European Journal of Obstetrics & Gynecology and
Reproductive Biology 115 (2004) 134–147
Review
Pathophysiology of preeclampsia: links with
implantation disorders
Philippe Merviela,b,*, Lionel Carbillonb,c, Jean-Claude Challierb,
Michèle Rabreaud, Michel Beaufilse, Serge Uzana,b
a
Department of Gynecology, Obstetrics and Reproductive Medicine, Hospital Tenon, 4 rue de la Chine, 75020 Paris, France
b
UPRES Physiology of Implantation and Development (EA 2396), Hospital Tenon, 4 rue de la Chine, 75020 Paris, France
c
Department of Gynecology and Obstetrics, Hospital Jean-Verdier, Avenue du 14 Juillet, 93143 Bondy, France
d
Institut d’Histo-Cyto-Pathologie, ZA du Limancet, 114-116 Avenue Leon Blum, 33495 Le Bouscat Cedex, France
e
Department of Internal Medicine, Hospital Tenon, 4 rue de la Chine, 75020 Paris, France
Received 5 May 2003; accepted 22 December 2003
Abstract
The phenomenon of implantation anchors the embryo into the uterine wall and produces a hemochorial placenta that maintains the
pregnancy and fetal growth. Implantation and placentation are intimately linked and cannot be dissociated either in time or in space.
Preeclampsia is characterized by hypertension and proteinuria. It is secondary to an anomaly of the invasion of the uterine spiral arteries by
extra-villous cytotrophoblast cells, associated with local disruptions of vascular tone, of immunological balance and inflammatory status, and
sometimes with genetic predispositions. Preeclampsia is a disease of early pregnancy, a form of incomplete spontaneous abortion, but is
expressed late in pregnancy. Aspirin may play a favorable role in implantation which is related to the genesis of preeclampsia and some cases
of intra-uterine growth restriction. The most important points in obtaining a preventive effect from low-dose aspirin during the pregnancy are
early treatment (before 13 weeks of gestation) and the prescription of a sufficient dose (more than 100 mg per day).
# 2004 Published by Elsevier Ireland Ltd.
Keywords: Aspirin; Extra-villous cytotrophoblast; Implantation; Preeclampsia
1. Introduction
Implantation of the human embryo leads to the invasion
by the extraembryonic trophoblast of the endometrium and
to the colonization of the uterine arteries. This phenomenon enables the embryo to be anchored in the uterine wall
and thus makes possible the maintenance of the pregnancy
and fetal growth via the placenta. For this semi-allogenic
graft to occur, the endometrium must first undergo structural and biochemical modifications, called decidualization. An implantation window therefore occurs, the result
of the synchronization between embryonic development
and endometrial maturity. The interactions between the
embryo and various components of the decidua then lead to
implantation in the strict sense of the term. Finally, the
trophoblastic cells transform the uterine vascular system;
*
Corresponding author. Tel.: þ33-1-56-01-68-76;
fax: þ33-1-56-01-60-62.
E-mail address: philippe.merviel@fcvnet.net (P. Merviel).
0301-2115/$ – see front matter # 2004 Published by Elsevier Ireland Ltd.
doi:10.1016/j.ejogrb.2003.12.030
this change, together with the action of vasomotor factors,
will adequately nourish the fetal-placental unit [1].
Accordingly, implantation and placentation are actually
two aspects of the same phenomenon, in different places
and moments of the pregnancy [2].
Preeclampsia is characterized by hypertension (>140/
90 mmHg) and proteinuria (>0.3 g/l). It is secondary to
an anomaly of the invasion of the uterine spiral arteries by
cytotrophoblast cells. It may be considered finally as one
form, incomplete, of spontaneous abortion, in view of the
many similarities between them (and their frequent association in the same woman). Like spontaneous abortion,
preeclampsia is a disease of early pregnancy and even
precedes implantation, beginning at the follicular phase.
It is, however, only expressed late in pregnancy (from the
second-trimester), after the activation of a cascade of events
has finally led to the appearance of clinical signs. The aim of
this review is to reconsider the current theories about
preeclampsia, by looking at it together with the mechanisms
of embryo implantation, and to try to identify the therapeutic implications.
P. Merviel et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 115 (2004) 134–147
2. An anomaly of the extra-villous cytotrophoblastic
invasion of the uterine spiral arteries
The extra-villous cytotrophoblast cells (EVCT) must
invade the decidua before they modify the walls of the spiral
arteries [3,4]. The trophoblast behaves like a ‘‘pseudotumor’’ invading the endometrium, which tolerates it in a
controlled way. Unlike an invasive tumor or an inflammatory
reaction, however, implantation is an invasion controlled in
time and space. Any anomaly between the factors promoting
and those limiting this invasion may cause a pregnancyrelated disease. Preeclampsia is one of these [5].
To invade the decidua, the trophoblast cells need both to
recognize the different components of the membrane and of
the extracellular matrix ((ECM) integrins, cadherin) and
break them down (metalloproteases). To control this invasion, the endometrium modifies the composition of its
extracellular matrix (ECM), secretes transforming growth
factor (TGF) b and tissue metalloprotease inhibitors (TIMP)
[6]. Moreover, the decidua is colonized by immune system
cells (NK cells, lymphocytes and macrophages) that are
responsible for the local production of cytokines that promote or inhibit the trophoblastic invasion.
Except during pregnancy, the ECM is composed of collagens I, III, Vand VI, fibronectin and periglandular tenascin
deposits. During decidualization, the endometrial stromal
(decidual) cells produce a pericellular matrix composed of
collagen IV, laminin and heparan sulphate; substantial
hydration of the stroma occurs at the same time. This change
in the composition of the ECM and its hydration make it
easier for the EVCT to invade the decidua. The modified
ECM also establishes close contacts with the lymphoid cells
present in the decidua, thereby increasing the cellular interaction between trophoblastic and lymphoid cells.
The adhesion of EVCT to ECM components (collagen IV,
laminin, proteoglycans, heparan sulphate, entactin and fibronectin) requires the intervention of receptors on the plasmic
membrane that enable the cell to identify and then bind to
them: these receptors are the integrins and cadherins. Integrins are heterodimeric glycoproteins with two subunits: a
and b. Their combination forms many integrins that bind to
various components of the ECM. A ‘‘switch’’ changes the
profile of the integrins as the cytotrophoblast cells change
from proliferative (at the base of anchoring villi) to interstitial (in the deepest portion of the decidua and spiral
arteries). Thus, proliferative EVCT expresses only integrin
a6b4 (receptor for laminin, a component of basement
membrane), then as they migrate (becoming invasive) they
acquire the ability to express integrin a5b1 (fibronectin
receptor). When the cytotrophoblastic cells become interstitial, integrins a1b1 (laminin and type I and IV collagen
receptors), avb1 and avb3 (vitronectin receptor) also appear
[7].
Because the ECM is organized in a tridimensional network that prevents passive cell migration, the adhesion of
trophoblast cells to the ECM components is necessary but
135
not sufficient to guarantee their invasiveness. Accordingly,
the trophoblast cell must be able to proteolyse the ECM
conponents. Matrix metalloproteases (MMP) are endoproteinases that require the presence of Ca2þ and Zn2þ ions;
they include 13 members in three families: collagenases
(MMP 1, 8, 13), which break down types I and III collagens;
gelatinases A (MMP 2) and B (MMP 9), which break down
gelatin, collagen IV and elastin; and the stromelysins (MMP
3, 7, 10 and 11), which have a broader spectrum. These
enzymes are regulated by their activation level (most are
secreted as the inactive forms, zymogens) and by the presence of specific tissue inhibitors, the TIMPs (tissue inhibitors of metalloproteinases, secreted by the decidua), which
block the active site of the enzyme. The trophoblast cells
secrete some MMPs during the first-trimester. These include
gelatinase B, which plays a primordial role in the invasion.
TIMP 1 expression, which is highest at term, balances
gelatinase B activity and thereby controls the invasiveness
of the trophoblast. In addition, integrins can modulate MMP
expression.
TGF b is a growth factor expressed at the feto-maternal
interface by the decidua, from the first-trimester through
term. It inhibits the proliferation and invasion of the trophoblast. TGF b1 is essentially expressed by the villi, and TGF
b2 by the decidua. TGF b1 promotes ECM formation, in
particular collagen and fibronectin, inhibits plasminogen
activator production, induces TIMP 1 expression, and
reduces EVCT migration by overexpressing a5b1. This
overexpression makes the EVCT more adherent to the
ECM and activates the differentiation of the cytotrophoblast
into non-invasive syncytiotrophoblast.
This endometrial maturation is also linked to the growth
of the spiral arteries (branches of the uterine arteries), which
will then carry maternal blood toward the intervillous spaces
of the placenta. The growth and structure of the spiral
arteries depend on ovarian hormonal secretions [8]. Under
the influence of estrogens, their diameter increases as they
grow longer and become progressively twisted [9]. This
endothelial proliferation continues during the luteal phase
and the first weeks of gestation. Growth factors also play a
role in neoangiogenesis: fibroblast growth factor (FGF) b, a
powerful angiogenic factor, is increased by estradiol and
inhibited by progesterone; vascular endothelial growth factor (VEGF), stimulated by estrogens and hypoxia, is mitogenic for endothelial cells and increases vascular
permeability; and platelet-derived growth factor (PDGF),
which contributes to angiogenesis and to the growth of
smooth muscle cells. Finally, other factors, including
TGF b, tumor necrosis factor (TNF) a, interleukin (IL)-1
and IL-6, also participate in this angiogenesis. This neoangiogenesis can be disrupted by conditions that are accompanied by microangiopathy, such as insulin-dependent or
gestational diabetes or chronic or gestational hypertension
after a kidney transplant.
The establishment of the uteroplacental vascular system
begins with the invasion of the maternal decidua by the
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EVCT. Two successive and interdependent phenomena
are necessary to accomplish the complete transformation
of the uterine spiral arteries by the trophoblastic cells
[10,11]:
3. The first vascular invasion by the cytotrophoblast
During the first-trimester (from 8 until 12 weeks,
approximately), the EVCT sheathes the outer wall of the
decidual capillaries and the intra-endometrial branches of
the uterine spiral arteries, thereby creating a trophoblastic
shell around these vessels. The trophoblast cells invade
from the exterior towards the inner capillary walls, where
they are organized in loose but interrelated clusters of
trophoblastic shell. These intravascular plugs obstruct
almost all of the decidual capillaries. The plugs are more
of a filter than a barrier [12]. Nonetheless the permeability
of these plugs enables plasma, with some maternal red
blood cells, to diffuse past them towards pools of blood that
result from the vascular invasion and which are the future
intervillous spaces [13].
3.1. Oxygen partial pressure
This anatomical phenomenon results in the increase of
oxygen partial pressure (PO2 ) upstream from these plugs and
its decrease downstream from them. The increased PO2
observed upstream diminishes lipid peroxidation in the
endothelial cells of the intramyometrial spiral arteries,
which in turn is translated into an increase in prostacyclin
(so called prostaglandin I2 or PGI2) and a diminution of
thromboxan A2 (TXA2), and the consequent increase in the
vasodilatation of these vessels. The increase in PO2 also
diminishes production of endothelin-1 (ET-1), which is
vasoconstrictive. Downstream from these plugs, the reduced
PO2 works toward guaranteeing the best possible environment for the embryo’s organogenesis. Inversely, the high
pressure upstream from the plugs increases the release of
nitric oxide (NO) by the endothelins of the myometrial spiral
arteries and thus helps to further increase local vasodilatation [14,15] showed that placental PO2 , while lower than
endometrial PO2 during the first-trimester, but between 8 and
12 weeks, PO2 increases progressively. Moreover, because
first-trimester embryos lack defense systems against oxygen
free radicals, this low PO2 level protects their tissues against
the harmful effects of oxygen [16,17]. Finally, embryos at
this term have embryonic hemoglobin, which has a greater
affinity for oxygen in low partial pressure conditions, such as
those encountered in plasma.
3.2. Hemostasis in the vascular spaces
The existence of plugs in the endometrial capillaries
should theoretically be accompanied by a stacking of
maternal red blood cells upstream and the appearance
of extensive thrombi. This is not observed in vivo, however, because of systems that regulate local hemostasis:
thrombomodulin, tissue factor and plasminogen activator.
These local factors work together to ensure that blood
flows through the uterine spiral arteries and to prevent
extravasation following the EVCT invasion. Thrombomodulin (TM) is secreted by the endothelial cells and activates protein C, which has a proteolytic activity and
inhibits the formation of blood clots. By its anticoagulant
action, TM prevents the formation of intravascular thromboses. Tissue factor (TF) is a pro-coagulant factor located
on the membranes of endometrial stromal cells (during the
secretory phase) and of perivascular decidual cells. Stimulable by progesterone, it contributes to the perivascular
endometrial hemostasis necessary after the EVCT vascular invasion (by synthesizing thrombin, which transforms
fibrinogen into fibrin). At the same time, fibrinolysis in the
decidua is inhibited by the activation of plasminogen
activator inhibitor type 1 (PAI-1) and the diminution of
tissue type and urokinase-type plasminogen activators
(tPA, uPA). Some authors have hypothesized that arterial–venous shunts may exist upstream from the plugs,
which might explain the diminution of maternal blood
intake at the plugs and thus the absence of thrombi. This
has never been shown clearly during pregnancy. Remember that the uterine spiral arteries are connected in parallel
to the uterine radiate arteries and are not the final branches
of the latter. Accordingly, supplemental blood reaching
the placenta during pregnancy (in connection with the
opening of vascular space and the increase in the maternal
heart rate) is distributed evenly throughout all the spiral
arteries; the blood influx is thus moderated. In these
conditions arterial–venous shunts do not seem strictly
necessary.
Recently, Schaaps [18] pointed out the importance of the
myometrial arterial network set up from the beginning of
pregnancy. Ultrasound studies show the significant diminution of this network, parallel to the uterine axis, in cases of
preeclampsia. It appears to cushion the mother’s bouts of
hypertension by functioning as a vascular valve, but also
ensures better distribution of the blood flow and adequate
nutrition for fetal growth.
3.3. Hemodynamic protection of the embryo
The plugs in the decidual capillaries provide hemodynamic protection for the embryo, by preventing strong
vascular pressure in the blood lakes. The increased sinuosity
of the spiral arteries at the beginning of pregnancy (which
have a damper effect on maternal blood flow) and the
extraembryonic coelom also play a role in this protection.
In cases of spontaneous abortions, it is frequently observed
that due to the absence of intravascular plugs, the mother’s
blood has flooded the intervillous lakes [19]. The leads to the
cessation of the embryonic-placental circulation and the
death of the embryo.
P. Merviel et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 115 (2004) 134–147
3.4. Early maternal–embryonic exchanges, followed by
embryonic–maternal exchanges
At the beginning of pregnancy, the embryo evacuates its
wastes towards the yolk sac. There is no embryonic circulation and the pressure in the villous capillaries is less than that
in the blood lakes. The exchanges therefore occur solely
towards the embryo from the mother (transfer of nutrients
and oxygen). From 4 to 5 weeks, fetal heart activity begins
and pressure in the villous capillaries increases, thereby
enabling exchanges from the embryo to the mother. The
plugs in the maternal vessels protect these embryonic–
maternal exchanges, for a substantial increase in the blood
lake pressure would interrupt them and cause a vascular
collapse of the villous vessels (and lead the embryo to stop
thriving).
The first trophoblastic invasion can be observed from 5
weeks in the intra-endometrial arteries. Between 5 and 8
weeks, the plugs obstruct the vascular lumina almost completely and prevent the passage of maternal blood to the
intervillous lakes; they then progressively disaggregate from
week, 8–13.
4. The second vascular invasion by the cytotrophoblast
The second trophoblastic invasion of the intramyometrial
spiral arteries thus occurs between 13 and 18 weeks, at
which time it is totally completed. Because these are continuous phenomena, an intramyometrial vascular invasion
can sometimes be observed before 13 weeks [20].
Starting at 8 weeks and through 13 weeks, the trophoblastic shell surrounding the decidual spiral arteries
becomes discontinuous, persisting only at the anchoring
villi of the placenta; this induces the progressive release of
the intravascular plugs. A portion of the trophoblastic cells
from the plugs will move backwards to colonize the inner
wall of the intramyometrial spiral arteries and then penetrate into the thickness of the vascular wall [21]. This
intraparietal encroachment causes the endothelial cells
and the smooth muscle cells of the tunica media and the
internal elastic layer to disappear progressively [22]. The
latter is replaced by a fibrin deposit that deprives the vessels
of their contractility. The trophoblast cells progressively
develop an endothelial phenotype because of the switch
from E- to VE-cadherin and the acquisition of endothelial
cell molecules such as VCAM-1 and PECAM-1 [23,24].
Decreased resistance in the uterine arteries occurs and starts
the continuous blood flow through the intervillous spaces
that is necessary to fetal growth during the second and thirdtrimesters. Intervillous blood flow increases at around 10–
12 weeks of gestation and results in exposure of the
trophoblast to increased oxygen tension (PO2 ) [25]. Expression of hypoxia inductible factor-1 (HIF-1) and TGFb3 (an
inhibitor of early trophoblast differentiation) is high in early
pregnancy and falls at around 10 weeks of gestation when
137
placental PO2 levels are believed to increase. When the
oxygen tension fails to increase, HIF-1 and TGFb3 expression remain high, resulting in shallow trophoblast invasion
and predisposing the pregnancy to preecclampsia [26].
Effective fetal–maternal interactions during early placentation are critical for a successful pregnancy [25]. These
anatomical and hemodynamic processes can be seen in a
doppler study by the disappearance of the uterine artery
notch, by the increased diastolic flow through these arteries,
and by the blood flow that appears in the intervillous spaces.
This progressive replacement of the collagen and elastin
frame and the transformation of the intramyometrial spiral
arteries is most often completed at 18 weeks, but sometimes
requires several additional weeks (notches not infrequently
disappear between the 22- and 26-week doppler ultrasounds). The defective development of the myometrial
arterial network, as described by Schaaps [18], also plays
a role in the persistence of the notches in preeclampsia. At
the same time, the endothelial cells detach from the uterine
veins and arteries, proliferate, and migrate towards the
internal face of the intervillous spaces, thus separating
the fetal circulation from the maternal blood by a double
cellular layer, trophoblastic and endothelial. During this
period, the fetus acquires fetal hemoglobin (HbF) with
oxygen-uptake capacities in line with its greater needs
for growth.
5. Vasomotor factors
Pregnancy is associated with a diminution in blood pressure, a drop in systemic and uterine vascular resistance and a
reduced response to various vasopressor (vasoconstrictive)
agents. The uteroplacental vessels are subjected to various
factors that regulate their vascular tone. Even before implantation, the sexual hormones regulate the balance in the uterus
between vasoconstricting and vasodilating agents. During
the follicular phase, NO secretion (together with 17ß-estradiol) increases and then diminishes during the luteal phase.
Similarly, endothelin-1 (ET-1) also diminishes during the
follicular phase. Estradiol has an indirect vasodilating action
(NO, ET-1 and prostaglandins) and inhibits vasoconstrictors,
while progesterone functions as an estradiol antagonist.
Nonetheless progesterone alone or combined with estrogens
inhibits the vasoconstrictive response to angiotensin II (AII)
[27].
Schematically, uterine vascular tone is regulated principally by two opposing vasomotor systems: a vasoconstrictor
system (endothelin/enkephalinase) and a vasodilator system
(nitric oxide/guanylate cyclase). These agents are involved
in the placental regulation of the vascular flow: they set up a
local balance that enables adequate blood intake. Some
diseases, such as the vascular complications of hypertension,
may be due to the deregulation of these systems [28]. It
is now generally agreed that endothelial cells, together
with endocrine and nervous system factors, participate in
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regulating vasomotor tone [29,30]. They also ensure the
continuous inhibition of platelet aggregation.
5.1. Endothelins
Endothelin (ET) is one of the most powerful vasoconstrictive factors in the fetal-placental circulation. It is a 21amino-acid peptide, existing in three isoforms (ET-1, ET-2
and ET-3); its target is the spiral artery endothelial cell. It is
synthesized through post-translational maturation: preproET-1 is transformed into proET-1, then into big ET-1
and finally into ET-1, through endothelin conversion enzyme
(ECE). Its receptors (ETA, ETB) are coupled with a protein
G: ET-1 coupled with ETA causes vasoconstriction via Ca2þ
and phospholipase C (PLC) (principal action); and ET-1
coupled with ETB is vasodilating through the action of NO
and PGI2 [31]. Endothelin is broken down by the enzyme
enkephalinase, whose production is induced by progesterone. Thus, in the middle of the luteal phase, at the progesterone peak, the ratio of endothelins to enkephalinase favors
the breakdown of the endothelins and therefore contributes
to the absence of vasoconstriction of the implantation site
vessels. Moreover, the hypothesis of the involvement of ET1 in disorders such as intra-uterine growth retardation and
preeclampsia seems to be confirmed by the increase in the
concentration of immunoreactive endothelin in both the
umbilical vessels and the maternal blood in these cases
and by the increase in the expression of the ET-1 gene in
the placental villi in preeclampsia [32,33].
5.2. Nitric oxide
When its integrity is intact, endothelin produces a highly
labile vasodilator product that allows local up-regulation of
the blood flow [34]. This factor, first called endothelial
derived relaxing factor (EDRF), has since been identified
as nitric oxide [35]. This gas, diffusible through cell membranes, penetrates the smooth muscle cells surrounding the
vessels and there reaches its target, guanylate cyclase. This
enzyme is required for the formation of cGMP, which
activates the intracellular protein kinases and keeps the
smooth muscle cells relaxed. NO is synthesized from Larginine in the presence of NO synthase (NOS), which exists
in three isoforms. Two, endothelial (eNOS) and neuronal,
are constitutive and require calcium for their action. Several
stimuli (acetylcholine, bradykinin, serotonin, ATP, vascular
shearing forces) increase eNOS activity, ensuring self-regulation of the blood flow [36]. In women, eNOS has been
found in the uterine and umbilical arteries, chorionic vessels
and placental villi [37]; during normal pregnancy, urinary
excretion of cGMP, nitrates (NO2) and nitrites (NO3) (both
NO metabolites) increases. NO relaxes the vascular smooth
muscle cells by activating cGMP [38]. NO vasodilatation
depending on the spiral arteries appears to precede the
trophoblastic invasion. NO is produced by the endothelial
cells after stimulation of the receptors (associated with a
protein G) by acetylcholine and bradykinin [39]. Modifications of the sex hormones disrupt NO secretion. Pregnancy is
associated with increased NO production. Gude et al. [40]
showed that administration of inhibitors of either NOS or
guanylate cyclase amplifies the vasoconstriction observed
with ET-1 and TXA2. Other mechanisms are probably also
involved: sensitivity and affinity of the endothelial receptors,
effects on intermediate levels of the NO chain, modulation
of proteins G.
NO is a powerful vasodilator released by the endothelial
cells. Experiments performed with glyceryl dinitrate, an NO
donor, and prostacyclin show that administration of the
former during the first-trimester diminishes uterine artery
vascular resistance while the latter has no effect. Ramsay
et al. [41] administered glyceryl trinitrate (GTN) between 8
and 10 weeks: a decrease in peripheral resistance and an
increase in blood flow were then observed. Similarly, GTN
administered between 24 and 26 weeks to women with an
elevated uterine artery resistance index and a bilateral notch
decreased the index. Moreover, there were no modifications
of the doppler umbilical index or of maternal blood pressure
or pulse. Thaler et al. [42] administered an NO donor
(isosorbide dinitrate) to women between 17 and 24 weeks
and observed a diminution of the resistance index for both
the uterine and umbilical arteries.
5.3. Vascular effects of steroid hormones [43,44]
Estrogens (in particular estradiol) have a direct (nongenomic) and indirect (by protein synthesis) vasodilating
effect on the uterine arteries, in the latter case by the
intermediary of ET-1, NO and prostaglandins [45]. This
vasodilation seems local, because it does not occur in the
renal or mesenteric arteries when estrogens are administered. Moreover this effect is independent of the adrenergic,
histaminic and cholinergic receptor system. Estrogens facilitate Ca2þ entry into the endothelial cell (either directly or by
the intermediary of acetylcholine receptors); this leads to
NO synthesis by stimulation of NO synthase and then to a
relaxant effect on the muscle via cGMP [46]. Estradiol
affects endothelin synthesis by inhibiting ECE and its
transformation of big ET-1 into ET-1. ET-1 synthesis is thus
reduced [47].
Progesterone modulates the effect of vasopressin on the
uterine arteries; the effect depends on the progesterone
concentration: it is vasodilating alone or combined with
micromolar estradiol doses, but vasoconstrictive at lower
doses (1–10 nM).
5.4. Prostaglandins
Other factors also participate in the regulation of vascular
tone. Prostaglandins are molecules derived from the metabolism of arachidonic acid; they have auto/paracrine activity
and are thus either vasoconstrictive (PGF2a, TXA2) via an
increase in intracellular Ca2þ and protein kinase C (PKC)
P. Merviel et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 115 (2004) 134–147
stimulation, or vasodilating (PGE2, PGD2, PGI2), with
action mediated by adenylate cyclase and cAMP formation
[48]. Prostaglandins also modulate the action of some
hormones, amplifying or inhibiting their effects. In particular, PGI2 diminishes the sensitivity of maternal vessels to
angiotensin II; it accounts for the resistance observed to the
vasoconstrictive action of AII during normal pregnancy.
Moreover, some agents, such as interleukin 1, gonadotrophin releasing hormone (GnRH) and corticotropin releasing
hormone (CRH), stimulate prostaglandin synthesis [49].
During a normal pregnancy, the ratio of prostacyclin to
thromboxan increases progressively throughout the pregnancy. Prostacyclin is produced by vascular endothelin and
trophoblastic cells. Its action is vasodilating (relaxes vessels
contracted by angiotensin II), muscle-relaxing, and antiaggregating. Thromboxan A2 is synthesized by the platelets
and is a powerful vasoconstrictor that also promotes platelet
aggregation and uterine contractility. During a normal pregnancy, the intravascular plugs formed by the extra-villous
cytotrophoblast cells at the junction between the spiral
arteries and the intervillous spaces inhibit membrane lipid
peroxidation and diminish TXA2 levels [50]. The hCG
secreted by the trophoblastic cells also participates in regulating the vascular bed, by promoting PGI2 synthesis and
diminishing that of PGE2 and TXA2. It also stimulates
placental production of prorenin. Accordingly, the predominance of PGI2 action compared with that of TXA2
(increase in the PGI2/TXA2 ratio) causes vasodilation and
decreases vascular resistance. The absence of these plugs in
preeclampsia, caused by a defect in the EVCT vascular
invasion, reduces the PGI2/TXA2 ratio (decreases PGI2
synthesis and increases that of TXA2), leading to an augmentation in both the sensitivity of maternal vessels to
angiotensin II and vascular resistance, to the absence of
vasodilatation, and to the formation of localized microthromboses [51]. Moreover, the vasomotor action of the
prostaglandins can be modified by vascular alterations
(fibrin deposits, endothelial lesions, etc.). Studies show these
vascular lesions in the placentas of 57% of intra-uterine
growth retardation (IUGR) cases and 74% of women with
hypertension. They thus further reduce the perfusion of the
intervillous spaces.
5.5. ACTH and CRF
During pregnancy, adrenocorticotropin hormone
(ACTH) is present simultaneously in the maternal and
fetal circulations [52]; it enters the former from the syncytiotrophoblast and the latter from the fetal pituitary
gland. Its vasodilating action appears to be mediated by
either mastocyte degranulation or the release of histamine
or progesterone (all vasodilating). ACTH is a more powerful vasodilator (187) than PGI2 [53]. Its action is not
mediated by NO, cGMP or a prostaglandin, but involves a
specific receptor. In pregnancies complicated by preeclampsia or IUGR, ACTH levels in the umbilical artery
139
are elevated, in response to stress and to the hypoxemia that
follows the diminished blood flow.
Corticotropin releasing factor (CRF) is a powerful vasodilator (50/PGI2); its effect on the vascular musculature is
mediated by the NO–cGMP pair [54]. It increases regularly
in the fetal-placental circulation from 7 to 8 weeks until
term. It is a 41-amino-acid peptide that stimulates the
secretion of ACTH and of ß-endorphins in the placenta
and the maternal and fetal pituitary glands, as well as the
production of prostaglandins in the decidua and membranes.
In vitro, PGE2, PGF2, norepinephrine, acetylcholine, oxytocin, IL-1, angiotensin II, arginine vasopressin, neuropeptide Y (NPY) and the glucocorticoids stimulate CRF
secretion, while progesterone and NO inhibit it. There is,
nonetheless, no synergy during pregnancy between arginine
vasopressin and CRF as to ACTH secretion, and dexamethasone does not inhibit CRF. Its receptor has been found on
syncytiotrophoblastic and endothelial cells (eNOS located in
the latter). Its level is higher during pregnancies complicated
by hypertension or IUGR [55], in response to a diminished
placental vascular flow, but its vasodilating action is reduced
because of the endothelial alterations [56–58].
5.6. Neuropeptides
The vasomotor peptides such as vaso-intestinal peptide
(VIP), substance P and calcitonin gene-related peptide
(CGRP), which are synthesized from nerve fibers near
the uterine vessels, also help regulate the uteroplacental
blood flow. Their action may be mediated by the NO–
cGMP pair.
VIP and substance P (SP) exert a vasodilating action on
uterine vessels contracted with vasopressin (no effect on
basal parietal tension) and on villous vessels contracted with
PGF2a. This action is not mediated by acetylcholine, adrenaline or prostaglandin receptors.
In humans, CGRP appears to be a growth factor for the
endothelial cells of the umbilical vein and an angiogenic
factor in ischemic conditions [59,60]. It is a 37-amino-acid
peptide derived from the calcitonin/CGRP gene (chromosome 11) by alternative mRNA splicing. The concentration
of immunoreactive CGRP increases during pregnancy (multiplied by 2–3 at term) and diminishes during the first 7 days
postpartum [61]. The uterine arteries also appear to be more
sensitive to the effect of CGRP during pregnancy [62]. It is
secreted by nonadrenergic–noncholinergic A (@) and C
nerve fibers located at the artery adventitia-media junction,
in association with substance P. Its decay is associated with
enkephalinase, competing with substance P; this explains
the CGRP/substance P potentiation. Two types of receptors
are present throughout all of CGRP 1R and CGRP 2R; they
contain 7 transmembrane passages coupled with protein G.
Its endothelin-independent action binds onto the receptors of
the smooth muscle cells, activates adenylate cyclase and
produces cAMP as well as blocking calcium L channels,
thereby reducing the intracellular Ca2þ concentration [63].
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The result is powerful vasodilation of the uterine arteries.
CGRP also acts via NOS, increasing vasodilatation by
releasing cGMP. ß Adrenergic innervation diminishes during pregnancy (at term it is only 2% of that in non-pregnant
women), while CGRP innervation increases: both factors
help maintain uterine vasodilatation [64]. Experiments in
rats show that CGRP may inhibit the hypertension induced
by L-NAME (analogue of L-arginine, inhibiting NOS)
administration and reduce fetal mortality associated with
hypertensive syndromes, but it does not improve birth
weight [65]. The explanation is that CGRP does not cross
the placenta; it corrects the NO deficit on the mother’s side
but not in the fetus.
5.7. The effect of calcium
The beneficial effects of calcium supplementation in
reducing the risk of preeclampsia suggests that Ca2þ plays
a role [66–68]. The platelets of a woman with preeclampsia,
compared to those of a woman in a normal pregnancy,
contain more intracellular calcium [69], probably related
to an increase in the voltage-dependent calcium channel
activity [70]. Pregnancy and increased blood estradiol levels
affect these channels and reduce the concentration of intracellular Ca2þ.
6. Case of preeclampsia
In preeclampsia, decidual resistance, more powerful than
the trophoblastic invasion, prevents the EVCT from reaching the spiral arteries. Placentas of women with preeclampsia express lower levels of matrix metalloproteinase (MMP)
9, human lymphocyte antigen (HLA) G, placental lactogen
hormone (HPL) and a1ß1 than those of women with normal
pregnancies; the integrin a4ß5 level is stable and that of
a1ß1 increases [71]. Moreover, the switch from E-cadherin
to VE-cadherin does not occur, nor are VCAM-1 and
PECAM-1 produced [72]. These phenomena testify that
these cytotrophoblasts have lost their capacity for deep
invasion. Invasive EVCT dedifferentiates into syncytium
(giant cells) that thereby lose their penetrating power; the
increase in giant cells thus expresses this initial impulse
[73,74]. A related finding is the higher frequency of preeclampsia and intra-uterine growth restriction among nulliparas (75% of the cases): this may be associated with the fact
that the arteries colonized in a first pregnancy can be invaded
more easily during subsequent pregnancies. The role of the
decidual natural killer (NK) cells may explain why a subsequent invasion is facilitated; they can be thought of as the
endometrial memory of paternal antibodies. Preeclampsia
was similar in nulliparas and in the multiparas who had
changed partners (3.2 and 3%), but lower among multiparas
with the same partner (1.9%). A similar finding is noted in
pregnancies after ovocyte donation, sperm donation, or a
long period of contraceptive use. Accordingly we must
consider preeclampsia more as a disease of primipaternity
than primigravidity [75].
In preeclampsia, the second trophoblastic invasion either
does not occur or is incomplete because of the lack of
intravascular plugs. This is expressed by the persistence
of uterine vasoconstriction. Blood intake into the intervillous spaces is diminished and fetal growth retardation
ensues. The downstream consequence of this vasoconstriction is hypoxia, with an increase in lipid peroxidation
[76,77] and in the TXA2/PGI2 ratios [78], both of which
accentuate vasoconstriction and platelet aggregation.
Thromboses and disseminated fibrin deposits are usually
found in the placenta in this disease [79]. Moreover, downstream hypoxia increases ET-1 production and diminishes
that of NO (also related to the reduction of the mechanical
force of the artery wall).
Evidence of intravascular plugs is not found in preeclampsia. This absence explains why PO2 in the decidual spiral
arteries is on the whole lower than that observed upstream
from these plugs: this results in increased lipid peroxidation
[80] and a decreased PGI2/TXA2 ratio, with vasoconstriction
and platelet aggregation. This diminution of PO2 also causes
an increase in ET-1 and (in combination with the diminution
of the mechanical forces on the vascular wall) a decrease in
NO in the myometrial and decidual spiral arteries. The
stimulant effect of ET-1 on the release of NO partly compensates for this NO decrease. Moreover the absence of
plugs (resulting in relative high pressure in the blood lakes)
is responsible for the increase in the rate of spontaneous
abortions and the fetal ‘‘failure to thrive’’ observed in
patients at risk of preeclampsia [81].
Preeclampsia is thus characterised by an increase in
systemic vascular resistance and in vascular reactivity and
by a change in the distribution of the pelvic blood flow that
precedes the onset of hypertension [82]. All of these suggest
a dysregulation in the normal vasomotor factors of pregnancy. During preeclampsia, the sympathetic system/normal
pregnancy is activated [83]. Some older studies suggest that
preeclampsia is associated with low serum estradiol levels,
which are also found among women who live at altitudes
higher than 3000 m; they have an increased risk of preeclampsia and lower estradiol levels before the onset of
preeclampsia [84].
When preeclampsia occurs, modifications of the vasomotor imbalance and of the Ca2þ ion homeostasis can be
observed. The increase in the vasoconstrictor/vasodilator
ratio is proportional to the severity of the syndrome, and
NO metabolite levels also diminish [85]. Rats treated with an
NO inhibitor, nitro-L-arginine methyl ester (L-NAME)
develop hypertension and proteinuria; the growth of their
fetuses is retarded [86,87]. Grunewald et al. [88] administered GTN by IV to women with preeclampsia and observed
that both systolic and diastolic blood pressure fell significantly, and that the umbilical resistance index also fell. Lees
et al. [89] treated these women with an NO donor (Snitrosoglutathione, GSNO) and observed decreases in mean
P. Merviel et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 115 (2004) 134–147
blood pressure, platelet activation and uterine resistance.
The NO donors thus seem therapeutically interesting,
because they reduce BP, inhibit platelet activation and
improve uterine and fetal hemodynamics [90]. Moreover
GTN increases the blood flow in the uterine arteries without
modifying either heart rate or systemic blood pressure, as
occurs during the second-trimester; this suggests that this
effect on uterine artery vasodilatation may be a priority for
NO.
Finally chronic hypoxia, which results from a placentation defect, can induce the transcription of some genes [16],
including that of ET-1 (vasoconstrictor), angiotensin conversion enzyme (hypertensive), plasminogen activator [91]
(stimulating formation of active TGF ß, which inhibits the
EVCT invasion) and cyclooxygenase-1 (COX-1, an enzyme
involved in prostaglandin production).
7. Disruption of the uterine immune balance
In theory, an implanting embryo could be the target of
various types of immunological aggression: standard cellmediated lysis, lysis by cytotoxic antibodies associated with
complement and NK cell lysis. During pregnancy, the
embryo is protected from these dangers by its own early
antigenicity, by cytokine secretion and local immunosuppressors, intrinsic resistance to cellular lysis, and the MCPDAF system.
Two phases occur: an initial maternal immunological
reaction to the allograft, followed by the development of
allogenic tolerance [92].
141
metrial or trophoblast cells. Beginning in the preimplantation period, lymphocytes pour into the uterus, where the
levels of macrophage colony stimulating factor (M CSF or
CSF 1), granular cell and macrophage colony timulating
factor (GM CSF), granular cell colony stimulating factor (G
CSF), tumor necrosis factor (TNFa), interleukin-6 (IL-6)
and IL-1 increase substantially; they indicate the presence of
cellular and humoral inflammatory reactions.
9.1. Cytokines involved in the inflammatory reaction
IL-1 is detected in the decidua, and its receptors in the
epithelial cells of the endometrium. The embryo also
secretes IL-1, which suggests that it controls its own development via interferon (IFN), which is a trophic factor for the
trophoblast and for which the embryo has receptors. It
appears to stimulate the production of IFN, IL-6 and
PGE2 and to enable the expression of class II HLA antigens
(HLA-DR) in the uterus.
9.2. Cytokines involved in trophoblast development
CSF 1, GM-CSF and G-CSF are secreted in large quantities in the decidua, and their receptors are expressed by the
early trophoblast. CSF 1 favors the growth of the trophoblast. GM CSF plays a direct role in the attachment and
growth of the trophoblast and in the survival of the embryo.
This factor is secreted by large granular lymphocytes (LGL)
CD 56þ, present in the decidua. G CSF receptors, necessary
for implantation, are present in the trophoblast and the
decidua.
9.3. Immunosuppressive cytokines
8. Antigenicity of the early embryo
The trophoblastic cells in contact with maternal blood do
not possess class I or II HLA antigens; in this, they are unlike
the extra-villous cytotrophoblast cells at the top of the
trophoblastic columns or in the spiral arteries, both of which
are rich in class I HLA (HLA A–C). This HLA class presents
peptide autologous antigens to lymphocytes T (LT). Three
other class I antigens have also been identified: HLA E, F
and G. While HLA E and F have been found in numerous
tissues, both fetal and adult, HLA G is expressed solely in
the extra-villous cytotrophoblast cells, at the fetal–maternal
interface (where no other class I or II antigens are found).
This particular expression of HLA G plays a role in the
tolerance of the semi-allogenic graft that is the pregnancy
(NK response is inhibited by the disguise of trophoblastic
cells as self cells).
9. Cytokine and local immunosuppressor secretion
Cytokines may be produced by the secretion of leukocytes
infiltrated into the decidua or may be synthesized by endo-
IL-6 inhibits expression of IL-2 receptors, which would
otherwise support the proliferation of cytotoxic cells (lymphocytes T and NK cells), of B lymphocytes and of antibody-dependent cell-mediated cytotoxicity. IL-10 plays a
key role in preventing embryo resorption by antagonising
IFNg and TNFa.
10. Immunosuppressive hormones
Progesterone also participates in maintaining the semiallograft, because of its local anti-inflammatory activity: it
can inhibit phagocytosis and lymphocyte proliferation in the
uterus, either directly by blocking the LT CD4þ activity and
proliferation induced by IL-1, or indirectly, by inducing the
release of two immunosuppressor factors by the lymphocytes: T-suppressor-induced factor (TSIF), whose antibodies
can abort a pregnancy in mice, and progesterone-induced
blocking factor (PIBF), which blocks the lysis of embryo
fibroblasts by NK cells and inhibits mixed lymphocyte
reactions by preventing TNFa secretion by cytotoxic cells
(LT, NK, . . .). Progesterone also has an immunosuppressive
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action that works in synergy with prostaglandins E (PGE)
(and inhibits lymphocyte T proliferation).
E2 prostaglandin (PGE2) inhibits the proliferation of LT
CD4þ cells and their secretion of lymphokines (IL-2, TNFa
and IFNg); at the same time it (like IL-6) reduces expression
of IL-2 receptors on activated LT. PGE2 inhibits the production of IL-12 by antigen-activated monocytes.
11. Intrinsic resistance to cellular lysis
This anti-complement activity is caused by the embryo’s
expression of anti-complement molecules: membrane complement proteins (MCP or CD 46), protectin (CD 59), which
blocks complement binding on the constant region of the
antibody chain; and DAF (CD 55), which accelerates complement destruction. These molecules are expressed on the
membrane of gametes, fertilized eggs, and blastocysts. They
thus transform any cytotoxic antibody into a blocking antibody, a sub-class of facilitating antibodies. The concealment
of the antigens minimizes the risks that they will be
destroyed by the LT. The concept of humorally-mediated
abortions is theoretically possible if these molecules are
expressed slightly, badly, or not at all, or are expressed at the
wrong stage or in the wrong location.
12. Cases of preeclampsia and maternal autoimmune
syndrome
Cellular rejection involves a cascade of events that
include the participation of lymphocytes B and the production of humoral antibodies. Their action on local vessels may
not only explain the elementary lesions observed but also
induce a maternal autoimmune syndrome that may be
reactivated in subsequent pregnancies or capable of developing on its own. This initial impulse of immune rejection,
which corresponds to an antigen–antibody confrontation
that is particular in its genetic determinism, appears nonetheless compatible with the normal development of pregnancy until the end of the second-trimester. The purely
maternal or obstetrical environmental context sometimes
involves confirmed immune disease, lupus or the anti-phospholipid syndrome (APLS). In this respect, preeclampsia is
similar to some repeated spontaneous abortions. In addition,
morphologically, anomalies of the same type, which associate cellular reactions and elementary vascular lesions can be
observed in some types of abortions. These observations and
the notion of a sequence of preeclampsia–early repeated
abortions in the same patients suggests that they may be two
diseases on one continuum.
During preeclampsia, expression of HLA G antigen in the
trophoblastic cells diminishes. In such cases, HLA G gene
mutations have been found in African–American populations, although they are extremely rare in the white population. It is observed a diminution in the HLA G mRNA in the
trophoblast of patients with preeclampsia, proportional to
the reduction in the number of trophoblastic cells observed
in this disease. On the other hand, the existence of an HLA C
antigen is proved in the trophoblastic cells; it may act
synergistically with HLA G to enable NK cell recognition
and thus prevent cell lysis.
The decidua contains a large population of CD 56þ cells,
which are markers for LGL. These cells resemble NK cells
without expressing the same activity. Also found there are
macrophages (19%) and T lymphocytes (8%). As pregnancy
progresses, macrophages and lymphocytes T remain constant while the number of LGL falls. HLA G can inhibit LGL
NK activity. The LGL cells have a particular NK phenotype
and play a role in the phenomena of graft immunity. They
represent 2% of the circulating blood lymphocytes. One role
of these uterine myeloid cells is to produce cytokines. Some,
such as CSF-1, GM-CSF, IL-1, TNFa and IFNg are known to
regulate blastocyst attachment as well as trophoblast cell
proliferation and invasion. TNFa, IFNg and TGFb1 inhibit
trophoblastic proliferation while IL-1, GM-CSF and IL-6
increase it. These notions are related to the more general
concept of the Th1–Th2 systems. Th1 groups T helper cells
that secrete IL-2 and IFN g (cell-mediated immunity), while
Th2 produces IL-4, IL-6 and IL-10 (humoral-mediated
immunity). A successful pregnancy requires that the Th2
system be dominant. During preeclampsia, this relation is
inversed (Th1 > Th2), thereby increasing the rate of destruction of trophoblastic cells. They therefore cannot fully play
their necessary roles: anchorage of the embryo in the
decidua (as shown by the high rate of spontaneous abortions
in women with preeclampsia), modification of the uterine
spiral arteries, etc.
Different molecules are involved in the immunoendocrine
regulation of implantation: prostaglandin E2, GM-CSF, IL10 (which reduces the production of the Th1 system and
stimulates ACTH production) and TGFb. Anomalies in the
production of PGE2 and TGFb have been observed during
preeclampsia.
13. The genetic theory of preeclampsia [93,94]
There is no single gene for preeclampsia, but probably a
group of maternal genetic polymorphisms that, when associated with environmental factors, predispose her to this
disease. The hypothesis of recessive transmission of maternal genes seems the most probable [95]. Moreover the fetus’
genes too appear to contribute to the development of preeclampsia. This hypothesis is confirmed by the finding that
two identical twins do not have the same risk of preeclampsia [96]. Environmental factors may affect the expression of
these ‘‘predisposition’’ genes.
Preeclampsia at a microscopic level is morphologically
expressed as a disease of the vascular endothelium [79].
Researchers are beginning to understand the initial pathophysiology. Two types of mechanisms seem to be associated.
P. Merviel et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 115 (2004) 134–147
First, the spiral arterioles appear to develop insufficiently,
with an incomplete transformation of the decidual vessels
in the nidation area and conservation of the myometrial
vessel tunica muscularis, which is sensitive to vasoconstrictive amines. Second, lesions resembling those of acute
atherosis appear on the vessel walls. Accordingly, from the
beginning, a physical, cellular cause and a chemical,
humoral cause seem to be associated. The migration of
cytotrophoblasts towards the vessels is normally accompanied by a transformation in the cellular phenotype, which
changes from epithelial to endothelial. While the increasing rarity of these cells in preeclampsia is generally
accepted, the integrity of the cellular transformation during
the migration has not yet been demonstrated. The inflammatory alterations of the spiral arterioles outside the area of
nidation are related (local reactions to substances resulting
from the initial implantation anomaly). The causal pathogenic mechanism currently in favour involves the destruction of infiltrating cytotrophoblasts by a series of reactions
that bring into the picture the NK CD 56þ lymphocytes
specific to the decidua and the LT. It is therefore the
presence of these invading cytotrophoblastic cells with a
particular immune profile that is responsible for the rejection reaction. The involvement of endometrial NK brings to
mind first an anomaly of its specific target, HLA-G. This
immune-type inflammatory stage is more easily observed
in some clinical contexts that suggest a maternal recessive
gene whose transmission to the fetus involves a reaction
rejection only if the father passed on the same anomalous
gene. The antigenic presentation of the cytotrophoblastic
cells of the fetal envelope thus become unacceptable for the
mother. The fetal genetic contribution to the development
of preeclampsia is confirmed by findings that two identical
twins do not present the same risks. Accordingly, preeclampsia may result from a hereditary disease associated
with a recessive maternal gene; the disease expression thus
depends on the father.
Women born from pregnancies complicated by preeclampsia are at higher risk of this complication themselves;
the same is true for the daughters-in-law of women who have
had preeclampsia. Similarly, the risk of this complication for
a woman whose partner has already had a child with another
woman in a pregnancy with preeclampsia is twice as high as
the risk among women with no family history on any side.
There is thus a clear paternal role in the genesis of this
complication [97], as there is in the phenomenon of implantation (molar pregnancies, where paternal uniparental disomy is observed). It is thus highly likely that preeclampsia
involves a paternal genomic imprint of certain genes: IGF2,
allele T235 of the angiotensine gene, Factor V Leiden, and
methyl tetra-hydrofolate reductase (MTHFR). There are
others candidate genes, located on chromosomes 1, 3, 4,
9 and 18. Some disturbances are not necessarily secondary to
genetic anomalies.
This is the case for example for superoxide dismutase
(SOD): its expression is reduced during preeclampsia, with-
143
out any modification of the Cu–Zn SOD gene (on chromosome 21) [98].
In preeclampsia, levels of soluble TNFa (sTNFp55)
receptor increase before clinical signs appear; nonetheless
for neither preeclampsia nor hemolysis-enzymes liver-low
platelets (HELLP) syndrome is there any activation of the
promoter gene also located on chromosome 6 [93].
The candidate genes situated on chromosome 1 include
the genes for factor V and for methylene tetrahydrofolate
reductase (MTHFR).
Factor V is pro-coagulant, but this effect is normally
counterbalanced by activated protein C. Approximately
2–7% of the population carries a mutation of factor V called
a ‘‘Leiden mutation’’ (FVL) that makes them resistant to
activated protein C. This resistance is present among 20% of
the women with preeclampsia [99]; heterozygosity for this
mutation is found in 9% of women with preeclampsia and
only 4.2% of the general population. Additionally, Rigo et al.
[100] found relatively high rates of HELLP-syndrome
patients among those with the FVL mutation.
Similarly, a mutation of the MTHFR gene (C677T) has
been found that can reduce enzyme activity and increase
plasma concentrations of homocysteine, as has been
described in preeclampsia. Both monozygous and heterozygous status predispose the carrier to preeclampsia but are
not prerequisites for it. However, O’Shaughnessy et al. [101]
did not findany association of preeclampsia with either FVL
or MTHFR.
Additionaly, an association between preeclampsia and
polymorphisms in the prothrombin gene described by Kupferminc [102] was not found by others [103].The angiotensin gene is also on chromosome 1.
14. The inflammatory theory of preeclampsia [104]
Preeclampsia is a disease characterised by a generalized
dysfunction of the endothelial cell, linked to several factors:
fatty acids, lipoproteins, lipid peroxide, TNFa, decay products of fibronectin and microvillous fragments of syncytiotrophoblastic cells. All these factors together result from a
generalized intravascular inflammatory response present
during pregnancy but exacerbated in preeclampsia. During
inflammation, leukocyte adhesion proteins in the vascular
system increase, stimulated too early by thrombin and
histamine and then in the hours that follow by IL-1 or TNFa.
Vascular permeability then increases, together with extravasation, a cellular chemotaxis with phagocytosis.
During preeclampsia, granulocyte and monocyte activation occur together with the endothelial dysfunction; this
increases the level of adhesion molecules (CD11b and
CD64) or other factors (L-selectin and HLA-DR). These
cells also cause an increase in TNFa, IL-6 and phospholipase
A2 (important inflammatory reaction mediators) and they
produce and secrete oxygen free radicals. During preeclampsia, these radicals increase as does the expression
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of CD11b and CD64 (phagocytes), while L-selectin (granulocytes) and HLA-DR (monocytes) decrease. These disturbances also occur during normal pregnancies but are
significantly less important. Moreover, activated neutrophils
produce some proteases, including elastase, which increase
during preeclampsia. Elastase is associated with increased
production of endothelins and factor VIII and plays a role in
the endothelial alterations observed in this disease.
15. Targets of the action of preventive treatment with
aspirin and other therapies [105,106]
The lack of vasodilatation associated with the absence or
incompleteness of the EVCT invasion of the spiral arteries
and the resulting microthromboses associated with endothelial lesions lead to anomalies in the regulation and synthesis
of prostaglandins, in particular, prostacyclin (PGI2, a vasodilator) and thromboxan A2 (TXA2). Prostaglandins are
metabolites of arachidonic acid by the intermediary of
cyclooxygenase, and aspirin is an inhibitor of cyclooxygenase (COX). By diminishing TXA2, it modifies the PGI2/
TXA2 ratio and therefore tends to re-establish the physiological balance disturbed by the failed invasion [107]. The
continuous administration of aspirin at doses that range from
0.3 to 1.5 g/kg per day seems to inhibit platelet COX activity
more effectively than endothelial cell COX activity.
Endothelial cells are nucleated and can resynthesize
COX, unlike the anuclear platelets, which are permanently
inactivated. Only new platelets, formed from megacaryocytes, can renew TXA2, but they then become incapable of
producing more because the aspirin administration is
repeated. Inversely, endothelial cells renew PGI2 fairly
rapidly.
Accordingly, it is appropriate to prescribe a preventive
treatment with aspirin in pregnancies where the women have
poor obstetrics histories of previous early severe preeclampsia or severe intra-uterine growth retardation defined as <3rd
percentile. However, an abnormal result for the angiotensin
II test [108] (IV angiotensin dose necessary to increase
diastolic blood pressure by 20 mmHg, test abnormal if
the result <10 ng/(kg min)) or an anti-phospholipid syndrome (where the anticardiolipin antibodies can interfere
with endothelial synthesis of PGI2) were indications for lowdose aspirin prevention. Low-dose aspirin therapy prevention is ineffective among women with underlying medical
illness i.e. chronic hypertension, chronic nephropathy or
kidney transplant, diabetes [109]. There is no convincing
data to prescribe low-dose aspirin in patients with abnormal
uterine doppler findings between 22 and 24 week gestation
[110].
It appears necessary to begin the treatment as early as
possible: from 13 weeks or even earlier (depending on the
pathophysiologic bases explained above) when the indication is associated with the obstetrical history. This early
prescription will have as its goal to limit, but not to prevent,
the cascade of biological events in the mother (increase of
renin, angiotensin, and aldosterone) that follow the increase
in vascular resistance and the obstetrical complications that
can result from it. This treatment should be continued until a
term of 35 weeks. In some indications, this treatment can
begin even before conception (for autoimmune diseases
such as anti-phospholipid syndrome), combined with
heparin or corticosteroid therapy.
Although trials have been performed with varying doses
of aspirin (from 50 to 150 mg), the optimal dose does not
seem to have been established. Nonetheless, the initial dose
usually prescribed is from 100 to 150 mg per day. An aspirin
prescription should be based upon the mother’s weight and
the performance of an Ivy bleeding time test. The bleeding
time must be tested before the aspirin treatment begins and
must be less than 8 min. After 10–15 days of treatment,
bleeding time must be tested again (and must still be less
than 8 min) to see whether a dose adjustment is needed
(50 mg per day or even every other day). Inversely, a
variation of more than 2 min in the bleeding time before
and after the aspirin prescription demonstrates some platelet
anti-aggregation efficacy, which seems to reduce the risk
that pregnancy-related disorders (preeclampsia, IUGR, or
abruptio placentae) will recur [111].
In conclusion, an analysis of the literature shows that the
two most important points in obtaining a preventive effect
from low-dose aspirin during the pregnancy of a woman at
risk of vascular accidents (preeclampsia, IUGR) are early
treatment (between 8 and 15 weeks, or even around the
period of conception) and the prescription of a sufficient
dose (100–150 mg per day).
16. Conclusions
Preeclampsia is therefore only a form of spontaneous
abortion, incomplete because it involves only the vascular
face of the implanted embryo. Along with the anomaly of the
Abnormal vascular invasion by
extra-villous cytotrophoblast:
Only 30-50% of uterine spiral
arteries invaded (< plugs)
Abnormal vascular tone:
> endothelins, < nitric oxide;
> thromboxan A2, < prostacyclin
PREECLAMPSIA
Immunologic disorders: Th1
predominant / Th2; < HLA G
Genetic anomalies: > TNF α gene
factor V Leiden ?, MTHFR ?
Inflammatory theory:
dysfunction of the endothelial
cells: > TNFα , lipid peroxides
and fatty acids
<: decreased expression; >: increased expression
Fig. 1. Pathophysiologic mechanisms of preeclampsia.
P. Merviel et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 115 (2004) 134–147
trophoblastic invasion of the uterine spiral arteries, we find
local disruptions of vascular tone, of immunological balance, and inflammatory status, sometimes associated with
genetic predispositions [112] (Fig. 1). Preeclampsia, a disease defined in the second and third-trimesters of pregnancy,
is multifactorial from a pathophysiologic point of view, thus
complicating its prediction and treatment as well as the
efficacy of preventive measures against it.
Acknowledgements
The authors thank Pr Philippe Bouchard, Department of
Endocrinology, Hospital St. Antoine, Paris (France) and Pr
Jean-Michel Foidart, Department of Gynecology and Obstetrics, Hospital La Citadelle, Liege (Belgium) for their
comments, suggestions and critical reading of the manuscript.
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Pathophysiology of preeclampsia: links with implantation disorders
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