Placental Oxidative Stress: From Miscarriage
Graham J. Burton, MD, and Eric Jauniaux, MD, PhD
pregnancy, miscarriage and preeclampsia.
Review of published literature.
Miscarriage and preeclampsia manifest at contrasting stages of pregnancy, yet both have their
roots in deficient trophoblast invasion during early gestation. Early after implantation, endovascular
trophoblast cells migrate down the lumens of spiral arteries, and are associated with their physiological
conversion into flaccid conduits. Initially these cells occlude the arteries, limiting maternal blood flow into the
placenta. The embryo therefore develops in a low oxygen environment, protecting differentiating cells from
damaging free radicals. Once embryogenesis is complete, the maternal intervillous circulation becomes fully
established, and intraplacental oxygen concentration rises threefold. Onset of the circulation is normally a
progressive periphery-center phenomenon, and high levels of oxidative stress in the periphery may induce
formation of the chorion laeve. If trophoblast invasion is severely impaired, plugging of the spiral arteries is
incomplete, and onset of the maternal intervillous circulation is premature and widespread throughout the
placenta. Syncytiotrophoblastic oxidative damage is extensive, and likely a major contributory factor to
miscarriage. Between these two extremes will be found differing degrees of trophoblast invasion compatible
with ongoing pregnancy but resulting in deficient conversion of the spiral arteries and an ischemia-reperfusion-
type phenomenon. Placental perfusion will be impaired to a greater or lesser extent, generating commensurate
placental oxidative stress that is a major contributory factor to preeclampsia.
Miscarriage, missed miscarriage, and early- and late-onset preeclampsia represent a
spectrum of disorders secondary to deficient trophoblast invasion. (J Soc Gynecol Investig 2004;11:
342–52) Copyright © 2004 by the Society for Gynecologic Investigation.
To review the role of oxidative stress in two common placental-related disorders of
KEY WORDS: Oxidative stress, placenta, pregnancy, miscarriage, preeclampsia.
miscarriage. There is considerable evidence implicating pla-
cental oxidative stress in the pathogenesis of preeclampsia,1,2
and increasing evidence indicating that it may also contribute
to early pregnancy failure.3,4Our hypothesis is that these
disorders, although manifesting at contrasting stages of preg-
nancy, represent different points on a spectrum of placental
stress induced by changes in the intraplacental oxygen concen-
tration. Underlying these changes is a common deficit in
trophoblast invasion during the first and early second trimesters
of pregnancy, and hence incomplete conversion of the endo-
metrial spiral arteries. We review here the anatomic, physio-
logic, and pathologic evidence in support of this concept.
bnormalities of human placentation are associated with
disorders that are either unique to our species, such as
preeclampsia, or very rare in other species, such as
FREE RADICALS AND REACTIVE
Evolution from unicellular life in the oceans to multicellular
life on land has been associated with remarkable metabolic
changes linked to the increasing demand for energy required to
live, grow, and reproduce. Energy transformation of dietary
proteins, carbohydrates, and fats occurs mainly in the mito-
chondria of animal cells through a series of oxidation-reduc-
tion reactions, and the energy released in these reactions is used
to phosphorylate adenosine diphosphate (ADP), thus generat-
ing adenosine triphosphate (ATP). The final step of this pro-
cess uses oxygen (O2) as an electron recipient, and this became
possible some 2 billion years ago with the accumulation of O2
in the atmosphere due to the photosynthetic activities of
cyanobacteria.5The entire process is known as oxidative phos-
phorylation, and ATP is pivotal as the storage form of the
chemical energy required to drive many biochemical reactions
in the cell, in particular, protein biosynthesis, active transport
of molecules through cellular membranes, ionic homeostasis,
and muscular contractions.
Most of the O2used during the oxidation of dietary organic
molecules is converted into water through the integrated ac-
From the Department of Anatomy, University of Cambridge, Cambridge; and the
Academic Department of Obstetrics and Gynaecology Royal Free and University College
London Medical School, London, United Kingdom.
This work was supported by a grant from the WellBeing Charity, London, United
The authors are grateful to Dee Hughes for preparing the final version of Figure 4.
Address correspondence and reprint requests to: Graham J. Burton, MD, Department
of Anatomy, Downing Street, Cambridge CB2 3DY, United Kingdom. E-mail:
Copyright © 2004 by the Society for Gynecologic Investigation.
Published by Elsevier Inc.
tions of the enzymes of the mitochondrial respiratory chain.
However, these enzymes, in particular complex III, are not
totally efficient and electrons can “leak” onto molecular oxy-
gen to form the superoxide anion (O2
amount (1–2%) of the O2we consume is diverted into the
production of O2
rate dependent on the prevailing oxygen tension.7Because it
possesses an unpaired electron, the superoxide anion belongs to
a class of molecules termed free radicals, which along with
their nonradical intermediates fall under the umbrella term of
reactive oxygen species (ROS). ROS are characterized by
their high reactivity, and in order to prevent damage to
biomolecules an array of antioxidant defenses has evolved. Due
to its charge O2
within the mitochondrial matrix where it is detoxified by the
enzyme manganese superoxide dismutase (MnSOD). SOD is
present in all aerobic cells, and is found in the cytoplasm as the
alternative copper/zinc isoform (Cu/Zn SOD). The enzyme
reduced to water by the antioxidant enzymes catalase (CAT)
and glutathione peroxidase (GPX) (Figure 1). In addition to
the antioxidant enzymes, other molecules such as thiols, cer-
uloplasmin, or transferrin and dietary vitamins, for example,
ascorbate (vitamin C) and ?-tocopherol (vitamin E), play a
crucial role in the defense against oxygen free radicals.5
A complex homeostatic balance is thus achieved, and at
physiological levels free radicals regulate a wide variety of cell
functions through their actions on redox-sensitive transcrip-
tion factors.8,9It is essential that these defenses act in concert,
as an imbalance can lead to the production of other more
highly reactive radical species such as the hydroxyl (OH.),
peroxyl (RO2), and hydroperoxyl (HO2
eration of these radicals exceeds the cellular defenses, then
indiscriminate damage can occur to proteins, lipids, and DNA,
resulting in cellular oxidative stress. The consequences may
.?in this way, with O2
.?being formed at a
.?is membrane impermeable, and remains
.?to hydrogen peroxide (H2O2), which in turn is
.) anions.5If the gen-
range from the activation of stress-response proteins through
disruption of signaling mechanisms, structural damage to apo-
ptosis, or necrosis.10
Although under physiological conditions the main source of
intracellular ROS is as a byproduct of aerobic respiration, they
can arise from other metabolic reactions and oxidase enzymes.
These include NAD(P)H oxidase, a membrane-associated en-
zyme that plays an important role in oxygen sensing in endo-
thelial cells and myocytes,11and that is also present in the
placenta.12,13Under pathological conditions, however, differ-
ent mechanisms may come into play, and one potentially
important source is the enzyme xanthine dehydrogenase/xan-
thine oxidase. In the dehydrogenase form, this enzyme con-
verts hypoxanthine to xanthine, and xanthine to uric acid,
passing the electron released on to NAD?. During periods of
hypoxia, the enzyme can be cleaved by calcium-dependent
proteases to the oxidase form, which uses O2as the electron
recipient, so generating O2
for the burst of free radical production that is associated with
episodes of ischemia-reperfusion,14and accounts for why fluc-
tuations in O2concentration can be particularly damaging to
Fluctuations in O2concentration may occur within the
human placenta due to the unique pattern of development of
the maternal blood supply to the organ.
ONSET OF THE MATERNAL ARTERIAL BLOOD
SUPPLY TO THE PLACENTA IN
The definitive human placenta consists of the elaborately
branched fetal villous tree bathed by the maternal blood cir-
culating within the intervillous space, and so is classified his-
tologically as being of the hemochorial type (Figure 2). During
implantation the invading trophoblast erodes into capillaries
and small veins within the superficial endometrium,15and
shortly after maternal erythrocytes can be observed within the
precursors of the placental intervillous space. Traditionally,
therefore, it has been widely assumed that the maternal in-
traplacental circulation is established soon after implantation,16
and the precocious supply of nutrients this provides for has
been considered a key evolutionary advantage of the invasive
form of implantation displayed by the great apes and humans.
However, the presence of maternal erythrocytes does not
necessarily signify an effective circulation, and in the classic
texts describing placental development doubt was expressed as
to when connections between the maternal arteries and the
intervillous space are first observed.17,18Although this remains
a somewhat controversial subject, recent studies employing
diverse techniques, including hysteroscopy, perfusion of hys-
terectomy specimens with the placenta in situ, and Doppler
ultrasound studies of the early placenta in vivo, have presented
compelling evidence that the maternal intraplacental circula-
tion is only fully established at 10 to 12 weeks of pregnan-
cy.19–23Until then, the intervillous space is filled with a clear
fluid, most likely a maternal plasma filtrate supplemented by
secretions from the uterine glands.24,25The human placenta
.?. This conversion is responsible
Figure 1. Diagrammatic representation of the main detoxification
pathways for ROS. Excess production of superoxide anions (O2
can lead to formation of the more dangerous hydroxyl (OH.) ions
through the iron-catalyzed Fenton reaction. Alternatively, O2
react with nitric oxide to form the prooxidant peroxynitrite. The rate
reaction for this combination is some ten times faster than that
Placental Oxidative StressJ Soc Gynecol InvestigVol. 11, No. 6, September 2004343
cannot therefore be considered truly hemochorial until the end
of the first trimester. Fundamental to this new understanding is
the process of physiological conversion of the endometrial
In the nonpregnant state, the spiral arteries are small-caliber,
vasoreactive vessels that arise from the radial arteries and feed
into the superficial capillary plexus within the endometrium.
During pregnancy they undergo conversion into distended,
flaccid uteroplacental vessels, capable of accommodating the
increase in uterine arterial blood flow from just a few milliliters
per minute in the nonpregnant state to approximately 700
mL/min at term.18,23The architecture of their decidual and
myometrial segments is disrupted during this process by the
loss of myocytes from the media and the internal elastic lamina,
which are progressively replaced by fibrinoid.26,27The physi-
ological change only occurs in the presence of extravillous
trophoblast cells that arise from the tips of the cytotrophoblast
cell columns of anchoring villi.28Where these columns abut
the endometrium, the cytotrophoblast cells spread laterally to
form a continuous layer several cells deep, termed the cytotro-
phoblastic shell. Cells migrate from the deep surface of this
shell, invading between the uterine glands as interstitial tro-
phoblast, and down the lumens of the vessels as endovascular
trophoblast.26,28,29The process begins soon after the blastocyst
has implanted and gradually extends laterally, reaching the
periphery of the placenta around mid-gestation. Depth-wise
the changes normally extend as far as the inner third of the
myometrium within the central region of the placental bed,
but the extent of invasion is progressively shallower towards
the periphery.30Therefore, even in normal pregnancies not all
the arteries are completely transformed.31
In the early stages the volume of endovascular trophoblast
cells migrating down the arterial lumens is sufficient to occlude
or “plug” the tips of the maternal vessels.22,32Free flow of
maternal blood into the intervillous space is therefore not
possible, although slow seepage of plasma through the network
of intercellular clefts may occur. At about the 10th week these
plugs begin to dissipate, establishing free communications be-
tween the spiral arteries and the placenta (Figure 3). The
greater trophoblast invasion that occurs in the central region of
the placental bed30means that the plugs are more extensive and
complete in this region, and so it might be predicted that
dissipation of the plugs will occur first at the periphery of the
Figure 2. Photomicrograph of a placenta-in-situ associated with a
60-mm fetus (Boyd Collection) showing the definitive placenta (large
arrow). P ? placental tissue; D ? decidua; M ? myometrium. Note
the regression of villi over the nonembryonic pole to form the
chorion laeve, and the irregularity of the decidua with the presence of
maternal vessels in a septum (small arrow). *Fixation artifact.
Figure 3. Doppler mapping and spectral analysis of uteroplacental blood flows at 12 weeks’ gestation. A) Intervillous blood flow showing a
typical venous-like nonpulsatile flow. B) Spiral artery blood flow at the level of the placental bed.
344 J Soc Gynecol Investig Vol. 11, No. 6, September 2004 Burton and Jauniaux
placenta. Our recent Doppler studies have confirmed that is
the case in the majority of normal pregnancies.3
INTRAPLACENTAL OXYGEN CONCENTRATIONS
DURING EARLY PREGNANCY
The human fetoplacental unit is therefore exposed to major
fluctuations in O2concentration during pregnancy. The O2
tension in the oviduct and uterus of most mammalian species
at the time of implantation has been found to range between
11 and 60 mmHg, which corresponds to approximately 1–9%
O2.33–35The partial pressure of oxygen (PO2) measured
within the human placenta in vivo is less than 20 mmHg at 7
to 10 weeks gestation, and is therefore equivalent.36,37Main-
taining a low oxygen concentration during the embryonic
period appears to favor blastulation and normal cell differen-
tiation, and may protect from the damaging effects of oxygen
free radical species.38Once this process is complete at 11 to 14
weeks, the intraplacental oxygen tension rises to greater than
50 mmHg as the maternal circulation becomes fully estab-
lished.36,37Despite this rise values remain low within the fetus
as the diffusional characteristics of the placenta are limited at
this stage of gestation.39,40At 13 to 16 weeks, the PO2in the
fetal blood is 24 mmHg, whereas during the second half of
pregnancy that in the umbilical vein ranges between 35 and 55
mmHg. All of these values are relatively low compared to the
PO2values found in the maternal circulation,41suggesting that
there is a significant O2gradient between the maternal and
fetal tissues throughout pregnancy.
PHYSIOLOGICAL OXIDATIVE STRESS IN
EARLY PLACENTAL TISSUES
The sharp increase in O2tension experienced by the placenta
in vivo when the maternal circulation is fully established is
associated with a burst of oxidative stress within the placental
tissues.37This is particularly marked in the syncytiotrophoblast,
where we detected immunohistochemically the presence of
nitrotyrosine residues indicating the formation of peroxynitrite
hydroxynonenal adducts (HNE) indicating oxidation of lipids,
and expression of heat shock protein (Hsp) 70.37The latter is
recognized as a sensitive marker of oxidative stress in other
systems.42The expression of these markers can be induced in
vitro by exposing villi to 21% O2, and is associated with
increased generation of ROS as detected by the fluorescent
dye dichlorofluorescein diacetate (DCFH-DA).43,44The cel-
lular source of the ROS is not known, but the fact we
observed swelling of the mitochondrial intracristal space both
in vivo and in vitro suggests that mitochondria are a significant
contributor. This is supported by the finding that addition of
10 ?m diazoxide, a mitochondrial ATP-dependent K?chan-
nel opener, partially reduces both the generation of ROS and
the expression of markers of oxidative stress.45Generation of
ROS occurs within minutes of exposure to 21% O2, but if villi
are maintained for longer periods then mitochondrial mem-
brane potential is lost after 1 hour, and degeneration of the
syncytiotrophoblast occurs after 4 hours.46The tissue rapidly
?) from nitric oxide (NO.) and O2
undergoes vacuolation, dilation of the mitochondrial intracri-
stal space, loss of the microvillous covering, and blebbing of
the apical membrane. However, the underlying cytotropho-
blast and stromal cells remain viable, reflecting the greater
concentrations of the principal antioxidant enzymes within
these cell types.47,48Indeed, the cytotrophoblast cells differen-
tiate and fuse to form a new syncytiotrophoblastic layer that is
morphologically equivalent to the original.46Degeneration
and regeneration of the syncytiotrophoblast have subsequently
been reported for term villi maintained under 21% O2.49,50
The physiological role of this burst of oxidative stress is only
beginning to be elucidated, but a number of cell functions
within the placenta are now recognized as being influenced by
the prevailing oxygen concentration. These include matrix
and migration,53–55cytotrophoblast fusion,56,57endocrine se-
cretion,58,59and cytokine production.60A further and more
dramatic effect may be villous regression over the superficial
pole of the chorionic sac to form the smooth chorion or
chorion laeve (Figures 2 and 4). We recently reported that the
degree of oxidative stress is greatest in the peripheral regions of
early placentas, correlating with the pattern of onset of the
maternal blood flow.3Although measurements of the O2con-
centration within different regions of the early placenta are not
available, it is not unreasonable to assume on the basis of the
Doppler evidence of maternal blood flow that the PO2will be
greatest in the peripheral region. Examination of placentae-in
situ specimens has revealed that the villi over the superficial
pole are less extensive than their central counterparts at 8
weeks gestational age.3They are surrounded by maternal
erythrocytes but are themselves conspicuously avascular, con-
sistent with down-regulation of vascular endothelial growth
factor (VEGF), a hypoxically regulated gene.52They also have
a thin trophoblastic covering and a virtually acellular stromal
Hence, onset of the maternal circulation may have a pro-
found impact on villous function and integrity, and it is essen-
tial for a successful pregnancy that it happens in a carefully
coordinated periphery-central manner.
DEFECTIVE PLACENTATION, OXIDATIVE
STRESS, AND EARLY PREGNANCY FAILURE
In approximately two thirds of early pregnancy failures there is
anatomical evidence of defective placentation, which is mainly
characterized by a thinner and fragmented trophoblast shell and
reduced cytotrophoblast invasion of the lumen at the tips of
the spiral arteries.61This is associated with both premature
onset of the maternal circulation and loss of the periphery-
center coordination in most cases of miscarriage, with blood
flow occurring throughout the placenta.3,62,63These defects
are similar in euploid and most aneuploid miscarriages,64but
they are more pronounced in triploid partial moles. In com-
plete hydatidiform mole the extravillous trophoblast invasion
into the decidua and superficial myometrium is almost entirely
absent.65,66A recent histological investigation of the products
of conception from miscarriage associated with primary an-
Placental Oxidative StressJ Soc Gynecol Investig Vol. 11, No. 6, September 2004345
tiphospholipid (aPL) antibody syndrome has also confirmed
defective decidual endovascular trophoblast invasion in these
cases.67The data show that by contrast to what has been found
in other organs, in aPL syndrome the frequency of placental
thrombosis is not increased compared to aneuploid early preg-
nancy failure. In vitro, aPL antibodies induce VE-cadherin
down-regulation and E-cadherin up-regulation at both the
protein and mRNA levels.68The abnormal trophoblast adhe-
sion molecules expression found in aPL antibody syndrome,
and in particular the decrease in alpha-1 integrin expression, is
similar to that reported in preeclampsia.
As might be expected, the excessive entry of maternal blood
into the intervillous space has a direct mechanical effect on the
villous tissue, and an indirect oxidative stress effect, which
contributes to cellular dysfunction and/or damage. Levels of
oxidative stress are considerably higher within the whole pla-
centa than in normal cases3,4(Figure 4). Indeed, the extent of
syncytiotrophoblast degeneration on central villi from cases of
missed miscarriage is almost identical to that seen within the
peripheral regions of normal pregnancies (healthy syncytiotro-
phoblast represents 45.9 ? 20.8% versus 46.4 ? 19.6% of the
villous surface, P ? .964). Large areas of degenerate syncy-
tiotrophoblast may be seen sloughing from the villous surface,
accompanied by increased apoptosis and reduced proliferation
among the underlying cytotrophoblast cells.4,69Despite this,
some of the cytotrophoblast cells differentiate and fuse to form
a new syncytiotrophoblast layer that is immunoreactive for
human chorionic gonadotrophin. As a result, serum concen-
trations are within the normal range, maintaining the preg-
nancy as a missed miscarriage.64With time, however, the fetal
capillaries within the villi regress, presumably due to down-
regulation of VEGF in response to the increased oxygen ten-
sion prevailing, and the villous cores become virtually
acellular.4,70Villous atrophy follows, so that the placenta be-
comes only a thin shell, and finally the pregnancy is lost.
Overall, the placental histology closely reflects that seen
within the peripheral regions of the normal placenta, suggest-
ing that regression of the villi over the nonembryonic pole of
the chorionic sac to form the chorion leave and that seen in
missed miscarriage are manifestations of the same process in-
duced by an elevated O2concentration. The former might be
considered physiological and the latter pathological, although
it is arguable that miscarriage may be a physiological mecha-
nism for the removal of genetically abnormal conceptuses.
Maternal screening of the migrating extravillous trophoblast
cells and limitation of invasion may be the fundamental pro-
cess, with abnormal onset of the maternal blood flow provid-
ing the mechanism.
Figure 4. Diagrammatic representation of the proposed relationship between the degree of oxidative stress and placental development in normal
pregnancies, late-onset preeclampsia, early-onset preeclampsia, and miscarriage. In normal pregnancies trophoblast invasion is extensive and
aggregates of cytotrophoblast cells derived from the cytotrophoblastic shell effectively plug the tips of the spiral arteries. Onset of the maternal
circulation (arrows) starts in the periphery, and causes local oxidative stress (depicted by shading), villous regression and formation of the chorion
laeve. In miscarriage, trophoblast invasion is severely deficient, leading to a thin cytotrophoblastic shell, incomplete plugging of the spiral arteries,
premature and disorganized onset of blood flow, and overwhelming oxidative stress throughout the placenta. The situation is intermediate in
preeclampsia. In early-onset cases, the onset of the maternal circulation may be abnormal due to poor development of the cytotrophoblastic shell.
Early oxidative stress may lead to impaired villous growth, while secondary atherotic changes (depicted by shading) in the spiral arteries will cause
placental hypoxia and intrauterine growth restriction. In late-onset cases, the situation is less severe, and placental oxidative stress only develops
towards the end of gestation.
346 J Soc Gynecol Investig Vol. 11, No. 6, September 2004Burton and Jauniaux
There are, of course, other causes of oxidative stress that
may also contribute to pregnancy failure. For example, among
diabetic women, poor glycemic control is associated with an
increased risk of spontaneous miscarriage.71There is also in-
creasing evidence showing an association between miscarriage
and an anomaly of one of the enzymes involved in the me-
tabolism of ROS.72,73In addition, our recent data on the role
of uterine glands in early fetal nutrition and the transport of
vitamin E suggest that insufficient decidualization could have
an impact on placentation.25,74These glands remain active
until at least the 10th week of pregnancy, and their secretions
are delivered freely into the placental intervillous space. An
endometrial thickness of 8 mm or more is considered to be
favorable for embryo implantation.75Both adequate endome-
trial thickness and vascularization are needed for implantation,
and women with a good endometrial thickness on ultrasound
but a poor intra-endometrial blood flow tend to have a poor
reproductive outcome.76Furthermore, uterine perfusion ap-
pears to regulate endometrial receptivity, and a high uterine
resistance to blood flow is associated with recurrent miscar-
riages.77Decreased expression of SOD and increased levels of
lipid peroxidation have also been reported in the decidua of
women undergoing early pregnancy loss,78although whether
these changes are a primary cause or a secondary event is not
clear as they are only observed in those cases with associated
The causes of early pregnancy failure may therefore be
divided into three main anatomic categories: disorders affect-
ing primarily the villous development such as in aneuploidy
and/or lethal fetal anomalies, disorders affecting mainly the
cytotrophoblast invasion such as in the aPL antibody syn-
drome, and disorders of the uteroplacental interface such as in
luteal phase deficiency or chronic inflammatory reaction.
Some factors, particularly toxins contained within active or
passive cigarette smoke, radiation, or viral infection, can have
an impact at all three levels, whereas some fetoplacental anom-
alies, such as paternally inherited triploidy, can have an impact
on both villous development and cytotrophoblast invasiveness.
Whatever the initial factor, a major defect of the placentation
process will lead to an incomplete development of the pla-
cento-decidual interface and subsequent premature and wide-
spread onset of the intervillous circulation. This will result in
severe oxidative damage to the villous trophoblast, which
inevitably leads to a complete placental development arrest.
PLACENTAL OXIDATIVE STRESS IN LATER
PREGNANCY AND IN PREECLAMPSIA
Measurements of the O2concentration within the intervillous
space indicate that there is a gradual decline from approxi-
mately 60 mmHg at 16 weeks to about 40 mmHg at term.79
Despite this decline, and a supposed switch to a less oxidative
environment, we have found evidence of oxidative stress in
otherwise normal placentas delivered at term by cesarean sec-
tion.80The cause of this stress is not certain, but extrapolating
our findings from the first trimester suggests that hypoxia alone
is not a sufficient cause. The O2concentration at term is still
twice that during the first trimester, when the trophoblast
shows no evidence of oxidative stress. Equally, if villi from
term placentas are maintained in vitro under constant condi-
tions of low O2(12–16 mmHg), they display no increase in
oxidative stress.80However, reintroducing O2after a period of
hypoxia causes rapid production of ROS, and evidence of
tissue oxidative stress in terms of the formation of nitrotryosine
residues and lipid peroxidation. We have therefore proposed
that the constancy of the O2concentration may be a more
important factor in the generation of placental oxidative stress
than the absolute value.81
Oxygen concentrations may fluctuate within the intervillous
space during the second and trimesters through three principal
mechanisms: intrinsic contraction of the spiral arteries, external
compression of the arteries, and redistribution of maternal
blood flow. First, angiographic studies on the macaque, which
displays a similar maternal vascular anatomy to the human,
demonstrated that during normal pregnancy flow from spiral
arteries into the intervillous space is often intermittent.18,82As
these studies were performed during periods of uterine relax-
ation, the investigators concluded that the effect was due to
vasoconstriction within the unconverted segments of individ-
ual arteries rather than external compression. This was sup-
ported by the observation that an injection of L-epinephrine
into the maternal circulation caused a dramatic reduction in
the number of arteries that discharged into the intervillous
space. Second, towards term the strength of the uterine con-
tractions increases, and leads to transient compression of the
myometrial arteries, either blocking or severely impairing in-
flow into the intervillous space.18,83,84Third, major alterations
in uterine perfusion can occur as part of the general redistri-
bution of blood flow in response to factors such as maternal
exercise and changes in posture.85Since the placenta and fetus
continually extract oxygen from the maternal blood within the
intervillous space it is expected that transient hypoxia will
result during the periods of relative stasis. Some degree of
hypoxia-reoxygenation type injury is therefore likely be a
feature of the normal human pregnancy, especially towards
term when the fetal and placental extraction of oxygen are at
their highest.81This would certainly seem to be the case
during vaginal delivery when the contractions are at their
strongest, and there is evidence both of increased xanthine
oxidase activity within the placenta86and depletion of mater-
nal serum vitamin C.87
There is now compelling evidence that placental oxidative
stress plays a pivotal role in the pathogenesis of preeclampsia,
although the precise mechanism remains elusive.1,2,88Quali-
tatively, the situation within the placenta in preeclampsia ap-
pears to be an extension of that seen towards the end of normal
gestation, as there is evidence of increased nitrotyrosine for-
mation, increased lipid peroxidation, increased trophoblast ap-
optosis, decreased activity of the principal antioxidant
enzymes, and reduced tissue concentrations of nonenzymatic
antioxidant molecules such as vitamin E.89–94Again the cause
for the oxidative stress is not known, although it is widely
assumed to be secondary to placental hypoxia consequent to
Placental Oxidative StressJ Soc Gynecol Investig Vol. 11, No. 6, September 2004347
the deficient trophoblast invasion that typifies the majority of
cases.30,31The defect involves both the number of vessels that
are converted, and the extent of the transformation within
individual arteries. The cause for the incomplete conversion is
not known, but it appears that only the endovascular compo-
nent of trophoblast invasion is impaired. Interstitial invasion
extends as far as normal, and so there may be a primary defect
of the endovascular cytotrophoblast or an abnormality in the
uterine endometrium that these cells are attempting to in-
vade.27It has also been reported that macrophages, which are
found in excess in the placental bed of preeclamptic women,
are also able to limit the extravillous trophoblastic invasion,95
although their influence on the endovascular population is not
The end result is a failure to convert the distal portions of
the spiral arteries into large-caliber flaccid conduits. We sug-
gest that by itself this is likely to have relatively little impact on
the volume of intervillous blood flow and O2concentrations as
these sections of the arteries are not flow-limiting.96,97The
unconverted segment of the spiral artery where it arises from
the radial artery will always be of smaller caliber, and so serve
that function. By contrast, dilatation of the vessel distal to this
section will have a major impact on the rate and the pressure
with which the maternal blood enters the intervillous space,
reducing both. In doing so it will benefit materno-fetal ex-
change by ensuring an appropriate passage time through the
placenta and prevent collapse of the fetal villous capillaries.
There is also no conclusive evidence that the placenta is
hypoxic in preeclampsia, particularly in late-onset cases, or that
the placental changes seen in preeclampsia are typical of hyp-
oxia.81,98An alternative explanation may lie in the fact that due
to incomplete conversion the majority of spiral arteries within
the placental bed retain considerable smooth muscle within
their walls.99A greater degree of vasoreactivity will therefore
persist, exacerbating the intermittent perfusion seen in normal
pregnancies. Modeling these effects in vitro has shown that
hypoxia-reoxygenation is a much more potent stimulus for the
alone,80,100and so likely to be the causative insult under
THE SPECTRUM OF PLACENTAL
Preeclampsia is not an all or nothing phenomenon and there
are major differences in the clinical manifestations and out-
comes between the early-onset and late-onset forms of the
syndrome. In particular, early-onset preeclampsia is almost
universally associated with intrauterine growth restriction,
whereas this is rarely the case with late onset. Whether the two
forms represent different disorders or different maternal sus-
ceptibilities to the products of the stressed placenta is not
We propose the two forms represent a spectrum of oxidative
stress induced by differing degrees of impairment of tropho-
blast invasion. Recent longitudinal studies of placental growth
by ultrasound have revealed that in cases of early-onset pre-
eclampsia associated with intrauterine growth restriction, pla-
cental volume is reduced from as early as 12 weeks of
gestation.101This suggests the placental pathology is initiated at
the time of onset of the maternal circulation. Because endo-
vascular trophoblast invasion is associated with both plugging
of the spiral arteries during the first trimester and their physi-
ological conversion, it is likely that onset of the maternal
circulation will be perturbed in the most serious cases of
preeclampsia. We speculate that this will lead to high levels of
oxidative stress, although insufficient to cause pregnancy loss
(Figure 4). Nonetheless, there may be increased apoptosis and
decreased proliferation, as we have seen in the missed miscar-
riage specimens,4leading to a reduced villous development at
term.102The altered hemodynamics of maternal blood entry
into the intervillous space, with entry being at too great a rate
as result of the failure of the distal segments of the spiral arteries
to dilate, may also cause the blood-lakes and increased throm-
bosis that typify these cases.103,104In addition, early-onset
preeclampsia is commonly associated with acute atherotic
changes in the spiral arteries in later pregnancy, which restrict
their caliber still further.31,105Whether these are primary ef-
fects or secondary insults is not known. However, we speculate
that the distal segments of the arteries in which these changes
occur will themselves be involved in any hypoxia-reoxygen-
ation resulting from increased vasoconstriction of the uncon-
verted segments. We consider it most likely, therefore, that
these are secondary changes, and that as they develop there will
be an increasing impairment of placental perfusion. Placental
hypoxia will ensue, and this, along with reduced placental
function as result of increased oxidative stress, will contribute
to the fetal growth restriction observed. Similar atherotic
changes have also been reported in cases of intrauterine growth
restriction without hypertension, and so they are not in them-
selves causative of preeclampsia.106Whether the placentas
from these cases display equivalent oxidative stress to that seen
in preeclampsia is not known.
By contrast, in cases of late-onset preeclampsia, placental
volume is slightly larger than normal at 12 weeks, and grows
rapidly until 22 weeks.101The placental insult is clearly less
severe as villous growth is normal,102,107and the maternal
vascular changes are less extensive.31We propose that these
cases represent an exaggeration of the situation that normally
develops towards term, and that there is insufficient time for
atherotic changes in the spiral arteries to become manifest
(Figure 4). As a result, birth weight is normal, and there will be
considerable overlap in the values of clinical parameters be-
tween these cases and normal pregnancies.
Taken together, these findings emphasize the critical impor-
tance of the maternal circulation to the well-being of the
placenta. Although confirmatory physiologic data are not
available, the human placenta is probably unique in undergo-
ing a transition in oxygenation at the end of the first trimester.
In other species, that part of the placenta involved in hemotro-
phic exchange appears to develop under a more constant O2
348 J Soc Gynecol Investig Vol. 11, No. 6, September 2004Burton and Jauniaux
concentration. For example, the labyrinth of the mouse is
vascularized by a maternal circulation almost from its origin.
The difference is that in the mouse labyrinth development
commences about half-way through gestation, by which time
embryogenesis is almost complete, whereas in humans devel-
opment of the placenta occurs much earlier. Maternal meta-
bolic disorders, for example, diabetes, which are associated
with an increased production of ROS, are also known to be
associated with a higher incidence of fetal structural defects.108
Furthermore, the teratogenicity of drugs such as thalidomide
has recently been shown to involve ROS-mediated oxidative
damage,109indicating that the human fetus can be irreversibly
damaged by oxidative stress. These findings suggest fetal de-
velopment is highly sensitive to perturbation by ROS, and
hence maintaining a low O2environment inside the human
uterus during early pregnancy may confer protection.
By contrast, a profuse and steady maternal blood flow to the
placenta is clearly required to support fetal growth during the
second and third trimesters. What we observe, however, is that
the transition in the maternal placental circulation at 10 to 12
weeks is a potentially dangerous one. It must be carefully
orchestrated in a periphery-center fashion to prevent over-
whelming oxidative stress to the placenta, which may contrib-
ute to pregnancy failure. Plugging/unplugging of the spiral
arteries appears to be related to successful invasion of the
extravillous trophoblast cells, a process that is also linked to
conversion of the spiral arteries. Hence, we speculate that in
normal pregnancies trophoblast invasion is complete, unplug-
ging of the vessels is orderly, and the arteries are fully con-
verted. If trophoblast invasion is less complete, the vessels may
retain some of their vasoreactivity, leading to a greater degree
of intermittent perfusion of the intervillous space and placental
oxidative stress and predisposing the mother to preeclampsia. If
trophoblast invasion is particularly shallow, then unplugging of
the vessels may be premature and disorganized, resulting in
overwhelming placental oxidative stress and pregnancy failure
(Figure 5). Miscarriage and preeclampsia may therefore be part
of a continuum of placental oxidative stress, which although
being heavily influenced by the depth of trophoblast invasion,
may also integrate other factors such as polymorphisms in
enzymes either generating or scavenging ROS, metabolic dis-
orders, drug intake, dietary micronutrients, and maternal sus-
ceptibility to the products of placental oxidative stress.
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