shibata, F. Hakuno, D. Yamanaka et al., Paraquat-
induced Oxidative Stress Represses Phosphatidylinositol 3-
Kinase Activities Leading to Impaired Glucose Uptake in
3T3-L1 Adipocytes,Journal of Biological Chemistry,
vol. 285, no. 27, pp. 2091520925, 2010.
[18] M. G. Tuuli, M. S. Longtine, and D. M. Nelson, Review: Oxy-
gen and trophoblast biology - A source of controversy,Pla-
centa, vol. 32, no. 2, pp. S109S118, 2011.
[19] P. Celi, A. Di Trana, and S. Claps, Eects of plane of
nutrition on oxidative stress in goats during the peripar-
tum period,Veterinary Journal, vol. 184, no. 1, pp. 95
99, 2010.
[20] T. Hussain, B. Tan, Y. Yin, F. Blachier, M. C. Tossou, and
N. Rahu, Oxidative Stress and Inammation: What Poly-
phenols Can Do for Us?,Oxidative Medicine and Cellular
Longevity, vol. 2016, 9 pages, 2016.
[21] T. Hussain, B. Tan, G. Liu et al., Modulatory Mechanism of
Polyphenols and Nrf2 Signaling Pathway in LPS Challenged
Pregnancy Disorders,Oxidative Medicine and Cellular Lon-
gevity, vol. 2017, 14 pages, 2017.
[22] T. Hussain, B. Tan, N. Rahu, D. Hussain Kalhoro, R. Dad,
and Y. Yin, Protective mechanism of Eucommia ulmoids a-
vone (EUF) on enterocyte damage induced by LPS,Free
Radical Biology and Medicine, vol. 108, p. S40, 2017.
[23] D. Yuan, T. Hussain, B. Tan, Y. Liu, P. Ji, and Y. Yin, The
Evaluation of Antioxidant and Anti-Inammatory Eects of
Eucommia ulmoides Flavones Using Diquat-Challenged Pig-
let Models,Oxidative Medicine and Cellular Longevity,
vol. 2017, 9 pages, 2017.
[24] T. Hussain, B. Tan, G. Liu et al., The regulatory mechanism
of Eucommia ulmoides avone eects on damage repair in
enterocytes,Free Radical Biology and Medicine, vol. 120,
pp. S139S140, 2018.
[25] T. Hussain, D. Yuan, B. Tan et al., Eucommia ulmoides a-
vones (EU F) abrogated enterocyte damage induced by LPS
involved in NF-κB signaling pathway,Toxicology In Vitro,
vol. 62, article 104674, 2020.
[26] J. Fujii, Y. Iuchi, and F. Okada, Fundamental roles of reactive
oxygen species and protective mechanisms in the female
reproductive system,Reproductive Biology and Endocrinol-
ogy, vol. 3, no. 1, pp. 110, 2005.
[27] A. Bhattacharyya, R. Chattopadhyay, S. Mitra, and S. E.
Crowe, Oxidative stress: an essential factor in the pathogen-
esis of gastrointestinal mucosal diseases,Physiological
Reviews, vol. 94, no. 2, pp. 329354, 2014.
[28] L. W. Oberley, Mechanism of the tumor suppressive eect of
MnSOD overexpression,Biomedicine & Pharmacotherapy,
vol. 59, no. 4, pp. 143148, 2005.
[29] E. D. Harris, Regulation of antioxidant enzymes1,The
FASEB Journal, vol. 6, no. 9, pp. 26752683, 1992.
[30] J. Spallholz, A. Roveri, L. Yan, L. Boylan, C. Kang, and
F. Ursini, Glutathione peroxidase and phospholipid hydro-
peroxide glutathione peroxidase in tissues of Balb/C mice,
FASEB Journal (Federation of American Societies for Experi-
mental Biology), vol. 5, 1991.
[31] J. Fujii, J.-i. Ito, X. Zhang, and T. Kurahashi, Unveiling the
roles of the glutathione redox system in vivo by analyzing
genetically modied mice,Journal of Clinical Biochemistry
and Nutrition, vol. 49, no. 2, p. 78, 2011.
[32] A. B. Fisher, The phospholipase A
2
activity of peroxiredoxin
6 [S],Journal of Lipid Research, vol. 59, no. 7, pp. 11321147,
2018.
[33] E. B. Kurutas, The importance of antioxidants which play
the role in cellular response against oxidative/nitrosative
stress: current state,Nutrition Journal, vol. 15, no. 1, pp. 1
22, 2015.
[34] A. Agarwal, S. Gupta, and R. K. Sharma, Role of oxidative
stress in female reproduction,Reproductive Biology and
Endocrinology, vol. 3, no. 1, pp. 121, 2005.
[35] Y.-Z. Fang, S. Yang, and G. Wu, Free radicals, antioxidants,
and nutrition,Nutrition, vol. 18, no. 10, pp. 872879, 2002.
[36] D. Ramiro-Cortijo, T. Herrera, P. Rodríguez-Rodríguez et al.,
Maternal plasma antioxidant status in the rst trimester of
pregnancy and development of obstetric complications,Pla-
centa, vol. 47, pp. 3745, 2016.
7Mediators of Inammation
[37] M. Schieber and N. S. Chandel, ROS Function in Redox Sig-
naling and Oxidative Stress,Current Biology, vol. 24, no. 10,
pp. R453R462, 2014.
[38] A. Bąk and K. Roszkowski, Oxidative stress in pregnant
women,Archives of Perinatal Medicine, vol. 19, no. 3,
pp. 155155, 2013.
[39] K. Duhig, L. Chappell, and A. Shennan, Oxidative stress in
pregnancy and reproduction,Obstetric Medicine, vol. 9,
no. 3, pp. 113116, 2016.
[40] Z. Sultana, K. Maiti, J. Aitken, J. Morris, L. Dedman, and
R. Smith, Oxidative stress, placental ageing-related patholo-
gies and adverse pregnancy outcomes,American Journal of
Reproductive Immunology, vol. 77, no. 5, 2017.
[41] V. Toescu, S. L. Nuttall, U. Martin, M. J. Kendall, and
F. Dunne, Oxidative stress and normal pregnancy,Clinical
Endocrinology, vol. 57, no. 5, pp. 609613, 2002.
[42] P. A. Dennery, Oxidative stress in development: Nature or
nurture?,Free Radical Biology and Medicine, vol. 49, no. 7,
pp. 11471151, 2010.
[43] D. Hernández-García, C. D. Wood, S. Castro-Obregón, and
L. Covarrubias, Reactive oxygen species: A radical role in
development?,Free Radical Biology and Medicine, vol. 49,
no. 2, pp. 130143, 2010.
[44] H. D. Mistry and P. J. Williams, The importance of antioxi-
dant micronutrients in pregnancy,Oxidative Medicine and
Cellular Longevity, vol. 2011, 2011.
[45] R. K. Sharma and A. Agarwal, Role of reactive oxygen spe-
cies in gynecologic diseases,Reproductive Medicine and Biol-
ogy, vol. 3, no. 4, pp. 177199, 2004.
[46] M. Ishikawa, Oxygen radicals-superoxide dismutase system
and reproduction medicine,Nippon Sanka Fujinka Gakkai
Zasshi, vol. 45, no. 8, pp. 842848, 1993.
[47] K. Shkolnik, A. Tadmor, S. Ben-Dor, N. Nevo, D. Galiani, and
N. Dekel, Reactive oxygen species are indispensable in ovu-
lation,Proceeding National Academy of Sciences, U S A.,
vol. 108, no. 4, pp. 14621467, 2011.
[48] J. S. Richards, Hormonal control of gene expression in the
ovary,Endocrine Reviews, vol. 15, no. 6, pp. 725751, 1994.
[49] B. du, K. Takahashi, G. M. Ishida, K. Nakahara, H. Saito, and
H. Kurachi, Usefulness of intraovarian artery pulsatility and
resistance indices measurement on the day of follicle aspira-
tion for the assessment of oocyte quality,Fertility and Steril-
ity, vol. 85, no. 2, pp. 366370, 2006.
[50] N. Sugino, Roles of reactive oxygen species in the corpus
luteum,Animal Sciences Journal., vol. 77, no. 6, pp. 556
565, 2006.
[51] A. Rizzo, M. T. Roscino, F. Binetti, and R. L. Sciorsci, Roles
of reactive oxygen species in female reproduction,Reproduc-
tion in Domestic Animals, vol. 47, no. 2, pp. 344352, 2012.
[52] L. Myatt and X. L. Cui, Oxidative stress in the placenta,His-
tochemistry and Cell Biology, vol. 122, no. 4, pp. 369382,
2004.
[53] Y. Wang and S. W. Walsh, Placental mitochondria as a
source of oxidative stress in pre-eclampsia,Placenta,
vol. 19, no. 8, pp. 581586, 1998.
[54] E. Jauniaux, B. Gulbis, and G. J. Burton, The human rst tri-
mester gestational sac limits rather than facilitates oxygen
transfer to the foetusa review,Placenta, vol. 24, Suppl A,
pp. S86S93, 2003.
[55] K. H. Lim, Y. Zhou, M. Janatpour et al., Human cytotropho-
blast dierentiation/invasion is abnormal in pre-eclampsia,
American Journal of Pathology, vol. 151, pp. 18091818,
1997.
[56] S. Preutthipan, S. H. Chen, J. L. Tilly, K. Kugu, R. R. Lareu,
and A. M. Dharmarajan, Inhibition of nitric oxide synthesis
potentiates apoptosis in the rabbit corpus luteum,Reproduc-
tive Biomedicine Online, vol. 9, no. 3, pp. 264270, 2004.
[57] P. Ghafourifar and C. Richter, Nitric oxide synthase activity
in mitochondria,Federation of European Biochemical Socie-
ties Letters, vol. 418, no. 3, pp. 291296, 1997.
[58] R. Menon, S. J. Fortunato, J. Yu et al., Cigarette smoke
induces oxidative stress and apoptosis in normal term fetal
membranes,Placenta, vol. 32, no. 4, pp. 317322, 2011.
[59] R. Smith, K. Maiti, and R. J. Aitken, Unexplained antepar-
tum stillbirth: a consequence of placental aging?,Placenta,
vol. 34, no. 4, pp. 310313, 2013.
[60] Y. Oner-Iyidogan, H. Kocak, F. Gurdol, D. Korkmaz, and
F. Buyru, Indices of oxidative stress in eutopic and ectopic
endometria of women with endometriosis,Gynecologic and
Obstetric Investigation, vol. 57, no. 4, pp. 214217, 2004.
[61] L. O. Perucci, M. D. Corrêa, L. M. Dusse, K. B. Gomes, and
L. P. Sousa, Resolution of inammation pathways in pree-
clampsiaa narrative review,Immunologic Research,
vol. 65, no. 4, pp. 774789, 2017.
[62] F. Wu, F.-J. Tian, and Y. Lin, Oxidative Stress in Placenta:
Health and Diseases,BioMed Research International,
vol. 2015, 15 pages, 2015.
[63] K. Itoh, T. Chiba, S. Takahashi et al., An Nrf2/Small Maf
Heterodimer Mediates the Induction of Phase II Detoxifying
Enzyme Genes through Antioxidant Response Elements,
Biochemical and Biophysical Research Communications,
vol. 236, no. 2, pp. 313322, 1997.
[64] K. Itoh, N. Wakabayashi, Y. Katoh et al., Keap1 represses
nuclear activation of antioxidant responsive elements by
Nrf2 through binding to the amino-terminal Neh2 domain,
Genes & Development, vol. 13, no. 1, pp. 7686, 1999.
[65] H.-Y. Cho, S. P. Reddy, A. DeBiase, M. Yamamoto, and S. R.
Kleeberger, Gene expression proling of NRF2-mediated
protection against oxidative injury,Free Radical Biology
and Medicine, vol. 38, no. 3, pp. 325343, 2005.
[66] T. Ishii, K. Itoh, S. Takahashi et al., Transcription Factor
Nrf2 Coordinately Regulates a Group of Oxidative Stress-
inducible Genes in Macrophages,Journal of Biological
Chemistry, vol. 275, no. 21, pp. 1602316029, 2000.
[67] X. Cheng, S. J. Chapple, B. Patel et al., Gestational diabetes
mellitus impairs Nrf2-mediated adaptive antioxidant
defenses and redox signaling in fetal endothelial cells in
utero,Diabetes, vol. 62, no. 12, pp. 40884097, 2013.
[68] R. Lim, G. Barker, and M. Lappas, The transcription factor
Nrf2 is decreased after spontaneous term labour in human
fetal membranes where it exerts anti-inammatory proper-
ties,Placenta, vol. 36, no. 1, pp. 717, 2015.
[69] L. Guan, L. Zhang, Z. Gong et al., FoxO3 inactivation pro-
motes human cholangiocarcinoma tumorigenesis and che-
moresistance through Keap1-Nrf2 signaling,Hepatology,
vol. 63, no. 6, pp. 19141927, 2016.
[70] T. Gilmore, Introduction to NF-κB: players, pathways, per-
spectives,Oncogene, vol. 25, no. 51, pp. 66806684, 2006.
[71] M. Hayden, A. West, and S. Ghosh, NF-κB and the immune
response,Oncogene, vol. 25, no. 51, pp. 67586780, 2006.
[72] T. Cindrova-Davies, H.-W. Yung, J. Johns et al., Oxidative
Stress, Gene Expression, and Protein Changes Induced in
8 Mediators of Inammation
the Human Placenta during Labor,The American Journal of
Pathology, vol. 171, no. 4, pp. 11681179, 2007.
[73] C. Scheidereit, IκB kinase complexes: gateways to NF-κB
activation and transcription,Oncogene, vol. 25, no. 51,
pp. 66856705, 2006.
[74] Y. Sakamoto, T. Harada, S. Horie et al., Tumor necrosis fac-
tor-α-induced interleukin-8 (IL-8) expression in endometrio-
tic stromal cells, probably through nuclear factor-κB
activation: gonadotropin-releasing hormone agonist treat-
ment reduced IL-8 expression,The Journal of Clinical Endo-
crinology & Metabolism, vol. 88, no. 2, pp. 730735, 2003.
[75] V. Veillat, C. Herrmann Lavoie, C. N. Metz, T. Roger,
Y. Labelle, and A. Akoum, Involvement of nuclear factor-
κB in macrophage migration inhibitory factor gene transcrip-
tion up-regulation induced by interleukin-1βin ectopic
endometrial cells,Fertility and Sterility, vol. 91, no. 5,
pp. 21482156, 2009.
[76] W. Cao, M. Morin, V. Sengers et al., Tumour necrosis fac-
tor-αup-regulates macrophage migration inhibitory factor
expression in endometrial stromal cells via the nuclear tran-
scription factor NF-κB,Human Reproduction, vol. 21,
no. 2, pp. 421428, 2006.
[77] E. M. Grund, D. Kagan, C. A. Tran et al., Tumor necrosis
factor-αregulates inammatory and mesenchymal responses
via mitogen-activated protein kinase kinase, p38, and nuclear
factor κB in human endometriotic epithelial cells,Molecular
Pharmacology, vol. 73, no. 5, pp. 13941404, 2008.
[78] A. Brunet, A. Bonni, M. J. Zigmond et al., Akt promotes cell
survival by phosphorylating and inhibiting a Forkhead tran-
scription factor,Cell, vol. 96, no. 6, pp. 857868, 1999.
[79] K. E. van der Vos and P. J. Coer, The extending network of
FOXO transcriptional target genes,Antioxidants &Redox
Signaling, vol. 14, no. 4, pp. 579592, 2011.
[80] T. Goto, M. Takano, A. Albergaria et al., Mechanism and
functional consequences of loss of FOXO1 expression in
endometrioid endometrial cancer cells,Oncogene, vol. 27,
no. 1, pp. 919, 2008.
[81] T. Kajihara, J. J. Brosens, and O. Ishihara, The role of
FOXO1 in the decidual transformation of the endometrium
and early pregnancy,Medical Molecular Morphology,
vol. 46, no. 2, pp. 6168, 2013.
[82] T. Kajihara, M. Jones, L. Fusi et al., Dierential expression of
FOXO1 and FOXO3a confers resistance to oxidative cell
death upon endometrial decidualization,Molecular Endocri-
nology, vol. 20, no. 10, pp. 24442455, 2006.
[83] B. Gellersen and J. Brosens, Cyclic AMP and progesterone
receptor cross-talk in human endometrium: a decidualizing
aair,The Journal of Endocrinology, vol. 178, no. 3,
pp. 357372, 2003.
[84] A. S. Dhillon, S. Hagan, O. Rath, and W. Kolch, MAP kinase
signalling pathways in cancer,Oncogene, vol. 26, no. 22,
pp. 32793290, 2007.
[85] S. Matsuzaki and C. Darcha, Co-operation between the AKT
and ERK signaling pathways may support growth of deep
endometriosis in a brotic microenvironment in vitro,
Human Reproduction, vol. 30, no. 7, pp. 16061616, 2015.
[86] S. S. Andrade, A. D. C. Azevedo, I. C. Monasterio et al., 17 β
-Estradiol and steady-state concentrations of H
2
O
2
: antia-
poptotic eect in endometrial cells from patients with endo-
metriosis,Free Radical Biology and Medicine, vol. 60,
pp. 6372, 2013.
[87] G. J. Burton and E. Jauniaux, Oxidative stress,Best Practice
& Research Clinical Obstetrics & Gynaecology, vol. 25, no. 3,
pp. 287299, 2011.
[88] D. Sharma, S. Shastri, and P. Sharma, Intrauterine growth
restriction: antenatal and postnatal aspects,Clinical Medi-
cine Insights: Pediatrics, vol. 10, article CMPed.S40070,
2016.
[89] J. F. Frøen, J. O. Gardosi, A. Thurmann, A. Francis, and
B. Stray-Pedersen, Restricted fetal growth in sudden intra-
uterine unexplained death,Acta Obstetricia et Gynecologica
Scandinavica, vol. 83, no. 9, pp. 801807, 2004.
[90] U. Krishna and S. Bhalerao, Placental insuciency and fetal
growth restriction,The Journal of Obstetrics and Gynecology
of India, vol. 61, no. 5, pp. 505511, 2011.
[91] T.-H. Hung, J. N. Skepper, D. S. Charnock-Jones, and G. J.
Burton, Hypoxia-Reoxygenation,Circulation Research,
vol. 90, no. 12, pp. 12741281, 2002.
[92] A. Biri, N. Bozkurt, A. Turp, M. Kavutcu, Ö. Himmetoglu,
and I. Durak, Role of oxidative stress in intrauterine growth
restriction,Gynecologic and Obstetric Investigation, vol. 64,
no. 4, pp. 187192, 2007.
[93] J. Wang, L. Chen, D. Li et al., Intrauterine growth restriction
aects the proteomes of the small intestine, liver, and skeletal
muscle in newborn pigs,The Journal of Nutrition, vol. 138,
no. 1, pp. 6066, 2008.
[94] J. Armengaud, C. Yzydorczyk, B. Siddeek, A. Peyter, and
U. Simeoni, Intrauterine growth restriction: Clinical conse-
quences on health and disease at adulthood,Reproductive
Toxicology, vol. 99, pp. 168176, 2021.
[95] C. S. Rashid, A. Bansal, and R. A. Simmons, Oxidative stress,
intrauterine growth restriction, and developmental program-
ming of type 2 diabetes,Physiology, vol. 33, no. 5, pp. 348
359, 2018.
[96] C. Garcia-Contreras, M. Vazquez-Gomez, Z. Pardo et al.,
Polyphenols and IUGR pregnancies: eects of maternal
hydroxytyrosol supplementation on hepatic fat accretion
and energy and fatty acids prole of fetal tissues,Nutrients,
vol. 11, no. 7, p. 1534, 2019.
[97] A. Agarwal, A. Aponte-Mellado, B. J. Premkumar,
A. Shaman, and S. Gupta, he eects of oxidative stress on
female reproduction: a review,Reproductive Biology and
Endocrinology, vol. 10, pp. 131, 2012.
[98] E. Jauniaux, B. Gulbis, and G. J. Burton, Physiological impli-
cations of the materno-fetal oxygen gradient in human early
pregnancy,Reproductive Biomedicine Online, vol. 7, no. 2,
pp. 250253, 2003.
[99] D. Benjamin, R. K. Sharma, A. Moazzam, and A. Agarwal,
Methods for the detection of ROS in human sperm sam-
ples,in Studies on men's health and fertility, pp. 257273,
Springer, 2012.
[100] H. El Hachem, V. Crepaux, P. May-Panloup, P. Descamps,
G. Legendre, and P. E. Bouet, Recurrent pregnancy loss: cur-
rent perspectives,International Journal of Women's Health,
vol. Volume 9, pp. 331345, 2017.
[101] H. A. Homer, Modern management of recurrent miscar-
riage,Australian and New Zealand Journal of Obstetrics
and Gynaecology, vol. 59, no. 1, pp. 3644, 2019.
[102] M. Coughlan, P. Vervaart, M. Permezel, H. Georgiou, and
G. Rice, Altered placental oxidative stress status in gesta-
tional diabetes mellitus,Placenta, vol. 25, no. 1, pp. 7884,
2004.
9Mediators of Inammation
[103] D. A. Sacks, D. R. Hadden, M. Maresh et al., Frequency of
gestational diabetes mellitus at collaborating centers based
on IADPSG consensus panelrecommended criteria: the
hyperglycemia and adverse pregnancy outcome (HAPO)
study,Diabetes Care, vol. 35, no. 3, pp. 526528, 2012.
[104] M. Gauster, G. Desoye, M. Tötsch, and U. Hiden, The pla-
centa and gestational diabetes mellitus,Current Diabetes
Reports, vol. 12, no. 1, pp. 1623, 2012.
[105] T. Lekva, E. R. Norwitz, P. Aukrust, and T. Ueland, Impact
of systemic inammation on the progression of gestational
diabetes mellitus,Current Diabetes Reports, vol. 16, no. 4,
p. 26, 2016.
[106] K. P. T. Pendeloski, R. Mattar, M. R. Torloni, C. P. Gomes,
S. M. Alexandre, and S. Daher, Immunoregulatory mole-
cules in patients with gestational diabetes mellitus,Endo-
crine, vol. 50, no. 1, pp. 99109, 2015.
[107] B. G. Xie, S. Jin, and W. J. Zhu, Expression of toll-like recep-
tor 4 in maternal monocytes of patients with gestational dia-
betes mellitus,Experimental and Therapeutic Medicine,
vol. 7, no. 1, pp. 236240, 2014.
[108] T. K. Robakis, L. Aasly, K. E. Williams, C. Clark, and N. L.
Rasgon, Roles of inammation and depression in the devel-
opment of gestational diabetes,Current Behavioral Neuro-
science Reports, vol. 4, no. 4, pp. 369383, 2017.
[109] M. Lappas, U. Hiden, G. Desoye, J. Froehlich, S. H. D. Mou-
zon, and A. Jawerbaum, The role of oxidative stress in the
pathophysiology of gestational diabetes mellitus,Antioxi-
dants & Redox Signaling, vol. 15, no. 12, pp. 30613100, 2011.
[110] E. H. Ruder, T. J. Hartman, J. Blumberg, and M. B. Goldman,
Oxidative stress and antioxidants: exposure and impact on
female fertility,Human Reproduction Update, vol. 14,
no. 4, pp. 345357, 2008.
[111] A. Agarwal, A. Aponte-Mellado, B. J. Premkumar,
A. Shaman, and S. Gupta, The eects of oxidative stress on
female reproduction: a review,Reproductive Biology and
Endocrinology, vol. 10, no. 1, p. 49, 2012.
[112] I. Mironczuk-Chodakowska, A. M. Witkowska, and M. E.
Zujko, Endogenous non-enzymatic antioxidants in the
human body,Advances in Medical Sciences, vol. 63, no. 1,
pp. 6878, 2018.
[113] N. Ledee-Bataille, F. Olivennes, J. L. Lefaix, G. Chaouat,
R. Frydman, and S. Delanian, Combined treatment by
pentoxifylline and tocopherol for recipient women with a
thin endometrium enrolled in an oocyte donation pro-
gramme,Human Reproduction, vol. 17, no. 5, pp. 1249
1253, 2002.
[114] R. L. Thomson, S. Spedding, and J. D. Buckley, Vitamin D in
the aetiology and management of polycystic ovary syn-
drome,Clinical Endocrinology, vol. 77, no. 3, pp. 343350,
2012.
[115] M. G. Showell, R. Mackenzie-Proctor, V. Jordan, and R. J.
Hart, Antioxidants for female subfertility,Cochrane Data-
base of Systems Review, vol. 7, article CD007807, 2017.
[116] R. M. Smits, R. Mackenzie-Proctor, K. Fleischer, and M. G.
Showell, Antioxidants in fertility: impact on male and
female reproductive outcomes,Fertility and Sterility,
vol. 110, no. 4, pp. 578580, 2018.
[117] N. Mahmood, A. Hameed, and T. Hussain, Vitamin E and
Selenium Treatment Alleviates Saline Environment-Induced
Oxidative Stress through Enhanced Antioxidants and
Growth Performance in Suckling Kids of Beetal Goats,Oxi-
dative Medicine and Cellular Longevity, vol. 2020, 16 pages,
2020.
[118] A. Afzal, T. Hussain, and A. Hameed, Moringa oleifera sup-
plementation improves antioxidant status and biochemical
indices by attenuating early pregnancy stress in Beetal goats,
Frontiers in Nutrition, vol. 8, p. 444, 2021.
[119] J. Abdul-Barry, S. A. Al-Rubai, and Q. A. Qasim, Study of
Oxidant-Antioxidant status in recurrent spontaneous abor-
tion,TQMJ, vol. 5, pp. 3546, 2011.
[120] A. S. al-Kunani, R. Knight, S. J. Haswell, J. W. Thompson, and
S. W. Lindow, The selenium status of women with a history
of recurrent miscarriage,British Journal of Obstetrics and
Gynaecology, vol. 108, no. 10, pp. 10941097, 2001.
[121] E. A. Reece, Maternal Fuels, Diabetic Embryopathy: Patho-
mechanisms and Prevention,Seminars in Reproductive
Medicine, vol. 17, no. 2, pp. 183194, 1999.
[122] E. Malvy, R. Thiébaut, C. Marimoutou, F. Dabis, and the
Groupe dEpidémiologie Clinique du Sida en Aquitaine,
““Weight loss and body mass index as predictors of HIV dis-
ease progression to AIDS in adults, Aquitaine cohort,
France, 1985-1997,Journal of American College Nutrition,
vol. 20, no. 6, pp. 609615, 2001.
[123] A. M. Maged, H. Torky, M. A. Fouad et al., Role of antioxi-
dants in gestational diabetes mellitus and relation to fetal out-
come: a randomized controlled trial,Journal of Maternal-
Fetal & Neonatal Medicine, vol. 29, no. 24, pp. 40494054,
2016.
[124] B. Nath and H. Roy, Antioxidants in Female Reproductive
Biology,in Antioxidants-Benets, Sources, Mechanisms of
Action, IntechOpen, 2021.
[125] V. H. Parraguez, F. Sales, O. A. Peralta et al., Maternal Sup-
plementation with Herbal Antioxidants during Pregnancy in
Swine,Antioxidants, vol. 10, no. 5, p. 658, 2021.
[126] A. Taravati and F. Tohidi, Comprehensive analysis of oxida-
tive stress markers and antioxidants status in preeclampsia,
Taiwanese Journal of Obstetrics and Gynecology, vol. 57,
no. 6, pp. 779790, 2018.
[127] E. S. Idogun, M. E. Odiegwu, S. M. Momoh, and F. E. Okono-
fua, Eect of pregnancy on total antioxidant capacity in
Nigerian women,Pakistan Journal of Medical Sciences,
vol. 24, no. 2, p. 292, 2008.
[128] C. Ly, J. Yockell-Lelièvre, Z. M. Ferraro, J. T. Arnason,
J. Ferrier, and A. Gruslin, The eects of dietary polyphenols
on reproductive health and early development,Human
Reproduction Update, vol. 21, no. 2, pp. 228248, 2015.
[129] K. H. Al-Gubory, P. A. Fowler, and C. Garrel, The roles of
cellular reactive oxygen species, oxidative stress and antioxi-
dants in pregnancy outcomes,The International Journal of
Biochemistry & Cell Biology, vol. 42, no. 10, pp. 16341650,
2010.
[130] H. Ni, X. J. Yu, H. J. Liu et al., Progesterone regulation of glu-
tathione S-transferase Mu2 expression in mouse uterine
luminal epithelium during preimplantation period,Fertility
and Sterility, vol. 91, no. 5, pp. 21232130, 2009.
[131] C. Garrel, P. A. Fowler, and K. H. Al-Gubory, Developmen-
tal changes in antioxidant enzymatic defences against oxida-
tive stress in sheep placentomes,Journal of Endocrinology,
vol. 205, pp. 107116, 2010.
[132] A. Borchert, C. C. Wang, C. Ufer, H. Schiebel, N. E. Savaskan,
and H. Kuhn, The Role of Phospholipid Hydroperoxide
Glutathione Peroxidase Isoforms in Murine
10 Mediators of Inammation
Embryogenesis,Journal of Biological Chemisry, vol. 281,
no. 28, pp. 1965519664, 2006.
[133] A. Y. Warren, B. Matharoo-Ball, R. W. Shaw, and R. N. Khan,
Hydrogen peroxide and superoxide anion modulate preg-
nant human myometrial contractility,Reproduction,
vol. 130, no. 4, pp. 539544, 2005.
[134] K.̈
. H. al-Gubory, P. Bolifraud, G. Germain, A. Nicole, and
I.̀
. Ceballos-Bicot, Antioxidant enzymatic defence systems
in sheep corpus luteum throughout pregnancy,Reproduc-
tion, vol. 128, no. 6, pp. 767774, 2004.
[135] J. Lapointe and J. F. Bilodeau, Antioxidant defenses are
modulated in the cow oviduct during the estrous cycle,Biol-
ogy of Reproduction, vol. 68, no. 4, pp. 11571164, 2003.
[136] N. Sugino, S. Takiguchi, S. Kashida, A. Karube, Y. Nakamura,
and H. Kato, Superoxide dismutase expression in the human
corpus luteum during the menstrual cycle and in early preg-
nancy,Molecular Human Reproduction, vol. 6, no. 1,
pp. 1925, 2000.
[137] E. Jauniaux, A. L. Watson, J. Hempstock, Y. P. Bao, J. N.
Skepper, and G. J. Burton, Onset of Maternal Arterial Blood
Flow and Placental Oxidative Stress: A Possible Factor in
Human Early Pregnancy Failure,American Journal of
Pathology, vol. 157, no. 6, pp. 21112122, 2000.
[138] S. Qanungo and M. Mukherjea, Ontogenic prole of some
antioxidants and lipid peroxidation in human placental and
fetal tissues,Molecular and Cellular Biochemistry, vol. 215,
no. 1/2, pp. 1119, 2000.
[139] L. A. Baiza-Gutman, M. M. Flores-Sánchez, M. Díaz-Flores,
and J. J. Hicks, Presence of uterine peroxidase activity in
the rat early pregnancy,International Journal of Biochemis-
try & Cellular Biology, vol. 32, no. 2, pp. 255262, 2000.
11Mediators of Inammation
... Pregnancy is inherently a metabolically demanding condition, as the growth and maintenance of placental and fetal tissues require significant energy, resulting in a high metabolic rate with the corresponding production of reactive oxygen species (ROS) (Hussain et al., 2021). The maintenance of an adequate amount of ROS during pregnancy is crucial, as several obstetrical complications, including pre-eclampsia and premature birth, are associated with increased oxidative stress, leading to severe implications for the newborn (Couroucli, 2018;Zhang et al., 2024b). ...
... However, since ROS are unstable molecules with a short half-life, they are unlikely to be directly transferred from the mother to the fetus. More likely, an increase in ROS levels may affect the normal functioning of the maternal-fetal interface, impairing nutrient and oxygen transfer, and ultimately triggering significant downstream alterations with a major impact on the fetal brain (Buss, 2021;Hussain et al., 2021). Maintaining oxidative balance is crucial for fetal brain maturation since ROS are involved in neurodevelopmental processes including neuronal proliferation and migration, synaptogenesis and glial survival (Londono Tobon et al., 2016). ...
... However, there have been contradictory findings regarding the role of OS in complicated pregnancies. Decreased antioxidant capacity has been associated with gestational diabetes, premature birth and IUGR [5,6] whereas preeclampsia was associated with higher plasma total antioxidant capacity [7]. In terms of normal pregnancies, the relationship of OS biomarkers with in-utero fetal growth and ultrasound measurements has received limited attention with contrasting findings. ...
Article
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Background: Associations of antioxidants in prenatal over-the-counter multivitamin-mineral (OTC MVM) supplements with in-utero oxidative stress (OS), antioxidant capacity, and fetal growth are limited. Our objectives were to determine if five fetal ultrasound measurements [biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC), femur length (FL), and estimated fetal weight] were associated with OTC MVM supplements and with minerals, biomarkers of OS, and total antioxidant capacity in amniotic fluid (AF). Methods: For this retrospective study, 176 pregnant women who had undergone age-related amniocentesis for genetic testing were included. Questionnaires recorded prenatal OTC MVM supplementation (yes, no). Ultrasound measurements for early (16–20 weeks) and late (32–36 weeks) gestation were extracted from medical charts. AF concentrations for 15 minerals and trace elements and OS biomarkers in AF [nitric oxide (NO), thiobarbituric acid-reactive substances (TBARS), and ferric-reducing antioxidant power (FRAP)] were measured at 12–20 weeks of gestation. Associations of AF minerals, OS biomarkers, and ultrasound measures were analyzed using multiple linear regressions. Results: Positive associations were observed between AF TBARS and seven AF minerals/elements (calcium, copper, magnesium, nickel, strontium, zinc and iron). At 16–20 weeks, AF copper, nickel, strontium, and selenium were positively associated with BPD, HC, AC, and FL, respectively, NO was positively associated with FL, and FRAP was inversely associated with estimated weight. At 32–36 weeks, calcium was positively associated with BPD and chromium and arsenic were negatively with HC. At 16–20 weeks, higher AF FRAP was inversely associated with FL and this exposure continued to be inversely associated with estimated weight at 32–36 weeks. Conclusions: Concentrations of AF minerals, trace elements and biomarkers of OS and in-utero antioxidant capacity were linked to specific ultrasound measurements at different stages of gestation, suggesting a complex interplay among in utero OS, antioxidant capacity, OTC MVM supplements, and fetal growth.
... For example, bioactive components derived from herbs, such as menthol from peppermint and chlorogenic acid from various plant extracts, exhibit antimicrobial, antifungal, and antioxidant properties. These additions have been demonstrated to improve protein synthesis and enhance albumen quality in eggs, particularly through increasing the ovomucin content, which is critical for the functional properties of the thick albumen [105]. ...
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This study explores the nutritional benefits and health implications of omega-3- and omega-6-enriched eggs, positioning them within the context of functional foods aimed at improving public health outcomes. With rising consumer interest in nutritionally fortified foods, omega-enriched eggs have emerged as a viable source of essential fatty acids, offering potential benefits for cardiovascular health, inflammation reduction, and cognitive function. This research examines enrichment techniques, particularly dietary modifications for laying hens, such as the inclusion of flaxseed and algae, to enhance omega-3 content and balance the omega-6-to-omega-3 ratio in eggs. The findings indicate that enriched eggs provide significantly higher levels of essential fatty acids and bioactive compounds than conventional eggs, aligning with dietary needs in populations with limited access to traditional omega-3 sources like fish. This study further addresses consumer perception challenges, regulatory constraints, and environmental considerations related to sustainable production practices. The conclusions underscore the value of omega-enriched eggs as a functional food that aligns with health-conscious dietary trends and recommend ongoing research to refine enrichment methods and expand market accessibility.
... According to the literature, one of the factors of immune disorders during pregnancy can be oxidative stress, the destructive effect of which is an important factor in the development of inflammatory and autoimmune processes in the body, which is associated with disorders in the hemostasis system [16,41]. Recently, many publications have appeared indicating the pathogenetic influence of changes in the hemostasis system, namely hypercoagulation, on the occurrence of a missed pregnancy in the II and III trimesters of pregnancy and directly or indirectly related to a violation of the implantation process [13,40]. ...
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Reproductive losses remain an urgent problem among the female population, of which antenatal fetal death (AFD) takes a leading place. The pathogenesis of this pathology is multifactorial, but at the same time, it is impossible to accurately determine the single cause of AFD.Analyzing the frequency of AFD in the world, a tendency towards repeated episodes of AFD or AFD combined with reproductive losses in early pregnancy has been established. The literature has presented data on causal relationships with existing endometrial pathology, among which the inflammatory process in the endometrium takes the leading position, and pregnancy losses with inadequate immune system response.The objective: to determine the state of the immune system, infectious profile and features of the immunohistochemical state of the endometrium in women with a history of AFD at the stage of prepregnancy preparation.Materials and methods. A clinical examination was performed on 30 patients with a history of AFD who had applied to the antenatal clinic of the municipal non-profit enterprise “Kyiv City Maternity Hospital No. 3” regarding planning their next pregnancy. A general clinical examination, a detailed analysis of the general, gynecological anamnesis, and data on the course of the previous pregnancy and childbirth were performed.All patients underwent microscopic examination of vaginal discharge stained with Gram and assessed according to the Hay–Ison criteria. The state of the endometrium was studied by microscopic examination and immunohistochemical analysis with the determination of CD-138 and CD-56. The state of the immune system was assessed by determining the activity of the cellular component (T- and B-lymphocytes) and cytokine proteins (IL-1α, IL-6, IL-8, γ-INT, TNF-α).Results. According to the somatic anamnesis, a high percentage of morbidity of the urinary system of an infectious-inflammatory nature (53.3%) and pathology of the cardiovascular system (63.3%) was determined. Among gynecological pathology inflammatory diseases of the genital tract (53.3%) and uterine leiomyoma (33.3%) predominated. In the obstetric anamnesis the spontaneous miscarriage was detected in almost every second woman (46.7%) and in every seventh woman – AFD (13.3%).During microscopic examination of vaginal discharge, the majority of women were diagnosed with stage III and IV according to the Hay–Ison criteria. During microscopic examination of the endometrium, disorders of its proliferation was detected in 2/3 of the patients, and during immunohistochemical examination – a positive reaction of CD-138 and an increased concentration of CD-56. During the study of the state of the immune system a decreased level of T-suppressors, B-lymphocytes were observed, with increased in T-killers and pro-inflammatory cytokines.Conclusions. Women with a history of antenatal fetal death have certain features of the regulatory mechanisms of the immune system both at the local and generalized levels, which prompts a detailed study and diagnosis at the pre-gravid stage when determining further reproductive plans. Research of extragenital pathology, infectious profile and the state of local immunity in the uterine cavity is especially necessary.
... We also found that the frequency of the wild type MTHFR gene in preeclampsia is higher than the MTHFR gene polymorphism. Thus, the condition of polymorphisms occuring in preeclampsia patients may not be the leading risk factor for the disturbance of the balance of oxidants in the blood, which may cause one of the pathophysiology of preeclampsia (Hussain et al., 2021). ...
Article
Some of the rural areas in Central Java still have the highest maternal mortality rate. Preeclampsia is the leading cause of maternal death in Indonesia. One of the factors contributing to the oxidative stress associated with preeclampsia is lead exposure. Various studies have clearly shown that superoxide dismutase deficiency (SOD) and increased homocysteine (Hcy) levels are consistently associated with the incidence of preeclampsia. Several studies also show the role of MTHFR A1298C and C677T gene polymorphisms in the occurrence of preeclampsia. This study investigated the association between lead exposure, blood SOD and Hcy levels, and MTHFR A1298C and C677T gene polymorphisms in Preeclampsia. This analytical observational case-control study was conducted in 70 cases of preeclampsia and 70 controls. Blood SOD and Hcy levels were measured using Enzyme Linked Immunosorbent Assay (ELISA). Lead level was determined by atomic absorption spectrometry (AAS). MTHFR A1298C and C677T gene polymorphism was genotyped using polymerase chain reaction-restriction fragmentlLength polymorphism (PCR-RFLP). The data obtained were analyzed using the Mann-Whitney U test, chi-square test, independent samples T-test and multivariate linear regression analysis. There was a significant difference (p=0.001) between the lead level in preeclampsia group (mean: 44.50±10.72) compared to the control (mean: 32.78±14.40). The homocysteine level in the preeclampsia cases (mean: 9.06±4.03) also differed significantly (p=0.004) from that of the control group (mean: 7.18±3.09). Increased levels of blood lead and homocystein levels are associated with the incidence of preeclampsia. We found no significant difference in SOD levels, MTHFR A1298C and C677T gene polymorphism between preeclampsia and control group.
... The paradox of cell metabolism has a detrimental impact on live cells via the release of reactive oxygen species [1]. When body cells use oxygen to sustain themselves for food processing or environmental reactions, poisons known as free radicals containing unpaired electrons are created. ...
... A high level of oxidative stress promotes the appearance of disorders in reproduction in women and consequently triggers gynecological diseases that can end in infertility [215]. The action of antioxidants that block oxidizing species is crucial for maintaining an adequate level of oxidative stress, which is essential in the metabolism of oocytes, the maturation of the endometrium by the activation of antioxidant signaling pathways and the hormonal regulation of vascular action [216]. Their function as the cofactors of key enzymes in differentiation and cell development or of antioxidant enzymes is another way in which antioxidants work in the body. ...
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Background/Aim: Subfertility is characterized by a decrease in reproductive efficiency, which can result in delayed pregnancy, and affects one in six individuals during their lifetime. The present narrative review aims to evaluate the contribution of precision nutrition to changes in fertility in subfertile couples. Methods: The literature review was carried out through bibliographic research in the PubMed, Scopus, SciELO and Google Scholar databases. The following search criteria were applied: (1) original articles and narrative, systematic or meta-analytic reviews, and (2) the individual or combined use of the following keywords: “genetic variation”, “nutrigenetics”, “precision nutrition”, “couple’s subfertility”, and “couple’s infertility”. A preliminary reading of all the articles was carried out, and only those that best fit the themes and subthemes of the narrative review were selected. Results: Scientific evidence suggests that adherence to a healthy diet that follows the Mediterranean pattern is associated with increased fertility in women and improved semen quality in men, better metabolic health and reduced levels of inflammation and oxidative stress, as well as maintaining a healthy body weight. The integration of different tools, such as nutrigenetics, predictive biochemical analyses, intestinal microbiota tests and clinical nutrition software, used in precision nutrition interventions can contribute to providing information on how diet and genetics interact and how they can influence fertility. Conclusions: The adoption of a multidisciplinary and precision approach allows the design of dietary and lifestyle recommendations adapted to the specific characteristics and needs of couples with subfertility, thus optimizing reproductive health outcomes and achieving successful conception.
... the current study highlights a positive trend in preventing pregnancy gingivitis via periodontal treatment, even though the overall effect may not be statistically significant after accounting for potential publication bias. Furthermore, reducing oxidative stress and improving oral hygiene status may not only mitigate systemic inflammation but also enhance the overall quality of life for periodontitis and gingivitis patients, particularly in pregnant women, by reducing the risks of adverse pregnancy outcomes [58][59][60][61]. Although this study did not explore the specific biological mechanisms in detail, existing theories and research suggest that periodontal treatment may reduce oral and systemic inflammation, a known contributor to pregnancy complications. ...
Article
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Background Pregnancy gingivitis is a common oral health issue that affects both maternal and fetal health. This study aims to evaluate the effectiveness of periodontal treatment in preventing pregnancy gingivitis, preterm birth, and low birth weight through a systematic review and meta-analysis of randomized controlled trials (RCTs). Methods A systematic review and meta-analysis were conducted following PRISMA guidelines. A comprehensive literature search was performed across CINAHL, Scopus, Cochrane, and PubMed/Medline databases from 2000 to the present. Study selection and data extraction were independently carried out by two reviewers. Statistical analyses, including heterogeneity tests, sensitivity analysis, and publication bias assessment, were conducted using RevMan 5.4 and R software. Results A total of 13 studies were included. The meta-analysis indicated that periodontal treatment might have a potential effect on preventing pregnancy gingivitis, but this was not statistically significant (OR = 0.85, 95% CI [0.68, 1.06], I² = 51%). Subgroup analysis revealed that periodontal treatment significantly reduced the rates of preterm birth and low birth weight in lower-quality studies, but no significant effects were observed in higher-quality studies. Sensitivity analysis and publication bias tests confirmed the stability and reliability of the results. Conclusion While lower-quality studies suggest that periodontal treatment may positively impact pregnancy gingivitis, preterm birth, and low birth weight, these effects were not supported by higher-quality evidence. Further well-designed RCTs are needed to confirm these findings and ensure their reliability. Periodontal treatment could potentially be considered as part of prenatal care to improve maternal oral health and pregnancy outcomes.
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Recurrent pregnancy loss (RPL) is the occurrence of two or more consecutive miscarriages before 20 weeks of gestation. Recent research has increasingly focused on the role of oxidative stress in RPL, providing insights into its underlying mechanisms and potential therapeutic targets. Oxidative stress arises from an imbalance between reactive oxygen species (ROS) production and antioxidant defenses, leading to cellular damage and inflammation. Oxidative stress has been implicated in disrupting placental blood flow, inducing apoptosis in fetal and placental cells, and exacerbating inflammatory responses, all of which can contribute to pregnancy loss. Elevated levels of ROS have been associated with compromised placental function, impaired fetal development, and increased risk of RPL. Additionally, oxidative stress can modulate maternal immune responses, potentially leading to immune-related pregnancy complications. This review synthesizes current evidence on the mechanisms by which oxidative stress contributes to RPL and highlights emerging research on potential interventions, including antioxidant therapies and lifestyle modifications. Understanding these mechanisms is crucial for developing effective preventive and therapeutic strategies to reduce the risk of RPL and improve pregnancy outcomes. Future research should focus on elucidating the specific pathways involved and exploring novel treatments aimed at mitigating oxidative damage during pregnancy.
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This study investigated the effects of supplementing different levels of Moringa oleifera leaf powder (MOLP) on antioxidant status and blood biochemical indices during early gestation in Beetal goats. A total of 30 goats were randomly divided into three groups (n = 10) comprising control (basal diet without MOLP), the 1.6% MOLP supplemented group (basal diet + 1.6% MOLP), and the 3.2% MOLP supplemented group (basal diet + 3.2% MOLP). The experiment started 5 days before estrus synchronization and lasted till day 60 of gestation. The MOLP significantly increased plasma flavonoids in 1.6% as well as 3.2% supplemented group on days 40 and 60 of pregnancy, while total phenolic contents were observed to be higher in the 3.2% MOLP supplemented group throughout the experiment in comparison with the control group. The supplementation improved plasma total antioxidant capacity (TAC) by decreasing malondialdehyde (MDA) and total oxidant status (TOS) in contrast to the control group. The activities of superoxide dismutase (SOD) and peroxidase (POD) were enhanced in both supplemented groups, whereas catalase (CAT) activity was noticed to be significantly high in the 3.2% MOLP supplemented group. The protein contents were significantly elevated with 1.6 and 3.2% supplementation levels from day 40 to day 60 of the experiment. Plasma sugar level, carotenoids, progesterone profile, and hydrolytic (protease and amylase) enzymes activities were improved only when supplemented with 3.2% MOLP. The findings suggest that supplementing with 3.2% MOLP provides beneficial effects on early pregnancy stress in Beetal goats.
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The effects of a combined supplementation with herbal antioxidants during pregnancy on reproductive traits and piglet performance (number of live, dead, and mummified newborns and litter weight at birth and individual body weight at both birth and weaning) were assessed in a total of 1027 sows (504 treated and 523 control females) kept under commercial breeding conditions. The supplementation increased the number of live-born piglets (13.64 ± 0.11 vs. 12.96 ± 0.13 in the controls; p = 0.001) and the total litter weight, decreasing the incidence of low-weight piglets without affecting the number of stillbirths and mummified newborns. Such an effect was modulated by the number of parity and the supplementation, with supplementation increasing significantly the number of living newborns in the first, second, sixth, and seventh parities (0.87, 1.10, 1.49, and 2.51 additional piglets, respectively; p < 0.05). The evaluation of plasma vitamin concentration and biomarkers of oxidative stress (total antioxidant capacity, TAC, and malondialdehyde concentration, MDA) performed in a subset of farrowing sows and their lighter and heavier piglets showed that plasma levels of both vitamins were significantly higher in the piglets than in their mothers (p < 0.05 for vitamin C and p < 0.005 for vitamin E), with antioxidant supplementation increasing significantly such concentrations. Concomitantly, there were no differences in maternal TAC but significantly higher values in piglets from supplemented sows (p < 0.05). On the other hand, supplementation decreased plasma MDA levels both in the sows and their piglets (p < 0.05). Finally, the piglets from supplemented mothers showed a trend for a higher weaning weight (p = 0.066) and, specifically, piglets with birth weights above 1 kg showed a 7.4% higher weaning weight (p = 0.024). Hence, the results of the present study, with high robustness and translational value by offering data from more than 1000 pregnancies under standard breeding conditions, supports that maternal supplementation with herbal antioxidants during pregnancy significantly improves reproductive efficiency, litter traits, and piglet performance.
Chapter
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Human female reproductive biology is a complex system and its pathologies are varied. However, majority of the pathologic processes involves the role of reactive oxygen species (ROS). Imbalance between the ROS and antioxidants results in oxidative stress (OS). OS is the pathognomonic factor in various female reproductive system ailments. OS contributes to the pathophysiology of infertility, pregnancy related complications, endometriosis, ovarian cancers, etc. Evidence of elevated oxidative stress biomarkers can be found in various inflammatory conditions. Numerous strategies have been postulated for management of OS related pathologic conditions. Antioxidants supplementation may play a crucial in prevention and management of these conditions. However, robust evidence is needed to support the role of antioxidants supplementation in various female reproductive disorders.
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Intrauterine growth restriction (IUGR) affects 10–15% of all pregnancies worldwide. IUGR may result from maternal, placental or fetal origin. Maternal malnutrition before and during pregnancy represents the most prevalent non-genetic or placental cause. IUGR reflects an abnormal adaptive fetal growth in a deleterious environment. Individuals born after IUGR are more susceptible to develop diseases related to subsequent stressors through a lifetime. Animal models help to decipher the underlying causes of dysregulated pathways and molecular modifications conditioning health and disease in adult offspring born after IUGR. The aim of this review is to summarize current knowledge on long term consequences of IUGR, integrating animal models and human studies for a better care of IUGR-born individuals in a life course perspective.
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Preeclampsia is a hypertensive disorder in pregnant women, which can be the leading cause of maternal and neonatal death or premature birth. Although the cause of preeclampsia is still not clear, local or systemic oxidative stress may explain the pathological features associated with this complication. However, it is not clear whether oxidative stress is the cause or the result of preeclampsia. For this purpose, the present meta-analysis was intended to evaluate the oxidant and antioxidant status in women with preeclampsia. Relevant studies were identified after a preliminary investigation of research articles published up to September 2017. In the overall analysis, including 2953 cases and 3621 controls, a statistically significant reduction in total antioxidant capacity, nitric oxide, superoxide dismutase, glutathione, vitamin E and C was observed in preeclampsia women. On the other hand, a statistically significant increase in malondialdehyde, protein carbonyl, total peroxide, glutathione peroxidase, catalase and uric acid were observed in preeclampsia women. The increased products of oxidative stress, which were found in the present meta-analysis might be an underlying mechanism for endothelial dysfunction in preeclampsia. This meta-analysis provides a scientific support that primary reduction of antioxidant capacity and increased levels of oxidative stress products may induce a condition in which the pathways responsible for blood pressure homeostasis are disrupted. In conclusion, it is hypothesized when oxidative stress is established, a protective response is induced by increasing some antioxidants. Further studies are warranted to investigate the role of dietary supplementation and genetic variation in women with different ethnicity.
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Salinity is a worldwide, threatening problem affecting socioeconomic status globally. Saline land comprises salt content in soil, plants, and drinking water. Livestock farming is the worthy option for proper utilization of saline land in a cost-effective approach. Animals reared on this land experience a variety of stresses. Such stresses promote oxidative stress and reduced animal performance. The purpose of this study was to investigate the antioxidative function of vitamin E and selenium (Se) on pregnant/nonpregnant animals reared on the saline environment. A total of 36 multiparous pregnant (n=18) and nonpregnant (n=18) goats weighing about 38-45 (average 41.5) kg were equally divided into control and supplemented groups. The experiment lasted from 120 days of gestation to 15 days after parturition for pregnant goats and 0 to 45 days for nonpregnant cyclic goats (>50 days post-kidding). The supplemented group was administered vitamin E (1000 mg/kg BW) and selenium (3 mg/50 kg BW), while the control group was kept on normal saline (0.9% NaCl) with the same route 15 days apart. The blood samples were collected with 15 days apart during the entire experimental period of 45 days and subjected to assessment of enzymatic/nonenzymatic antioxidants, hydrolytic enzymes, oxidants, stress metabolic biomarkers, Se, and progesterone concentration of (pregnant) animals. Results revealed that vitamin E and Se supplementation significantly enhanced the activity of enzymatic (catalase and peroxidase) and nonenzymatic antioxidants such as total phenolic/flavonoid content and vitamin C and increased blood plasma level of Se concentration in comparison with the control group (P
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Maternal supplementation with hydroxytyrosol, a polyphenol present in olive leaves and fruits, is a highly promising strategy to improve the oxidative and metabolic status of fetuses at risk of intrauterine growth restriction, which may diminish the appearance of low-birth-weight neonates. The present study aimed to determine whether hydroxytyrosol, by preventing lipid peroxidation, may influence the fat accretion and energy homeostasis in the liver, as well as the fatty acid composition in the liver and muscle. The results indicate that hydroxytyrosol treatment significantly decreased the energy content of the fetal liver, without affecting fat accretion, and caused significant changes in the availability of fatty acids. There were significant increases in the amount of total polyunsaturated fatty acids, omega-3 and omega-6, which are highly important for adequate fetal tissue development. However, there were increases in the omega-6/omega-3 ratio and the desaturation index, which make further studies necessary to determine possible effects on the pro/anti-inflammatory status of the fetuses.
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Recurrent miscarriage (RM), also known as recurrent pregnancy loss, is a distressing condition affecting around 1% of couples trying to conceive It can be very frustrating for both clinicians and patients as, despite intensive workup, no clear underlying pathology is forthcoming in at least 50% of couples. This leads to despair for patients and leaves clinicians at a loss for how to help. Desperation in both camps can promote the uptake of investigations and interventions of unproven benefit. The pathophysiology underpinning RM is incredibly diverse, involving areas such as haematology, endocrinology, immunology and genetics. During the seven to eight years since the UK Royal College of Obstetricians and Gynaecologists published guidelines on this topic in 2011, new evidence and guidance from expert authorities have emerged. Here, these important advances in this challenging field of clinical practice will be reviewed.
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This study was conducted to explore the regulatory mechanism of Eucommia ulmoids flavone (EUF) using enterocyte damage model induced by lipopolysaccharide (LPS). Intestinal porcine epithelial cell line (IPEC-J2) cells were cultured in Dulbecco's modified eagle medium with high glucose (DMEM-H) medium containing 0 or 10 μg/ml EUF, 0 or 40 ng/mL LPS. The results showed that LPS impaired DNA synthesis, cell viability, mitochondrial function, arrested cell cycle and induced apoptosis, reduced SOD activity while the EUF treated cells provide beneficial effect on all these parameters (P < 0.05). The addition of EUF increased phosphorylated Akt, IκBα and phosphorylated IKKα/β, but decreased Bax and Caspase-3 protein expressions in LPS-treated cells (P < 0.05). For the second experiment, cells were treated by DMEM-H medium containing 10 μg/mL EUF+ 40 ng/mL LPS or 10 μg/mL EUF+ 40 ng/mL LPS+ 10 μmol/L LY29400. EUF + LPS + LY29400 treatment significantly reduced cell viability, proliferation, mitochondrial bioenergetics parameters, SOD activity, and decreased protein expressions of PI3K, p-Akt, p-IKKα/β, p-NFκB and Bax (P < 0.05). These findings reveal the cytoprotective effects of EUF in enterocyte, which may involve the PI3K-NFκB signaling pathway, and it provides a theoretical basis for exploration of EUF as a potential anti-inflammatory compound to intervene intestinal inflammatory diseases.
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A couple may be considered to have fertility problems if they have been trying to conceive for over 1 year with no success. Worldwide, the inability to have children affects 10% to 15% of all couples. Subfertility can be divided into either male or female factor, or both partners can be affected. However, for some couples the cause for subfertility cannot be identified, and this is called unexplained subfertility. It is thought that oxidative stress is involved in the pathophysiology of subfertility, and antioxidants are thought to reduce the damage caused by oxidative stress. Antioxidants are widely available and inexpensive. However, there is currently little high-quality evidence to show that taking antioxidants will provide any benefit or harm for infertile couples.