REPRODUCTION

REVIEW

Involvement of oxidative stress in placental dysfunction, the

pathophysiology of fetal death and pregnancy disorders
1,2
Zakia Sultana , Yixue Qiao1,2, Kaushik Maiti1,2 and Roger Smith 1,2

1
Mothers and Babies Research Program, Hunter Medical Research Institute, The University of Newcastle, New
Lambton Heights, New South Wales, Australia and 2School of Medicine and Public Health, College of Health
Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia
Correspondence should be addressed to R Smith; Email: Roger.Smith@newcastle.edu.au

Abstract
In brief: Placental oxidative stress contributes to both normal and abnormal placentation during pregnancy. This review discusses the
potential consequence of oxidative stress-induced placental dysfunction on pregnancies complicated by fetal death and
pregnancies with a high risk of fetal death.
Abstract: The placenta is a source of reactive oxygen free radicals due to the oxidative metabolism required to meet the demands of
the growing fetus. The placenta has an array of efficient antioxidant defense systems to deal with rising oxidative stress
created by free radicals during pregnancy. Properly controlled physiological (low-level) free radical production is a
necessary part of cellular signaling pathways and downstream activities during normal placental development; however,
poorly controlled oxidative stress can cause aberrant placentation, immune disturbances and placental dysfunction.
Abnormal placental function and immune disturbances are linked to many pregnancy-related disorders, including early and
recurrent pregnancy loss, fetal death, spontaneous preterm birth, preeclampsia and fetal growth restriction. This review
discusses the role of placental oxidative stress in both normal and pathological settings. Finally, based on previously
published work, this review presents multiple lines of evidence for the strong association between oxidative stress and
adverse pregnancy outcomes, including fetal death and pregnancies with a high risk of fetal death.
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Introduction Oxidative stress, cellular senescence and aging

The placenta is the organ that connects the fetus to the Oxidative stress is ‘an imbalance between the production
ex-utero world. It enables the maternal–fetal exchange of reactive oxygen species (ROS) and the capacity of a
of nutrients and waste products. The placenta evades biological system to detoxify the reactive intermediates
the maternal immune system to allow the survival of a or repair the resulting damage’ (Freinbichler et al.
semi-allogeneic fetus and maintain a healthy pregnancy. 2011). ROS, also called free radicals, are oxygen-
However, physiological or environmental factors can containing molecules with unpaired electrons. The
interfere with placental development and function unpaired electrons allow ROS to react with other
at any time during gestation. A poorly developed molecules readily and can initiate large chain reactions
placenta is unable to transfer adequate oxygen and called oxidation. These highly reactive free radicals are
nutrients from the mother to the growing fetus. capable of oxidation of DNA, RNA, lipids, and proteins,
Placental insufficiency can have serious consequences which can lead to irreversible cellular damage and tissue
for the fetus, such as intrauterine fetal death, low birth or organ failure. Antioxidants are defense mechanisms
weight, and premature birth. A dysfunctional placenta that can terminate the chain reactions (oxidation) by
also carries an increased risk of complications for the removing reactive intermediates or neutralizing harmful
mother, including preeclampsia. This review focuses radicals by reduction. Antioxidants are generally
on the current understanding and evidence regarding reducing agents, such as thiols or phenols.
the involvement of oxidative stress in placental Generally, ROS (such as peroxides and superoxides)
abnormalities and its impact on adverse pregnancy are generated as by-products of cellular oxidative
outcomes, including fetal death and pregnancies with phosphorylation (created by the mitochondrial electron
a high at risk of fetal death. transport chain, Fig. 1). These ROS are shortlived

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R26 Z Sultana and others

Figure 1 The formation of ROS by the mitochondrial electron transport chain. In the mitochondrial electron transport chain, electrons donated
by NADH and FADH2 are transported from complex I to complex IV where oxygen is ultimately reduced to form water. Mitochondria produce
the superoxide anion radical (O2•−) from the leakage of electrons at complex I and complex III. In the matrix, O2•− is rapidly converted to
hydrogen peroxide (H2O2) by the action of manganese-dependent superoxide dismutase (MnSOD, SOD2). Then H2O2 is broken down to water
by catalase (CAT) and glutathione peroxidase (GPx). When O2•− is produced in the intermembrane space, it may escape to the cytosol, where
O2•− is converted to H2O2 by copper/zinc superoxide dismutase (CuZnSOD, SOD1). Then, H2O2 is fully reduced to form water by CAT and
glutathione (GSH) in the cytoplasm. Alternatively, H2O2 may react with free ferrous (Fe2+) or ferric (Fe3+) ions (Fenton’s reaction) to form the
reactive hydroxyl radical (OH•) or hydroperoxyl radicals (HOO•). The highly reactive hydroxyl or hydroperoxyl radicals then target and oxidize
mitochondrial or cellular DNA, RNA, lipids, and proteins.

and rapidly converted to hydrogen peroxide (H2O2), Senescence is a process by which the functional
which is further broken down to water by the action properties of a cell deteriorate, and the cell permanently
of antioxidant enzymes. ROS are also produced stops dividing but does not die. Cellular senescence is a
as a result of arachidonic acid metabolism by biological process underlying aging in various tissues. In
cyclooxygenase 2 (COX-2), lipoxygenases, xanthine mitotic tissues, the gradual accumulation of senescent
oxidase (XO), aldehyde oxidase (AOX1), cytochrome cells is the leading cause of aging (Kajdy et al. 2021).
P450, and nicotinamide adenine dinucleotide Aging is a ‘process in which a progressive deterioration
phosphate (NADPH) oxidases (Nox) (Kundu et al. 2012, in function at the cellular, tissue, and organ levels
Aouache et al. 2018). Dysfunctional mitochondria or leads to organisms being more susceptible to stress
dysregulation of these enzymes may lead to elevated and disease’ (Fedarko 2011). Accelerated aging occurs
ROS synthesis. Oxidative stress can also result from a because of oxidative stress caused by ROS, which
lack of antioxidants. Moreover, environmental factors results in diminished cell function.
(such as ultraviolet radiation, ionizing radiation, Pregnancy is a state of metabolic challenge and is
xenobiotics, pollutants, and heavy metals) can trigger associated with an elevated level of oxidative stress,
ROS generation (Andersson 2018). Physiological (low- especially with regard to the placenta (Morris et al.
level) ROS play a central role in redox signaling and 1998). The placenta is a primary source of ROS due
redox regulation via post-translational modifications, to its high metabolic rate and increased mitochondrial
whereas elevated levels of ROS lead to disturbed redox activity, and oxidative stress is a physiologic response
signaling and oxidative damage to biological molecules to fetal and placental energy demands (Marseglia et al.
(Sies 2019). Disruption in the cellular redox state can 2014). In the placenta, oxidative stress has both
cause harmful effects on normal cellular function. beneficial regulatory effects and adverse harmful effects
Oxidative stress caused by elevated ROS levels is key (Wu et al. 2015). Physiologic oxidative stress is essential
for the induction of the cellular senescence process. for the normal development and function of the
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 Oxidative stress and negative birth outcomes R27

placenta, for example, trophoblast invasion, placental lipids (Benedetti et al. 1980). Malondialdehyde (MDA),
remodeling, vascular growth, and organogenesis during produced as a secondary product during lipid oxidation,
early gestation and parturition at term (Schoots et al. has also been used as a biomarker of oxidative stress.
2018). The activity of placental Nox is higher before Both HNE and MDA play important pathogenic roles;
10 weeks of gestation and is the main source of free however, 4HNE, in particular, can form covalent
radicals in the first-trimester chorionic villi. These adducts with nucleophilic functional groups in various
Nox-derived ROS play a major role in physiological biomolecules, including circulating or cellular proteins,
placental function and healthy early development nucleic acids, membrane lipids, and mitochondria, thus
of the placenta (Hernandez et al. 2019). However, leading to their functional decay and affecting many
pathological oxidative stress is linked to abnormal cellular processes (Zhong & Yin 2015).
placentation, immune disturbances, and placental The level of antioxidants is an indirect measure of
dysfunction, and there is a clear association of oxidative cellular oxidative stress. Antioxidants can reduce the
stress with many pregnancy-specific disorders such as oxidation of cellular molecules by scavenging and
recurrent pregnancy loss (RPL), preeclampsia, fetal eliminating them from biological systems. A balance
growth restriction (FGR), preterm birth (PTB), preterm between antioxidants and ROS maintains the cellular
premature rupture of the membranes (pPROM), and redox system; however, oxidative stress occurs when
fetal death. However, it is still unclear whether aberrant free radicals and antioxidants are out of balance.
oxidative stress is the cause or the consequence of Antioxidants are divided into (i) enzymatic antioxidants,
placental dysfunction and pregnancy complications. such as superoxide dismutase (SOD), catalase (CAT),
glutathione peroxidase (GPx), glutathione reductase
(GR), and glutathione-S-transferase, and (ii) non-
Biomarkers of oxidative stress and aging
enzymatic antioxidants, including glutathione (GSH),
Oxidative biomarkers are valuable tools for detecting selenium, vitamins C and E, nicotinamide adenine
levels of oxidative stress and aging in the placenta in dinucleotide (NADH), and NADPH. Measuring
pathologic pregnancies. Direct measurement of ROS, the activity and levels of these enzymatic and non-
such as hydrogen peroxide (H2O2), hydroxyl radicals enzymatic antioxidants has been used as a marker of
(OH•), hydroperoxyl radicals (HOO•), and superoxide oxidative stress.
anion radical (O2•−), and their reactive metabolites Markers of cellular senescence have also been used
are biomarkers that reflect cellular or tissue levels of as biomarkers of oxidative stress and tissue aging. An
oxidative stress. However, direct measurement of essential biomarker of cellular senescence and aging
these free radicals is troublesome as they are highly is telomere length reduction. A telomere is a region
reactive, short-lived molecules. Therefore, oxidative of repetitive nucleotide sequences at the end of linear
stress is generally measured by detecting the damage chromosomes. Telomeres protect DNA ends from
to molecules, such as deoxyribonucleic acid (DNA), degradation. Telomeres are gradually shortened in each
proteins, and lipids caused by ROS. cell division; when they reach a critically minimum
One of the main targets of ROS is nucleic acid- length, the cell no longer divides successfully, and the
containing molecules such as ribonucleic acid (RNA) cell becomes inactive or ‘senescent’. This phenomenon
and DNA. ROS, especially OH•, can alter nucleic is called replicative senescence. The telomere length
acid structures by modifying DNA/RNA bases, creating reduction that typically happens during DNA replication
double-strand breaks, and DNA cross-linking. Among the can be accelerated by environmental influences, such
nitrogenous bases, the guanine base is very susceptible as hypoxia, inflammation, and oxidative stress (Saretzki
to oxidation by ROS due to its low redox potential. For & Von Zglinicki 2002). Telomeres are particularly
mitochondrial and nuclear DNA, ROS action leads to the vulnerable to oxidative stress because of their high
formation of 8-hydroxy-2-deoxyguanosine (8-OHdG, guanosine content. Telomere length reduction from
an oxidative derivative of 2-deoxyguanosine), which oxidative stress occurs due to single and double-strand
has been used as a marker for oxidative stress and aging breaks in the telomere sequences of DNA (Von Zglinicki
(Valavanidis et al. 2009). The mutagenic oxidative 2002). ROS can also cause end-to-end fusion and the
lesion present in RNA is 8-hydroxyguanine (8-OHG) aggregation of telomeric DNA, telomere uncapping,
which acts as a biomarker of oxidative RNA damage. and telomere dysfunction (Kajdy et al. 2021). Other
Another target of ROS is the membrane lipid, especially markers of senescence include senescence-associated
the polyunsaturated fatty acids (PUFAs) chains in lipids. β-galactosidase (SA-β-galactosidase), the senescence-
Oxidation of PUFAs produces an array of primary associated secretory phenotype (including inflammatory
lipid oxidation products, which may decompose to cytokines and chemokines) and senescence-associated
form reactive lipid electrophiles. Among these lipid heterochromatin foci (SAHF). In addition, p53-p21 and
peroxidation products, 4-hydroxy-2-nonenals (4HNE) p16-pRB, two key pathways that play essential roles in
is an active lipid electrophile and has been widely used regulating the cell cycle, have been shown to associate
as a marker of ROS-mediated damage to membrane with the senescent processes and are regarded as
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R28 Z Sultana and others

markers of cellular senescence and aging (Bernardes de fold shorter in unexplained fetal death pregnancies
Jesus & Blasco 2012). compared with term live-birth pregnancies, indicating
In response to telomeric DNA damage, that premature senescence and aging may lead to
phosphorylation and activation of the tumor-suppressor placental dysfunction that leads to fetal demise in
protein p53 result in the activation of the cyclin- unexplained stillbirth.
dependent kinase inhibitor p21CIP1, while stress- Maiti et al. (2017) demonstrated increased oxidative
induced DNA damage causes activation of p16INK4a, damage in the placentas from unexplained fetal death
independent of telomere length. Activation of either as measured by an increase in the production of
p21 or p16 leads to inhibition of pRb, which results 8-OHdG (a biomarker of DNA oxidation) and 4HNE (a
in the inactivation of the E2F transcription factor, biomarker of lipid peroxidation) in stillbirth placentas
leading to cell cycle arrest (Bernardes de Jesus & Blasco compared with term placentas. Also, the expression
2012). These processes lead to the reorganization and of AOX1 mRNA is increased in stillbirth placentas
accumulation of heterochromatin in senescent cells in and is co-localized with 4HNE in placental samples
the form of SAHF (Kajdy et al. 2021). when immunostained (Maiti et al. 2017). AOX1, a
molybdoflavoenzyme, catalyzes the oxidation of a
range of substrates; specifically, it reacts with 4HNE
Role of pathological oxidative stress in the genesis to produce ROS (Garattini & Terao 2011, Kundu et al.
of pregnancy complications 2012). As the ROS produces more 4HNE, this enzymatic
reaction becomes a self-propagating process, leading
Placental oxidative stress in stillbirth
to the further generation of ROS and 4HNE. These
The World Health Organization defines stillbirth, also data suggest that AOX1 may be involved in regulating
known as fetal death, as ‘the birth of a baby showing ROS generation and 4HNE production in stillbirth
no signs of life at or after 28 weeks’ gestation or pregnancies (Maiti et al. 2017). However, it is still not
weighing 1000 g or more at birth’. This definition is clear whether increased oxidative stress is the actual
widely accepted and used by healthcare professionals cause or consequence of impaired placenta function
and researchers around the world. Stillbirth is a in stillbirth pregnancies. The placental oxidative stress
devastating experience for parents and families, and it and aging-associated changes are replicated in cultured
is an important public health issue that affects millions human placental explants when oxidative stress is
of people worldwide. The psychosocial and economic induced by removing serum from the culture medium
impact of stillbirth on parents and care providers are (Maiti et al. 2017). The increased lipid oxidation that
broad and long-lasting (Heazell et al. 2016). There has is observed under oxidative stress condition is blocked
been little to no improvement in overall fetal death rates when the explants are treated with the AOX1 inhibitor,
for over three decades, even in developed countries with raloxifene, suggesting that AOX1 play a causative role
adequate obstetric care (Lawn et al. 2016, Flenady et al. in placental oxidative damage in pregnancy pathologies
2020). For example, in Australia, 7.7 per 1000 births (Maiti et al. 2017).
were stillbirths in 2020 compared with 7.4 per 1000 In addition, several earlier studies investigated the
in 1991 (Flenady et al. 2020, AIHW 2022). Clinically effect of oxidative stress on negative birth outcomes
identified causes of fetal death include intrauterine using in vivo animal models. A group of researchers
growth restriction, congenital abnormality, antepartum found that maternal exposure to endotoxins, such
hemorrhage, spontaneous PTB, and maternal conditions as lipopolysaccharide (LPS), is associated with fetal
such as preeclampsia and infection. However, most death in experimental animals (Silver et al. 1995,
cases of fetal death at term are not clearly explained, and Ogando et al. 2003). LPS a toxic substance present in
the rates of unexplained stillbirth increase dramatically the outer cell membrane of gram-negative bacteria,
as pregnancy advances beyond 38 weeks (Yudkin et al. which are widely present in the gastrointestinal tract
1987, Smith 2001, Sutan et al. 2010). of humans and animals. LPS is linked to elevated
Evidence supports the role of placental oxidative oxidative stress in experimental animals, as shown
stress in the pathology of many unexplained stillbirth by a significant decrease in antioxidant defense
cases. The placenta is metabolically very active, enzymes with an increase in lipid peroxidation in rats
especially late in pregnancy when fetal demands for and piglets (Zhou et al. 2022, Halawa et al. 2018).
nutrients and oxygen rise significantly. This stimulates In a mouse model of LPS-induced fetal death, LPS
continuous ROS generation and oxidative stress. significantly increased placental oxidative stress as
Placental tissues from late gestation (≥41 weeks) indicated by increased lipid peroxidation, inducible
show signs of oxidative damage and aging (Maiti et al. nitric oxide synthase (iNOS), nitrotyrosine (a marker
2017). Oxidative stress generated by ROS can trigger for peroxynitrite) and decreased GSH content, and
DNA damage (both telomeric and genomic DNA) elevated endoplasmic reticulum (ER) stress and hypoxic
and activate the DNA damage response. Ferrari et al. stress (Chen et al. 2006, Wang et al. 2011). Maternal
(2016) reported that placental telomere length is two- administration of melatonin, a powerful free radical
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 Oxidative stress and negative birth outcomes R29

scavenger, alleviated LPS-induced oxidative stress support the role of oxidative stress in the pathophysiology
in the placenta and protects the fetus from stillbirth of spontaneous abortions and recurrent miscarriage.
(Chen et al. 2006, Wang et al. 2011).
Placental oxidative stress in preterm delivery
Placental oxidative stress in recurrent pregnancy loss
PTB, a baby is born too early (before 37 completed
RPL is defined as two or more miscarriages before weeks of gestation), is the commonest cause of
20 weeks of gestation, and it affects <5% of families neonatal death and is the leading cause of death during
(Hong Li & Marren 2018). There are many potential childhood (Romero et al. 2014). Babies who survive
causes; however, in 50–75% of women with repeated may have lifelong disabilities, including breathing and
miscarriages, the cause is unknown. The early stages of eating difficulties, blindness, hearing problems, cerebral
fetal development are crucial for a successful pregnancy. palsy, and developmental delay. Prematurity may also
An altered balance between antioxidants and ROS take an emotional toll and be a financial burden for
can trigger oxidative stress during this critical time parents and carers. Some risk factors or causes of PTB
and is one of the potential causes of idiopathic RPL. include multiple pregnancies, infections, diabetes, and
Al-Sheikh et al. (2019) found an elevated production hypertension; however, often, no cause is identified.
of superoxide anions and H2O2 in placental tissues Preterm labor mostly happens spontaneously due to the
and plasma of women with RPL compared to healthy early onset of myometrial contractions and ripening of
and non-pregnant women. Ghneim et al. (Ghneim & the cervix with or without the pPROM. But the precise
Alshebly 2016) reported a high level of H2O2 in the mechanisms of the onset of preterm labor remain
plasma of women with a history of RPL compared to vague. Labor occurs through the activation of final
women with no history of RPL. An elevated level of common pathway–uterine contractions and cervical
MDA, a lipid peroxidation product, has been found in dilation; in term delivery, physiological stimuli activate
the placenta and plasma of women with a history of the pathway to labor; in preterm labor, pathological
recurrent miscarriage vs healthy subjects (Simşek et al. processes or conditions induce labor by activating this
1998, El-Far et al. 2007, Baban 2010, Ghneim & pathway (Romero et al. 2014).
Alshebly 2016, Al-Sheikh et al. 2019). Alrashed et al. Human parturition is associated with senescence-
(2021) found increased levels of 8-OHdG in women mediated changes in placental membranes regulated
with a history of RPL, further supporting a central role by the telomere-dependent p38 mitogen-activated
of oxidative stress in the pathogenesis of RPL. protein kinase (p38 MAPK) pathway. These include
Evidence also suggests an association of RPL with activation of p38 MAPK and increased expression of
a decrease in the maternal and placental antioxidant p53, p21, senescence-associated inflammatory factors,
defense systems. Several studies reported that the and SA-β-galactosidase (Behnia et al. 2015). Senescent
activity and expression of key antioxidant enzymes such cells may transmit these inflammatory and senescence-
as SOD, CAT, GR, and GPx were significantly reduced promoting signals, which may cause changes in gene
in RLP pregnancies (El-Far et al. 2007, Yiyenoğlu et al. expression patterns in fetoplacental membranes
2014, Ghneim & Alshebly 2016, Al-Sheikh et al. 2019, and in amniotic fluid that induce the production of
Alrashed et al. 2021). These reports are supported by uterotonics and trigger labor (Haddad et al. 2006).
Ghneim et al. (2016), who observed that plasma and Elevated oxidative stress at term causes DNA damage
placental SOD1 (CuZnSOD) and SOD2 (MnSOD) and accelerates telomere shortening, leading to
activities were significantly lower in RLP than in control telomere-dependent senescence of the placental
pregnancies. membranes and activation of a senescence-associated
The association of oxidative stress in RPL has also inflammatory response that may play a part in human
been investigated using in vivo animal models. Using a parturition (Polettini et al. 2015).
transgenic mouse model of an abnormal mitochondrial ROS activates pathways that involve inflammatory
respiratory chain, Ishii et al. (2014) suggested that and immune responses, including nuclear factor-kappa
mitochondrial respiratory chain dysfunction induces B, potentially leading to systemic inflammation with
chronic intracellular oxidative stress. This causes subsequent parturition (Agarwal et al. 2012). Increased
hypoxia and decreases the vascular endothelial growth levels of pro- or anti-inflammatory factors, including
factor (VEGF) receptor, Flt-1, leading to placental interleukin (IL)1B, IL6, IL8, and tumor necrosis factor-
angiodysplasia, fetal abnormal angiogenesis, and alpha (TNFA), have been found in cervical discharge in
developmental arrest that provoke spontaneous women having delivered preterm, which are associated
miscarriage and RPL (Ishii et al. 2014). Also, maternal with induction of labor (Bowen et al. 2002), and early
exposure to LPS, which produces NOS and triggers onset of these inflammatory signals are likely to trigger
oxidative damage in the gestational tissue, is associated premature labor. ROS-related oxidative damage to
with embryonic resorption in mice (Ogando et al. 2003, DNA has been found to contribute to preterm deliveries
Aisemberg et al. 2012). Together, these data strongly and pPROM (Menon 2014, Dutta et al. 2016) and is
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likely mediated via the senescence-associated secretory maternal deaths are directly linked to preeclampsia,
phenotype (Bonney et al. 2016, Menon et al. 2016). whereas hypertensive pregnancy disorder was associated
Increased levels of oxidized lipid metabolites (MDA with 26% of all maternal deaths in Latin America and
and thiobarbituric acid reactive substances) and DNA the Caribbean (Khan et al. 2006). Preeclampsia is
damage product, 8-OHdG, while reduced levels of responsible for 500,000 perinatal deaths annually. The
antioxidants (GSH, glutathione-S-transferase, and risk for perinatal mortality increases in preeclamptic
selenium) have been reported in the placenta and pregnancy largely due to iatrogenic preterm delivery
maternal serum collected from preterm deliveries (Khan et al. 2006). There is a higher risk of stillbirth
(Ahamed et al. 2009, Cinkaya et al. 2010, Mustafa et al. in preeclampsia, especially when diagnosed in the
2010, Rayman et al. 2011). preterm period. The relative risk of fetal death in pre-
Premature senescence of the fetoplacental eclamptic pregnancies at 26 weeks is 86-fold compared
membranes, triggered by oxidative DNA damage by to pregnancies without preeclampsia. Although the risk
ROS, may contribute to spontaneous preterm labor or of fetal death decreases as pregnancy progresses to
pPROM. A recent review by Phillippe (2022) supports term, however, at 34 weeks, the risk is still 7-fold higher
a potential relationship between oxidative stress- in preeclamptic pregnancies than in normotensive
induced telomere shortening and gestational lengths. pregnancies (Harmon et al. 2015).
Ferrari et al. (2016) showed that telomeres are shorter Although the exact cause of preeclampsia is unknown,
in PTB with pPROM than in spontaneous PTB. Menon it is believed to be a disease of placental origin, as
et al. (2012) reported significantly shorter telomeres rapid and complete recovery occurs after delivery of
in fetal membranes in pPROM than in gestational the placenta. An injury to the vascular endothelium
age-matched spontaneous preterm deliveries without mediated by increased oxidative stress is considered
pPROM. Moreover, increased expression of senescence a key pathological event that leads to preeclampsia
biomarkers, including p38 MAPK, p21, and p53, was (Hubel et al. 1989). Preeclampsia with severe features
reported in the fetoplacental membranes in preterm is frequently accompanied by FGR and shares similar
deliveries with ruptured membranes as opposed to pathophysiologies as FGR (Biri et al. 2007). However,
spontaneous preterm and term births (Menon et al. preeclampsia (with or without FGR) distinguishes itself
2014). These studies indicate that accelerated telomere from FGR because its impact extends into the maternal
shortening and premature senescence of the placental vasculature (Redman 1991, Hubel 1999).
membranes may lead to pPROM. FGR, also known as intrauterine growth restriction
In animals, excessive oxidative stress can induce (IUGR), is an obstetric complication in which the
pre-term labor. Maternal administration of LPS at 14.5 fetus fails to meet its growth potential in utero. FGR
days of gestation caused 100% of the pregnancies to is difficult to define, and there is currently no gold
terminate within 24 h (Gross et al. 2000). The study standard for its diagnosis. The most commonly used
suggested that LPS administration induces the COX2 diagnosis parameter of FGR is an ultrasound estimation
pathway during LPS-induced pre-term labor (Gross et al. of fetal weight that is below the 10th percentile for the
2000). The stimulation of COX2 is a physiological gestational age (Sharma et al. 2016). However, one of
response to oxidative stress caused by LPS exposure, as the biggest challenges is to differentiate between small
evidence from other studies suggested a potential link for gestational age (SGA) and growth-restricted fetuses.
between oxidative stress and cyclooxygenase induction SGA fetuses are constitutionally small but otherwise
(Malek et al. 2001). COX2 plays a role in initiating healthy, with a lower risk of an adverse perinatal
or augmenting the parturition (Burdon et al. 2007) as outcome, while FGR fetuses present with a certain
inhibit ion of COX2 effectively stops preterm delivery in extent of placental insufficiency and a higher risk for
this model (Gross et al. 2000). fetal death (Hanley & Janssen 2012). To establish a
consensus definition of early and late FGR and to make
an accurate diagnosis of FGR, researchers conducted a
Placental oxidative stress in preeclamptic and fetal
Delphi survey amongst an international panel of experts
growth-restricted pregnancies
and refined parameters that are sufficient to diagnose
Preeclamptic pregnancy is characterized by new- FGR (Gordijn et al. 2016). According to this consensus,

of gestation (BP ≥ 140/90 mm Hg), proteinuria (≥ 300

onset maternal hypertension identified after 20 weeks the cutoff for early FGR is 32 gestational weeks, and the
three characteristics to define early FGR: fetal abdominal
mg/24 h), diminished uteroplacental blood flow and circumference (FAC) < 3rd centile OR estimated fetal
pulmonary edema. Preeclampsia affects 2–8% of weight (EFW) < 3rd centile OR no end-diastolic flow
pregnancies globally and is a major cause of maternal, in the umbilical artery on Doppler were agreed. The
fetal, and infant morbidity and mortality (English et al. four contributory factors are EFW or FAC < 10th centile
2015). It is estimated that preeclampsia is responsible for combined with a pulsatility index > 95th centile in
70,000 maternal deaths per year worldwide (Sibai et al. the uterine and umbilical arteries. For late FGR (≥ 32
2005). In developed countries, more than 16% of all weeks), two criteria: FAC or EFW < 3rd centile and the
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 Oxidative stress and negative birth outcomes R31

contributory parameters are: the combination of at least stress impairs the vascular remodeling of spiral arteries
two of the following parameters: (i) EFW or FAC < 10th and results in shallow trophoblast invasion. The failure
centile, (ii) the reduction of EFW or FAC crossing to remodel the spiral arteries results in reduced organ
centiles greater than two quartiles in the growth curve, blood flow (ischemia), followed by reperfusion and
and (iii) the cerebroplacental ratio < 5th centile, or the reoxygenation. This repetitive sequence of intermittent
pulsatility index of the umbilical artery > 95th centile hypoxia-reoxygenation is thought to be the primary
for gestational age were agreed upon in the consensus source of increased local oxidative stress in both
(Gordijn et al. 2016). preeclampsia and FGR as it represents a powerful stimulus
In 2021, a modified Delphi survey (Beune et al. for the mitochondrial respiratory chain complexes and
2020) was conducted to establish a consensus the activation of ROS-producing enzymes, including
regarding the definition of FGR retrospectively NADPH oxidase and XO (Chiarello et al. 2020).
diagnosed at fetal autopsy in intrauterine fetal death. Increased XO and NADPH activities promote ROS
Based on this consensus, FGR in intrauterine fetal synthesis and disrupt the placental redox system, leading
death is defined as evidence of an antenatal clinical to oxidative stress-induced damage to DNA, proteins,
diagnosis of FGR, OR a birth weight < 3rd centile OR and lipids (Jauniaux et al. 2006). The increased release of
at least five of the following ten contributory variables: placental-derived oxidative metabolites in the maternal
(i) risk factors in the clinical antenatal history, (ii) birth circulation, in particular lipid peroxidation products,
weight < 10th centile, (iii) body weight at the time of causes the oxidation of lipoproteins, especially low-
autopsy < 10th centile, (iv) brain weight < 10th centile, density lipoproteins present in the maternal blood. This
(v) foot length < 10th centile, (vi) liver weight < 10th initiates a self-propagating lipid peroxidation chain
centile, (vii) placental weight < 10th centile, (viii) brain reaction, leading to maternal vascular dysfunction
weight to liver weight ratio > 4, (ix) placental weight (Lorentzen & Henriksen 1998).
to birth weight ratio > 90th centile, and (x) histologic In contrast to normotensive pregnant women,
or gross features of placental insufficiency/ vascular significantly higher placental and plasma levels of MDA
malperfusion (Beune et al. 2020). and 4HNE were observed in women with preeclampsia
FGR is a leading cause of fetal, neonatal, and (Wang & Walsh 1998, Madazli et al. 2002, Aydın et al.
perinatal morbidity and mortality (Brodsky & Christou 2004, Sahay et al. 2015, Guerby et al. 2019). A recent
2004). More than 75% of fetal deaths are linked to meta-analysis suggests that MDA level correlates
FGR, especially in unexplained cases (Frøen et al. with the severity of preeclampsia (Afrose et al. 2022).
2004, Flenady et al. 2011), and the babies who survive Similarly, MDA levels are increased in maternal and cord
face life-long health effects such as developmental blood and the placentas of FGR pregnancy compared
disorders in early childhood, and cardiovascular to pregnancy with normally grown fetuses (Biri et al.
and endocrine disorders in adulthood (Chan et al. 2007). 4HNE was found to be involved in oxidative
2010, Meher et al. 2015). Some common causes or stress-induced protein modification by forming adducts
associations of FGR include maternal factors such as with proteins, including SIRT1 (a key protein of oxidant/
age, infection, smoking, obesity, poor obstetric care, antioxidant signaling pathways) in preeclampsia
and fetal factors such as chromosomal abnormalities (Guerby et al. 2019, Tasta et al. 2021). Likewise, SIRT1
and placental factors, or a combination of any of these modification by 4HNE was also observed in placental
factors. Among the placental factors, poor placental tissues from a murine FGR model (Tasta et al. 2021).
function due to abnormal uteroplacental vasculature The addition of 4HNE to cultured human HTR-8/SVneo
and reduced placental blood flow is the leading trophoblasts activates SA-β-galactosidase and increases
cause of FGR (Krishna & Bhalerao 2011). Placental the accumulation of acetylated proteins, consistent
oxidative stress and aging are thought to be central to with 4HNE-SIRT1 adduct formation (Tasta et al. 2021).
abnormal placental function in preeclampsia and FGR Elevated levels of protein carbonyl, a marker of protein
pregnancies. oxidation, in placental and decidual cells occur in
During early gestation, physiological (mild) oxidative preeclampsia (Zusterzeel et al. 2001). Derivatives of
stress occurs in the healthy placenta and is essential for reactive oxygen metabolites (d-ROMs) are increased
placental vasculature development and angiogenesis; in the maternal blood of pregnancies complicated by
in fact, diminishing ROS with potent antioxidants preeclampsia (with or without FGR) (Fujimaki et al. 2011,
during the early stage of placentation reduces Kimura et al. 2013). While the d-ROMs are increased
placental angiogenesis and increases the risk of FGR in the umbilical cord blood in preeclampsia with FGR
and preeclampsia (Yang et al. 2022). First-trimester but not in preeclampsia without FGR (Fujimaki et al.
oxidative stress initiates in the periphery of the placenta 2011). The d-ROMs in maternal blood may be of
and gradually expands to the center; however, a recent placental origin, as the levels of d-ROMs decline after
study suggests that oxidative stress is increased in both delivery (Fujimaki et al. 2011). A significantly higher
the central and peripheral placenta in severe cases of level of placental 8-OHdG, a marker of oxidative
preeclampsia (Bînă et al. 2022). Increased oxidative DNA damage, occurs in placentas from preeclamptic
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Table 1 Biomarkers of placental oxidative stress and aging in pregnancy complications.

Pregnancy
complications Biomarkers References
Fetal death Accelerated telomere shortening, increased 8-OHdG, Chen et al. (2006), Wang et al. (2011), Ferrari et al. (2016),
4HNE, iNOS, peroxynitrile, reduced autophagy, GSH Maiti et al. (2017)
Recurrent pregnancy Elevated oxidants (superoxide anions and hydrogen Simşek et al. (1998), El-Far et al. (2007), Baban (2010),
loss peroxide), NADPH oxidase, MDA and 8-OHdG, reduced Ishii et al. (2014), Ghneim et al. (2016), Yiyenoğlu et al.
antioxidants (SOD, CAT, GR, and GPx), Flt1 (2014), Ghneim and Alshebly (2016), Al-Sheikh et al.
(2019), Alrashed et al. (2021)
Premature rupture of Accelerated telomere shortening, increased IL1B, IL6, IL8, Gross et al. (2000), Bowen et al. (2002), Burdon et al.
membranes and TNFA, MDA, 8-OHdG, p38 MAPK, SA-β-galactosidase, (2007), Ahamed et al. (2009), Cinkaya et al. (2010),
preterm delivery p21 and p53, COX2 Mustafa et al. (2010), Rayman et al. (2011), Menon et al.
(2012, 2014), Dutta et al. (2016), Ferrari et al. (2016)
Preeclampsia Increased MDA, 4HNE, 4HNE-protein adducts, protein Mikhail et al. (1994), Wang and Walsh (1996, 1998),
carbonyl, d-ROMs, 8-OHdG, Ref-1 and H2AX; reduced Mutlu-Türkoglu et al. (1998), Sağol et al. (1999), Kharb
antioxidants (SOD, GPx, glutathione-S-transferase, CAT, (2000), Kumar and Das (2000), Aydın et al. (2004),
selenium, GSH, ascorbic acid, α-tocopherol, vitamin A, Zusterzeel et al. (2001), Madazli et al. (2002), Llurba et al.
β-carotene and lycopene); short telomeres, reduced (2004), Takagi et al. (2004), Wiktor et al. (2004),
telomerase activity and increased senescence-associated Atamer et al. (2005), Beauséjour et al. (2007), Biron-
secretory phenotype, TNFA Shental et al. (2010), Fujimaki et al. (2011), Kimura et al.
(2013), Tadesse et al. (2014), Sahay et al. (2015),
Zhang et al. (2016), Bharadwaj et al. (2018), Guerby et al.
(2019), Sukenik-Halevy et al. (2016), Huang et al. (2020),
Tasta et al. (2021)
Fetal growth Increased MDA, d-ROMs, 8-OHdG, Ref-1 and H2AX; Kudo et al. (2000), Okatani et al. (2001), Takagi et al. (2004),
restriction short telomeres and reduced telomerase activity; Nagai et al. (2008), Davy et al. (2009), Biron-Shental et al.
SA-β-galactosidase, increased acetylated proteins, GPx, (2010), Fujimaki et al. (2011), Raunig et al. (2011),
GSH, CAT Toblli et al. (2012), Kimura et al. (2013), Sukenik-
Halevy et al. (2016), Tasta et al. (2021)

pregnancies with or without FGR compared to healthy Placentas from both preeclampsia, FGR or
placentas (Takagi et al. 2004, Wiktor et al. 2004, preeclampsia coexisting with FGR demonstrate signs
Fujimaki et al. 2011, Kimura et al. 2013). In contrast, of senescence and aging markers, including short
redox factor-1 (ref-1, an indicator of oxidative DNA telomeres, reduced or dysfunctional telomerase, and
damage repair function) is higher in the placentas of increased expression of senescence-associated secretory
preeclamptic women without FGR (Takagi et al. 2004, phenotype factors compared to non-preeclamptic
Fujimaki et al. 2011, Kimura et al. 2013). Also, H2AX, pregnancies (Kudo et al. 2000, Davy et al. 2009, Biron-
a marker of DNA double-strand breaks, is increased in Shental et al. 2010, Sukenik-Halevy et al. 2016).
placental and decidual cells from human preeclamptic The involvement of oxidative stress in FGR and
pregnancies compared to controls (Tadesse et al. 2014, preeclampsia has also been investigated in the
Tasta et al. 2021). Similarly, in a murine model of FGR laboratory using in vivo models. Microcystin-LR (MC-
pregnancy, an increase in placental H2AX levels are LR), a toxin produced by cyanobacteria, decreased
observed compared to the controls (Tasta et al. 2021). both fetal and placental weight in mice (Zhao et al.
Preeclampsia and FGR are associated with altered 2020). Histological examination of the placentas
placental antioxidant levels. In preeclampsia, reduced revealed that blood vessels decreased in the placental
maternal circulating and placental levels of antioxidant labyrinth layer of mice treated with MC-LR. Also,
enzymes, including SOD, GPx, glutathione-S- placental growth factors, such as VEGFA and PGF,
transferase, and CAT occur (Wang & Walsh 1996, nutrient transport pumps, GLUT1 and PCFT are
Mutlu-Türkoglu et al. 1998, Kumar & Das 2000, Wang decreased in the placentas of MC-LR exposed mice. A
& Walsh 2001, Madazli et al. 2002, Atamer et al. 2005). significant increase in placental MDA, while reduced
Significantly decreased levels of several non-enzymatic GSH level, total antioxidant capacity, and antioxidant
antioxidants such as selenium, GSH, ascorbic acid, enzyme activity are observed in the placenta of MC-LR
α-tocopherol, vitamin A, β-carotene, and lycopene treated mice suggesting oxidative stress. Moreover,
have been reported in preeclampsia (Mikhail et al. the ER stress pathway in the placenta is activated,
1994, Sağol et al. 1999, Kharb 2000, Llurba et al. 2004, which suggests that both oxidative stress and ER stress
Atamer et al. 2005). Supporting these observations, caused by MC-LR exposure contribute to placental
Bharadwaj et al. (Bharadwaj et al. 2018) reported maldevelopment and reduced fetal weight (Zhao et al.
reduced maternal total antioxidant levels in subjects 2020). Toblli et al. (Toblli et al. 2012) revealed that
with preeclampsia. In FGR, the SOD and GPx are iron deficiency anemia in rats is associated with
elevated in maternal and umbilical blood and placentas, placenta oxidative stress as indicated by increased
whereas the activity of CAT is depleted (Biri et al. 2007). MDA levels and SOD1 activity and reduced GSH,
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Figure 2 Schema summarizing the role of pathological oxidative stress in the genesis of adverse pregnancy outcomes.

CAT, and GPx activities, which causes FGR dams and hypoxic and ER stress in mice (Wang et al. 2011),
reduced litter size. Other studies showed that maternal and ischemia-reperfusion-induced oxidative damage
administration of melatonin preserves fetal growth by in DNA (8-OHdG and ref-1) and mitochondria
protecting the placenta from LPS-induced oxidative, (Okatani et al. 2001, Nagai et al. 2008).

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Similarly, in a rat model of preeclampsia, markers better understanding of the role of placental oxidative
of oxidative stress, TNFA, endothelial NOS protein, stress, premature senescence, and aging in the genesis
apoptotic index, and vasoconstrictor substances of obstetric complications and identifying biomarkers
are increased, while GSH content is decreased to predict these pregnancy pathologies are necessary
(Beauséjour et al. 2007). Zhang et al. (Zhang et al. 2016) to improve obstetric care. The early prediction and
reported that serum and placental levels of oxidative prevention of these pregnancy pathologies could lessen
DNA damage (8-OHdG), total antioxidant capacity and the enormous psychosocial and economic impacts on
Nox are increased in a Cadmium-induced rat model families and healthcare systems.
of preeclampsia. Oxidative stress in preeclampsia is
thought to be regulated by the mammalian target of
rapamycin (mTOR) pathway. Huang et al. (Huang et al. Declaration of interest
2020) investigated the effect of antioxidant treatment in The authors declare no conflict of interest that could be
a mouse model of preeclampsia associated with FGR. perceived as prejudicing the impartiality of the research
The study demonstrated that mangiferin, an antioxidant reported.
molecule, ameliorates elevated systolic blood pressure
and proteinuria, and increases fetal weights in pre-
eclamptic mice, by attenuating maternal blood and Funding
placental oxidative stress as indicated by the reduction This work was supported by an Early Career Research
in MDA and increase in SOD, GPx, and GSH levels. Fellowship to ZS from the Hunter Medical Research Institute
Mangiferin decreases oxidative stress via activating and Haggarty Foundation.
the mTOR pathway in this mouse preeclampsia model
(Huang et al. 2020). Collectively, evidence of elevated
oxidative stress and diminished antioxidant defence Author contribution statement
in both humans and using in vivo models supports
Conceptualization, data collection, and interpretation:
the concept that oxidative stress plays a part in the
ZS; original draft preparation: ZS and YQ; preparation of
pathology of preeclampsia and FGR.
illustrations: ZS and YQ; review and editing: ZS, RS, KM.
All authors have read and agreed to the final version of the
Summary manuscript to be published.

Table 1 summarizes placental oxidative stress and aging

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