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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 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.
1. Introduction
Several reproductive problems have been linked to oxidative
stress. Oxidative stress occurs when the body’s 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 effect 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 [6–8], 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 inflam-
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, 15–18].
Oxidative stress has been linked to a number of meta-
bolic processes that affect 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 difficulties [20–25]. The factors responsible
for overproduction of ROS are ultraviolet radiation, cigarette
smoking, alcohol, non-steroidal anti-inflammatory medica-
tion, ischemia-reperfusion injury, chronic infections, and
inflammatory 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 deficiency 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 effect
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
influence 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 influence fetal devel-
opment. The major causes are a lack of nutrition and oxygen
for developing fetuses, which causes hypoplasia and disrupts
2 Mediators of Inflammation
placental function [39, 40]. The difference in total plasma
antioxidants status between pregnant and non-pregnant
individuals has been observed, implying a low level in the
first 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 differences 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
[42–44].
4. Oxidative Stress in Ovary, Uterus
and Placenta
Almost every stage of pregnancy is affected 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 flow and finally 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 beneficial
effects 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 mother’s 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 significantly
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 [57–59]. The TNF-αcytokine
that influences endothelial cell dysfunction and the antioxi-
dant Mn-SOD are both disrupted and have protective
effects. 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 influence 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 influence 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 deficiency of Nrf2
induced fetal DNA damage and neurological discrepancies
and inactivation of Nrf2 were also exhibited inflammation
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 Inflammation
of FOXO3, Nrf2 is activated by AKT and protects cells
against OS [69]. Lastly, we hypothesized that OS causes
inflammation 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 five
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 inflammatory response [71].
Therefore, the beneficial effects of NF-κB are evident in
embryonic stress that activates NF-κB and other diverse
inflammatory 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 inflammation. Endometriosis is a condition
induced by OS which increases the concentration of TNF-
α, resulting in inflammation thereby; NF-κB is activated.
Moreover, IL-1βactivates NF-κB, which in turn produces
inflammatory 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 differ-
ent biological processes such as proliferation, apoptosis,
autophagy, metabolism, inflammation, differentiation and
stress tolerance [79]. The FOXC1 displays a pivotal role in
reproduction and also mediates cyclic differentiation 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 inflamma-
tion and growth factors, and JNK and p38 MAPK, which are
mostly activated by stress and inflammation [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 influenced
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-
nificant cause of IUGR is utero-placental dysfunction occurs
due to the congested maternal utero-placental blood flow
[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
influence placental function [91]. Cellular injury occurs as
a result of lipid peroxidation and fatty acid oxidation, and
Table 1: Positive effect 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 Influencing 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
differentiation 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 effects of hydrogen peroxide actions Rat [139]
4 Mediators of Inflammation
it is mostly utilised to identify oxidative stress indicators
[92]. Evidence of IUGR in livestock has been raised through
environmental factors and affects goats, sheep, pigs and
other animals. Of note, that significant 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 [94–96]. More evidence is required to
be revealed the underlying molecular mechanisms.
6.2. Spontaneous Miscarriage and Recurrent Pregnancy Loss.
Spontaneous abortion can be classified 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 influence pregnancies due to the
depletion of antioxidant capacity within the body [99]. The
influence 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 different 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-inflammatory 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 Inflammation
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
inflammatory 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 effects 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 affected
by different levels of ROS and antioxidants [6]. Endometri-
osis and unexplained infertility conditions are also linked
to the OS [111].
Antioxidant supplementation possess positive effects
through a variety of pathways, including direct scavenging
of reactive oxygen species (ROS) and damage repair [112].
The protective effects on fertility consisting enhanced blood
circulation in endometrium, reduced hyperandrogenism,
lowered insulin resistance, and positive impact on prosta-
glandin synthesis and steroidogenesis [112–114]. 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 offering various kinds of antioxidants. Antioxidants
have shown various responses when they are taken alone
or in combination exerted a positive effect on pregnancy rate
[116]. Moreover, dietary/injectable source of antioxidants
during periparturient period provide beneficial effects 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 signifi-
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 affect 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 affects 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, 124–129].
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 conflict of interest.
Acknowledgments
This project was funded by the National Natural Science
Foundation of China (32072745, 31960666) and Innovation
Province Project (2019RS3021).
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11Mediators of Inflammation
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