Hindawi

Mediators of Inflammation
Volume 2021, Article ID 9962860, 11 pages
https://doi.org/10.1155/2021/9962860

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 of signaling pathways, as well as cellular and physiological

processes [1]. However, excess ROS may cause cellular toxic-
Several reproductive problems have been linked to oxidative ity [2]. Animals have an enzymatic antioxidant defense
stress. Oxidative stress occurs when the body’s antioxidant mechanism that suppresses the formation of reactive oxygen
system is depleted owing to an excess of reactive oxygen spe- species (ROS). It is worth noting that cellular integrity is
cies (ROS). ROS are highly reactive molecules that are unsta- maintained by a balance of enzymatic and non-enzymatic
ble and short-lived. These molecules contribute to the control antioxidant systems. When oxidative stress increases, both
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2 Mediators of Inflammation

antioxidant systems are depleted resulting in reproductive inflammatory diseases [26, 27]. The enzyme superoxide dis-
problems [3, 4]. Enzymatic antioxidants like glutathione per- mutase converts the superoxide anion radical to hydrogen
oxidase (GPx) and superoxide dismutase (SOD) are antioxi- peroxide and oxygen [28], and catalase eliminates hydrogen
dants to neutralize free radicals. On other hand, the non- peroxide when its quantities in the cell are higher [29]. Glu-
enzymatic antioxidants such as vitamin C, vitamin E, plant tathione reductase is found throughout the body tissues and
polyphenol, carotenoids, and glutathione interrupt free radi- operates similarly to GPx. Using several systems; the GSR
cal chain reactions. Importantly, antioxidants may have ther- enzyme reduced oxidized glutathione by utilizing NADPH
apeutic promise in the treatment of reproductive-related [30, 31].
problems [5]. The secondary defense is based on the GPx enzyme,
ROS has a biological effect on various reproductive pro- which possesses peroxidase activity and may eliminate lipid
cesses, such as oocyte maturation, fertilization, embryo hydroperoxides irrespective phospholipase A2 [32]. There
development, pregnancy, as well as oocyte maturation and are also a number of oxido-reductases that catalyse thiol
fertility. A number of research studies, including animals and other protein reduction processes. Protective enzymes
and humans, showed that ROS has been implicated with against free radicals are produced once the cellular compo-
female reproduction, particularly ovaries [6–8], fallopian nents have been oxidatively damaged. For example, DNA
tubes [9] and embryos [10]. nuclear enzymes are known to protect DNA from oxidative
The primary function of the placenta is to exchange damage induced by free radicals [33]. Vitamin E functions as
nutrients and oxygen between mother and fetus. Therefore, a cofactor for glutathione peroxidase enzymes, and its pres-
interference in these functions leads to hypoxia due to oxida- ence in all cellular membranes suggests that it can protect
tive stress. The disruption in placental function is due to lipids from oxidation. The ascorbic acid-GSH redox couple
many factors resulting in pregnancy complications [11]. A directly reduces the tocopherol radical. While β-carotene
large number of studies reported that pregnancy problems functions in concert with vitamin E, which is a strong scav-
have been associated with overwhelming oxidative stress enger of free radicals, but β -carotene only works at low oxy-
from the placenta and or maternal tissues [12]. Other mech- gen pressure. Vitamin E, on the other hand, protects β-
anisms are also implicated in the etiology of these complica- carotene against oxidative damage [34]. In addition, some
tions; oxidative stress has evolved to regulate the cellular and antioxidants work as free radical quenchers [35]. Early preg-
molecular pathways such as altered angiogenesis and inflam- nancy deficiency in antioxidants has been associated with
mation to mediate disease outcomes [13]. The oxidative sce- the development of maternal-related disorders such as gesta-
nario develops due to increased ROS and depletion of the tional hypertension, gestational diabetes, and other compli-
antioxidant system [14]. Though the development of abnor- cations [36]. Therefore, the generation of ROS molecules
mal oxidative stress leads to spontaneous abortion, idio- controls several signaling pathways that govern a variety of
pathic recurrent pregnancy loss and embryogenesis defect cellular functions. The activation of these signals causes a
[2, 15–18]. change in cellular function, which has a pathogenic effect
Oxidative stress has been linked to a number of meta- on the cell [37].
bolic processes that affect animal health and performance
[19]. The study of oxidative stress has increased as a result 3. Oxidative Stress Scenarios in Pregnancy
of its role in adverse pregnancy outcomes. Oxidative stress
exhibits dual functions, it aids in the maintenance of redox In normal pregnancy, the developing tissues and organs of
balance and it plays a part in female reproductive processes. the fetus require enough nutrition and oxygen. These pro-
As a result, oxidative stress may aggravate IUGR, endometri- cesses generate ROS in both maternal and fetal tissues that
osis, and other reproductive issues. Oxidative stress also reg- influence fetal growth development. To provide a suitable
ulates signaling networks including Kelch-like ECH- environment for the fetus and maternal body, the balance
associated protein 1, Nuclear factor erythroid 2-related fac- between ROS and antioxidants could be maintained [38].
tor 2 (Keap1-Nrf2), nuclear factor kappa-B (NF-κB), fork- During pregnancy, the body undergoes numerous physio-
head transcription factors of the O class (FOXO) and logical changes. The evidence of ROS formation in the sec-
Mitogen-activated protein kinase (MAPK). Lastly, targeting ond trimester of pregnancy was assumed by the
these pathways appears attractive as a potential therapeutic researchers. Increased production of ROS occurs due to the
strategy against pregnancy-related anomalies [5]. enhanced metabolism, high consumption of oxygen and uti-
lization of fatty acids. During third trimester of pregnancy,
2. Oxidative Stress and Its increase insulin resistance, fat catabolism, and release of free
Regulatory Mechanism fatty acids resulting in enhanced production of hydrogen
peroxide [39]. Placental cells have a lot of mitochondria,
ROS are oxidative metabolic byproducts that play an impor- which are the main source of pro-oxygenates. The superox-
tant part in cellular activity. They are also implicated in a ide anion radical produces more radical species and their
number of pathological diseases, including in-vitro and in- generation rises as the pregnancy continues.
vivo pregnancy difficulties [20–25]. The factors responsible Several studies have found that oxidative stress is linked
for overproduction of ROS are ultraviolet radiation, cigarette to pregnancy complications that may influence fetal devel-
smoking, alcohol, non-steroidal anti-inflammatory medica- opment. The major causes are a lack of nutrition and oxygen
tion, ischemia-reperfusion injury, chronic infections, and for developing fetuses, which causes hypoplasia and disrupts
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Mediators of Inflammation 3

placental function [39, 40]. The difference in total plasma second phase of the pregnancy. After that, maternal blood
antioxidants status between pregnant and non-pregnant pumps via interstitial space into the mother’s spiral artery
individuals has been observed, implying a low level in the [54, 55]. Free radicals are abundant in placental tissues,
first phase of pregnancy. The total antioxidant capacity of and oxidation occurs throughout the process. With the help
a pregnant woman increases during the second and third tri- of antioxidant activity, the placenta can slowly adapt to the
mesters, and by the last week of pregnancy, it has reached environment after recovering from stress [40].
the level of a non-pregnant woman. TAC activity increases SOD activity decreases during the late luteal phase due to
after the 8th week of pregnancy, and these changes are linked increased amounts of lipid peroxide. Importantly, ROS are
to differences in plasma uric acid levels [41]. Furthermore, known to have a role in numerous phases of the endometrial
reduced TAC levels in pregnancy have been linked to low cycle, and may also produce PGF2 through NF-κB activation
levels of serum albumin, bilirubin, and vitamin E [42]. As [56]. Estrogen and progesterone levels dropped significantly
result, it appears that plasma SOD activity is reduced during as a result of lower SOD expression. In a consequence, ROS
pregnancy [43]. The SOD reduction promoted triglycerides, accumulates in the uterus, leading to implantation failure.
total cholesterol, and low-density lipoprotein (LDL) choles- The basal level of ROS controls angiogenic activity in the
terol levels in blood plasma. Therefore, SOD refers as indica- endometrium and results in endometrial regeneration dur-
tor of oxidative stress and lipid peroxide activity followed by ing each cycle. Thus, appropriate ROS concentration is crit-
25 weeks of pregnancy. As a result, lipid peroxidation levels ical for normal homeostasis. However, an increased level of
in the blood are higher in pregnant women, serving as a ROS from the placenta has been associated with
marker of oxidative stress. Previous studies have found that pregnancy-related disorders [57–59]. The TNF-α cytokine
supplementing pregnant individuals with the dietary vita- that influences endothelial cell dysfunction and the antioxi-
mins, antioxidants, and minerals enhanced TAC activity dant Mn-SOD are both disrupted and have protective
[42–44]. effects. The production of cytokines and prostaglandins is
increased by ROS-related poor placental function, producing
4. Oxidative Stress in Ovary, Uterus endothelial cell injury and contributing to preeclampsia [60].
and Placenta
5. Regulation of Multiple Signaling
Almost every stage of pregnancy is affected by ROS. ROS is Pathways by Oxidative Stress
known to be the important regulator of ovarian cellular
activity [45]. The ROS positive impact has been already Oxidative stress has been linked to influence signaling path-
mentioned. Previous studies showed that the presence of ways, particularly in reproductive diseases ranging from egg
SOD in ovary, copper-zinc SOD (Cu-Zn SOD) in granulosa production to ovulation. It alters immune system of the
cells of follicles and manganese superoxide dismutase uterus resulting in embryonic failure [61, 62]. Oxidative
(MnSOD) in luteal cells of the corpus luteum in rats [46]. stress has also been involved in regulating molecular path-
The sources of ROS in the follicles are macrophages, leuko- ways in reproductive disorders such as p38 MAPK, Keap1-
cytes and cytokines [26]. Ovulation is dependent on concen- Nrf2, the Jun N-terminal kinase (JNK), the FOXO family,
tration of ROS. ROS suppressors have been demonstrated to and apoptotic pathways. Therefore, the research on this
interfere with the ovulatory process [47]. Follicles develop- aspect may yield new insights that might influence female
ment is associated with an increased metabolic function of reproductive system.
granulosa cells, particularly excess amount of cytochrome Nrf2 is a signaling molecule that protects cellular func-
P450 and steroidogenesis [48]. The presence of ROS in tion by acting as an antioxidant in response to oxidative
pre-ovulatory follicles alters blood flow and finally leads to stress [63]. Physiologically, Nrf2 binds with Keap1 in the
follicle rupture [49]. Furthermore, FSH stimulates the syn- cytoplasm before being degraded by the proteasome [64].
thesis of estrogen, while the overexpression of CAT in devel- Once the Nrf2 is activated, it translocate into nucleus, where
oping follicles protects them from apoptosis, ensuring that it activates several antioxidant genes [65]. In contrast, activa-
ovarian function is preserved [50]. Depletion of oxygen is tion of antioxidant genes and restoration of vascular redox
required for follicular angiogenesis [6]. The corpus luteum homeostasis are required when OS is evident suggesting
contributes to functional luteolysis by producing ROS. Dur- the crucial function of Nrf2 [66]. The deficiency of Nrf2
ing the luteal phase, both the ROS and antioxidants are induced fetal DNA damage and neurological discrepancies
linked to progesterone production [51]. The beneficial and inactivation of Nrf2 were also exhibited inflammation
effects of ROS and antioxidants in female reproductive and triggered trophoblastic apoptosis. Previous evidence showed
pregnancy outcomes are depicted in Table 1. that Nrf2 plays an important role in pregnancy and protects
The developing fetus has a high energy requirement due the fetus from OS in-utero [67]. The maternal immune sys-
to the placental hyperactive metabolic rate, resulting in oxi- tem is susceptible to Nrf2. Nrf2 is only decreased once the
dative stress [52]. Of note, that superoxide anions produced full-term foetus is delivered in a normal pregnancy. When
by placental mitochondria appear to be the essential source a fetus is infected in utero, the Nrf2 expression is favorably
of ROS and lipid peroxidation in the placenta [53]. As the reduced [68]. In the case of OS-induced metritis, it is
pregnancy progresses, mitochondrial synthesis of lipid per- expected that Nrf2 would be considerably decreased, and
oxides, free radicals, and vitamin E may also increase [54]. Keap1 would bind to Nrf2. Similarly, FOXO3 is essential
The placenta and large blood arteries mature slowly in the in the interaction between Keap1 and Nrf2. In the absence
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4 Mediators of Inflammation

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 H202 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
Rescue Corpus luteum form apoptosis Sheep [134]
pregnancy
↑ CAT and GPX and oviduct GSH in estrus
Govern hydrogen peroxide during fertilization Cow [135]
cycle
↑ expression of SOD1 in early pregnancy Directions of luteal functions Human [136]
Regulates hydrogen peroxide and activation of placental
↑ CAT and GPX, and GSH in placenta tissues Human [137]
differentiation
↑ CAT, SOD and GPX in placental and fetal
Defense against ROS toxicity in feto-placental system Human [138]
tissues
↑ uterine peroxide at blastocyst attachment Defense to negative effects of hydrogen peroxide actions Rat [139]

of FOXO3, Nrf2 is activated by AKT and protects cells reproduction and also mediates cyclic differentiation and
against OS [69]. Lastly, we hypothesized that OS causes apoptosis in normal endometrium [80]. Recent studies have
inflammation in the reproductive system, with FOXO3 play- shown that FOXO1 knockdown disrupts the expression of
ing a role in the interaction between Keap1 and Nrf2, which over 500 genes in decidualized human endometrial stromal
may be used as a marker for OS insults. cells [81]. Previous research has shown that FOXO tran-
NF-κB is an inert molecule, its family comprises five scription factors can control multiple gene responses to
transcription factors c-Rel, p50, p52, RelB and RelA (p65) change hormone levels [82]. Besides, that FOXO1 is also
[70]. NF-B is a redox-sensitive transcription factor that is responsible for the induction of decidual marker genes,
the primary regulator of the inflammatory response [71]. including WNT4, prolactin (PRL) and insulin-like growth
Therefore, the beneficial effects of NF-κB are evident in factor-binding protein 1 (IGFBP1) [83].
embryonic stress that activates NF-κB and other diverse Three signaling molecules are triggered by the extracel-
inflammatory cytokines which persuades apoptosis within lular milieu, including ERK, which is activated by inflamma-
placenta [72]. Hence, it was concluded that NF-κB plays an tion and growth factors, and JNK and p38 MAPK, which are
important role in the cell survival by releasing anti- mostly activated by stress and inflammation [84]. It has been
apoptotic genes. In normal conditions, NF-κB is bound to shown that ERK activation is increased in endometrial tis-
inhibitory IκB proteins and remains inactive in the cyto- sue, suggesting that ERK may play a role in endometriosis
plasm. The breakdown of IκB proteins activates NF-B, which and phosphorylated ERK is increased in primary eutopic
subsequently translocate into the nucleus and generates epithelial cells [85]. ERK activation can also be influenced
desirable genes, whereas IκB proteins are mediated by the by oxidative stress. In response to normal women, hydrogen
IκB kinase (IKK) complex (IKKα and IKKβ) [73]. Increased peroxide causes ERK phosphorylation in endometriotic stro-
expression of NF-κB in cultured endometrial stromal cells mal cells [86].
has been found in reproductive diseases such as endometri-
osis [74]. Altered production of NF-κB production has been 6. Contribution of Oxidative Stress in
associated with inflammation. Endometriosis is a condition Pregnancy Complications
induced by OS which increases the concentration of TNF-
α, resulting in inflammation thereby; NF-κB is activated. 6.1. Intrauterine Growth Restriction. Intrauterine growth
Moreover, IL-1β activates NF-κB, which in turn produces restriction (IUGR) is a pregnancy ailment in which an
inflammatory cytokines [75], comprising macrophage underweight/incomplete fetus develops in the uterus [87].
migration inhibitory factor (MIF) in endometrial stromal The causes are multifactorial such as maternal, fetal, placen-
cells [76] and TNF-α in immortalized epithelial (12Z) cell tal, infectious, or genetics [88]. About 76% of intrauterine
line [77]. In summary, OS-mediated reproductive disorders deaths have been associated with IUGR [89]. The most sig-
are caused by NF-κB activation. nificant cause of IUGR is utero-placental dysfunction occurs
FOXO1 and FOXO3 have been contributed to OS and due to the congested maternal utero-placental blood flow
pregnancy. The FOXO subfamily of Forkhead transcription [90]. Proper functioning of the placenta requires greater
factors is a direct downstream target of the PI3K/Akt path- energy demand for cell growth, proliferation and metabolic
way [78]. The family of FOXO proteins is involved in differ- activity which in turn produce oxidative stress. Oxidative
ent biological processes such as proliferation, apoptosis, stress plays an essential role against various stimuli which
autophagy, metabolism, inflammation, differentiation and influence placental function [91]. Cellular injury occurs as
stress tolerance [79]. The FOXC1 displays a pivotal role in a result of lipid peroxidation and fatty acid oxidation, and
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Mediators of Inflammation 5

ROS inducers: ROS scavengers:

mitochondria, immune cells, enzymatic & non-
inflammation, diabetes, enzymatic
infections and smoking etc antioxidants

Oxidative
stress

First trimester Second trimester Third trimester

(i) Presence of oxygenated blood results

in rise of oxygen tension and OS (i) Sudden rise in oxygen tension, (i) Enhanced OS leads to damage
(ii) Improver trophoblastic invasion overwhelmed ROS & oxidative stress lipids, proteins and DNA
results in influence spiral arteries (ii) Influence uterine perfusion (ii) Induced DNA damage results in
development (iii) Continuous accelerated OS leads to fetal anomalies
(iii) Enhanced vascular resistance in declining antioxidants (iii) Triggers advanced aging leads to
placenta & decreased uteroplacental (iv) Depletion of antioxidant as well as placental insufficiency
perfusion reducing system
(iv) Ischemia perfusion injury.

Early pregnancy loss,

recurrent miscarriage, Preterm birth, IUGR
preterm birth and IUGR and still birth
IUGR

Figure 1: The Impact of Oxidative Stress on Pregnancy Outcomes.

it is mostly utilised to identify oxidative stress indicators dence of oxidative stress occurred due to the depletion of
[92]. Evidence of IUGR in livestock has been raised through the antioxidants system and thus unable to scavenge free
environmental factors and affects goats, sheep, pigs and radicals [87, 98]. Although there is diversity in previous
other animals. Of note, that significant evidence of IUGR studies, it seems to be a relationship between ROS and anti-
exists in multi-fetal animals including pigs. It has been doc- oxidants in miscarriage. The abnormal placentation may
umented those animals with this condition have reduced arise from syncytiotrophoblasts and may be vulnerable to
birth weight, postnatal growth, development and liver dys- idiopathic recurrent pregnancy loss [97]. Oxidative stress
function [93]. A detailed description of IUGR occurrences enables the potential to influence pregnancies due to the
in clinical and health deviations is well been ascribed in depletion of antioxidant capacity within the body [99]. The
the previous studies [94–96]. More evidence is required to influence of oxidative stress in pregnancy problems is
be revealed the underlying molecular mechanisms. depicted in Figure 1. The issue of recurrent pregnancy losses,
research gaps, and their treatment has been thoroughly
6.2. Spontaneous Miscarriage and Recurrent Pregnancy Loss. reviewed [100, 101].
Spontaneous abortion can be classified as loss of pregnancy
before 20 weeks of gestation. The incidence may range from 6.3. Gestational Diabetes Mellitus (GDM). GDM is a type of
8-20% in pregnancies and is due to chromosomal aberration, diabetes mellitus in which pregnant women develops glucose
which accounts for 50% of all miscarriages. While, the rest intolerance to a different degree [102]. It was reported in 2-
are associated with congenital and uterine malfunctions, 5% of pregnancies while; data suggested the incidences
infections, maternal diseases and unknown causes [97]. increased up to 18% in all pregnancies [103]. GDM develops
In early pregnancy losses, elevated levels of MDA and during the second trimester of pregnancy, causing fetal
lipid peroxides were observed in placental tissues in compar- macrosomia, perinatal mortality, and making mother vul-
ison with controls. Previous studies have shown that over- nerable for T2DM [102, 104].
loading of ROS could lead to the premature and sudden The pregnancy has been linked to an imbalance of pro
formation of maternal placental perfusion [2]. Other evi- and anti-inflammatory mediators [105]. The levels of T cells
dence reported that oxidative stress damage the trophoblast subsets were increased in women with GDM compared to
and ultimately leading to early pregnancy losses. The inci- control healthy subjects whereas; T cells expressing CTLA-
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6 Mediators of Inflammation

4, a downregulation of the immune system which lightly pregnancy, changes in membrane lipids induce biological
expressed in Tregs were suppressed [106]. Changes in the prostaglandin events, and an enhanced level of ROS causes
Treg population suggest that the Treg pool in GDM is dysmorphogenesis in the fetus [121]. A reduced level of lipid
becoming less active [76]. Thus, it suggests that the lack of peroxidation in women with GDM was reported due to
immune down-regulation helps maternal-fetal tolerance. depletion of antioxidants activity. Hydroperoxide produc-
Although, the toll-like receptors TLR-2 and TLR-4 stimulate tion affects prostaglandin synthesis patterns, which may
inflammatory cytokines which were enhanced in peripheral result in morbidity owing to antioxidant depletion [122].
blood mononuclear cells of women with GDM [107]. Previ- GDM also triggers oxidative stress in fetus, thus the intake
ous literature revealed the ambiguous results of TNF-α in of antioxidants during pregnancy is essential factor for
GDM condition [79, 82], but more descriptive role of improving pregnancy health [123]. Further, a detailed
GDM is well-highlighted somewhere else [108]. An evidence description on the role of antioxidants in pregnancy is
of oxidative stress-related problems during pregnancy is well-discussed in the previous studies [2, 44, 124–129].
well-reviewed by others [12, 109].
8. Conclusion
7. Antioxidant Approaches in Pregnancy
Antioxidant defense has been established to regulate the
The detrimental effects of oxidative stress and ROS on generation of ROS; however the increased amount of ROS
female reproduction system have been well illustrated for cannot be controlled, resulting in oxidative stress. So, the
since long [110]. It was suggested that the generation of potential strategies of antioxidant to decrease ROS levels
ROS is impaired by cytochrome P450 and corpus luteum, are critical. According to a large number of studies, oxidative
which itself is considered a key source. The initiation of stress is the primary contributing factor in a variety of preg-
oocyte maturation and others processes are mostly affected nancy complications. Overstimulation of ROS can cause
by different levels of ROS and antioxidants [6]. Endometri- hyperglycemia, IUGR, miscarriage, and spontaneous abor-
osis and unexplained infertility conditions are also linked tion throughout all stages of pregnancy. Placental oxidative
to the OS [111]. stress is caused by a number of variables, including maternal
Antioxidant supplementation possess positive effects history, genetics, and environmental factors, and can lead to
through a variety of pathways, including direct scavenging negative pregnancy outcomes. Future research should focus
of reactive oxygen species (ROS) and damage repair [112]. on improving the breakdown of intracellular ROS and
The protective effects on fertility consisting enhanced blood enhancing antioxidant bioavailability. Targeting signaling
circulation in endometrium, reduced hyperandrogenism, molecules with natural bioactive compounds will be used
lowered insulin resistance, and positive impact on prosta- to minimize the occurrence of reproductive problems.
glandin synthesis and steroidogenesis [112–114]. A current
systematic review indicates the positive impact of antioxi-
dants in female fertility [115]. Antioxidants were also Conflicts of Interest
involved in enhancing live birth weight and clinical preg- All authors have no any conflict of interest.
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 Acknowledgments
have shown various responses when they are taken alone
This project was funded by the National Natural Science
or in combination exerted a positive effect on pregnancy rate
Foundation of China (32072745, 31960666) and Innovation
[116]. Moreover, dietary/injectable source of antioxidants
Province Project (2019RS3021).
during periparturient period provide beneficial effects on
pregnancy outcome and growth performance of suckling
kids of goats [117, 118]. References
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Mediators of Inflammation 7

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