Ultrasound Obstet Gynecol 2012; 40: 373382

Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.12280

Opinion
Uteroplacental ischemia in early- and late-onset pre-eclampsia: a role for the fetus?
Introduction
Pre-eclampsia is still considered a disease of theories.
However, recent evidence provides important insight
into the role of chronic uteroplacental ischemia and
angiogenic imbalances in the mechanism of injury of
this obstetric syndrome. This Opinion reevaluates the
association between chronic uteroplacental ischemia and
pre-eclampsia using Hills criteria of causation in the
light of recent developments. A possible role of the fetus
in the pathogenesis of pre-eclampsia and the possibility
that relative uteroplacental ischemia may be operative in
late-onset pre-eclampsia are also discussed.
Between 1938 and 1940, Ernest W. Page published the
results of a series of experiments providing transcendental
insight into the understanding of the pathogenesis of
pre-eclampsia. Ogden, Hildebrand and Page described
one of the earliest reports of experimental uteroplacental
ischemia in pregnant animals
1
. They reported that
placement of a clamp in the aorta below the renal arteries
in pregnant animals, aiming to reduce the femoral pressure
by half, produced a gradual increase in the carotid blood
pressure. Of note, this effect was not observed in non-
pregnant animals or in pregnant animals that underwent
hysterectomy following placement of the aortic clamp.
These observations indicate that ischemia below the renal
arteries is not sufcient to lead to systemic hypertension
and that, for this to occur, the presence of the fetus
and the uteroplacental unit is required. Using teleological
reasoning, Dr Page wrote
2
: if the placenta should be
unable to obtain a sufcient maternal circulation for its
demands, it might be capable of increasing this supply
by raising the systemic blood pressure. Since there are
no nervous connections by which the placenta could
accomplish this, such a postulate necessitates the concept
of a placental pressor substance. This revolutionary
concept described in 1939 has been proved correct, as
demonstrated by recent experimental
3,4
and clinical
3,5
evidence suggesting the identity of the pressor substance
proposed by Dr Page to include antiangiogenic factors of
placental origin (see below). In 1938, Dr Page reported
6
that transfusion of 100 mL blood from a woman with
postpartum eclampsia into a woman who was 7 months
pregnant led to a severe chill, pulmonary edema and
cyanosis with marked tachycardia. A chest plate showed
scattered patchy areas of consolidation. . . The symptoms
persisted for 36 hours then slowly subsided. . . The
blood pressure rose during the chill, but returned to
a normal level. He interpreted the response in the
pregnant recipient as a transfusion reaction; however,
according to the author, blood was again obtained from
both patients and cross-matched without agglutination.
Thus, it is unlikely that the signs and symptoms in the
pregnant recipient were due to a transfusion reaction. In
contrast, transfusion of 400435 mL blood from patients
with severe pre-eclampsia or eclampsia into four anemic
patients with incomplete abortion or in the postpartum
period did not signicantly increase their blood pressure
6
.
These observations suggest that pregnant women are
more susceptible than are non-pregnant women to the
effects of the circulating pressor substance proposed by
Dr Page. Moreover, the transient nature of these signs and
symptoms in the recipients of blood transfusion from pre-
eclamptic or eclamptic women suggest that a continuous
source of the pressor substance (such as the placenta)
is required for the hypertension to persist. The evidence
reviewed in this Opinion provides support for the validity
of Dr Pages postulates and for the association between
uteroplacental ischemia and pre-eclampsia.
Several mechanisms of injury have been proposed
in pre-eclampsia
79
, including: 1) chronic uteroplacen-
tal ischemia
10
; 2) immune maladaptation
10
; 3) very low-
density lipoprotein toxicity
10
; 4) genetic imprinting
10
;
5) increased trophoblast apoptosis/necrosis
11,12
; and
6) an exaggerated maternal inammatory response to
deported trophoblast
13,14
. Recent observations indicate
that angiogenic imbalances, characterized by an excess
of antiangiogenic factors including the soluble form of
vascular endothelial growth factor (VEGF) receptor 1
(sFlt-1) and soluble endoglin (s-Eng) as well as low cir-
culating maternal concentrations of VEGF and placental
growth factor (PlGF)
3,5
, are implicated in the mechanisms
of disease in pre-eclampsia. Novel observations suggest
that a combination of some of the proposed mechanisms
of injury may be responsible for the manifestations of the
clinical spectrum of pre-eclampsia. For example, clinical
and experimental evidence indicates that uteroplacen-
tal ischemia leads to increased circulating concentrations
of antiangiogenic factors and angiogenic imbalances
15
.
Another example is the recent report that deported tro-
phoblast, specically syncytial knot aggregates detached
from the placenta, may account for 25% of measurable
circulating sFlt-1 in women with pre-eclampsia
16
. sFlt-1 is
an antiangiogenic factor of placental origin that appears
to play a central role in the mechanisms of injury in
pre-eclampsia
15
.
Hills criteria of causation were originally described
by Austin Bradford Hill, a medical statistician, as a way
of determining the causal link between a specic factor
and disease
17
. These criteria form the basis of modern
Copyright 2012 ISUOG. Published by John Wiley & Sons, Ltd. OPI NI ON
374 Espinoza
epidemiological research, which attempts to establish sci-
entically valid causal connections between agents and
diseases, and include the following: 1) strength of associa-
tion; 2) biological gradient (doseresponse relationship);
3) specicity; 4) temporal relationship; 5) consistency;
6) biological plausibility; 7) coherence; 8) experiment
(reversibility); and 9) analogy (consideration of alternate
explanations). A recent review used some of these criteria
to evaluate a possible link between antiangiogenic factors
and pre-eclampsia
18
. This Opinion uses all of Hills cri-
teria to reevaluate a possible causal association between
chronic uteroplacental ischemia and pre-eclampsia.
Hills criteria
Strength of association
There is a solid body of evidence indicating that abnor-
mal uterine artery Doppler velocimetry (UtADV) in the
second trimester of pregnancy is a risk factor for the devel-
opment of pre-eclampsia in the index pregnancy
1924
.
Experimental evidence indicates that abnormal UtADV
is a surrogate marker of uteroplacental ischemia. Indeed,
studies in which gelfoam was used to embolize the uterine
circulation in pregnant animals showed that progressive
embolization of the uterine arteries was associated with
a linear increase in the uterine artery pulsatility index
(PI)
25,26
, a Doppler parameter commonly use in ultra-
sonography to measure impedance to blood ow. Another
parameter is the presence of bilateral uterine artery dias-
tolic notches
2729
. Ochi et al. reported that embolization
of the spiral arteries in pregnant sheep produced a dias-
tolic notch only when the uterine blood ow was reduced
to approximately one third, and the vascular resistance
was increased to three to four times the normal value
25,26
.
This experimental evidence indicates that high mean uter-
ine artery PI and/or the presence of uterine artery notching
are associated with reduced uteroplacental blood ow,
and is consistent with the results of a large longitudinal
study indicating that both high mean uterine artery PI
as well as bilateral uterine artery notching in the second
trimester are independent risk factors for the development
of pre-eclampsia in the index pregnancy
29
.
In the latter cohort study
29
, 4190 singleton women
underwent UtADVbetween 23 and 25 weeks of gestation.
Patients with chronic hypertension, multiple pregnancy,
fetal anomalies, pregestational diabetes mellitus or car-
diac disease were excluded from this study. Abnormal
UtADV was dened as the presence of bilateral uterine
artery notches and/or a mean uterine artery PI >95
th
percentile for gestational age. A multivariable logistic
regression analysis determined that abnormal UtADVwas
an independent factor for the identication of patients at
increased risk of developing early-onset pre-eclampsia
at less than 34 weeks of gestation (odds ratio (OR),
25.7 (95% CI, 9.0173.31)) and late-onset pre-eclampsia
(OR, 2.9 (95% CI, 1.854.40)) after adjusting for mater-
nal age >35 years, previous pre-eclampsia, nulliparity,
rst-trimester body mass index (BMI) >30 kg/m
2
and
smoking status. These results are consistent with previous
reports which were summarized in a recent systematic
review
30
. However, the former study
29
estimated the
risk conferred by abnormal UtADV while controlling
for other risk factors for pre-eclampsia. Of note, the
odds for developing pre-eclampsia conferred by abnor-
mal UtADV (OR, 4.0 (95% CI, 2.715.83)) was similar
to that conferred by other known risk factors, including
nulliparity (OR, 4.8 (95% CI, 3.117.42)) and prior pre-
eclampsia (OR, 5.77 (95% CI, 2.4913.31)), and was
higher than that conferred by maternal obesity (OR, 2.1
(95% CI, 1.303.31)). These observations indicate that
sonographic evidence of chronic uteroplacental ischemia
in the second trimester is an important risk factor for
the development of pre-eclampsia. In the rst trimester
of pregnancy it has been reported that the combina-
tion of high mean uterine artery PI, low maternal serum
concentrations of PlGF and other maternal parameters
identied 93.1% of patients who would develop pre-
eclampsia requiring delivery before 34 weeks
31
.
Collectively, this evidence indicates that abnormal
UtADVduring pregnancy is a surrogate marker of chronic
uteroplacental ischemia and is an important risk factor for
the development of pre-eclampsia. Chronic uteroplacental
ischemia appears to be more relevant in the pathogenesis
of early-onset pre-eclampsia than in term or postterm pre-
eclampsia
32,33
. This view is supported by the observation
that high impedance to blood ow in both uterine arteries
in the second trimester is associated with a higher risk
for pre-eclampsia at 34 weeks than at >34 weeks of
gestation
1922
. This is important, because early-onset pre-
eclampsia is more severe
34
and is associated with a higher
proportion of growth-restricted fetuses
34
, a higher risk
of maternal death
35
and a higher frequency of placental
pathology
36
than is late-onset pre-eclampsia.
Biological gradient (doseresponse relationship)
During pregnancy the uterus and placenta form an
anatomic and functional uteroplacental unit. Absolute
uteroplacental ischemia may result from: 1) placental
bed disorders; 2) vascular insults to the placenta; or
3) abnormal fetoplacental circulation. Recent reports
indicate not only that pre-eclampsia is associated with
placental vascular lesions consistent with maternal under-
perfusion, but also that the earlier the gestational age
at which pre-eclampsia develops, the higher the preva-
lence of lesions consistent with placental ischemia
36,37
.
For example, a retrospective nested casecontrol study
that included 743 patients with pre-eclampsia and 167
patients with chronic hypertension with superimposed
pre-eclampsia indicated that the frequency of placen-
tal histological lesions consistent with underperfusion is
higher at earlier gestational ages and gradually decreases
with advancing gestational age. The frequency of placental
histological lesions consistent with maternal underperfu-
sion ranges from75100%in pre-eclampsia that develops
before 27 weeks to 13% in pre-eclampsia that devel-
ops at more than 41 weeks
37
. Of note, the authors
Copyright 2012 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2012; 40: 373382.
Opinion 375
indicated that there was not an abrupt change in the
frequency of placental lesions consistent with maternal
underperfusion between early-onset and late-onset pre-
eclampsia, indicating that the frequency of histological
lesions consistent with chronic uteroplacental ischemia is
a continuum, and that the proposed cut-off of 34 weeks
to sub-classify pre-eclampsia into early and late onset may
have clinical value but does not correlate with the results
of placental pathology. Thus, any other cut-off, such as
32 weeks or 35 weeks, could also be used to sub-classify
pre-eclampsia.
Collectively, these observations suggest that there is
a doseresponse relationship between the magnitude of
uteroplacental ischemia and the timing of onset of pre-
eclampsia. A striking example of this is the development
of pre-eclampsia before 20 weeks of gestation in patients
with mole or partial mole. The conventional view is that
placental villi in partial and complete mole are avas-
cular or limited to villous capillary remnants
15
. Thus,
molar pregnancies may represent an extreme in the spec-
trum of ischemic disease of the trophoblast (see below).
The doseresponse relationship between the magnitude
of uteroplacental ischemia and the timing of development
of pre-eclampsia suggests that there is an absolute or
relative trophoblast ischemic threshold beyond which
pre-eclampsia develops. It is possible that the response
to this threshold may be modied by geneenvironment
interaction, the magnitude of angiogenic imbalances and
fetal signaling in response to uteroplacental ischemia
15
.
Specicity
Fetal strategies to cope with chronic uteroplacental
ischemia may include growth restriction, fetal signaling
to increase the maternal systemic blood pressure lead-
ing to pre-eclampsia, or preterm parturition to exit an
inadequate intrauterine environment. Since the pathogen-
esis of these pregnancy complications may overlap, it is
not unusual to observe a combination of these obstetric
syndromes. Indeed, pre-eclampsia and gestational hyper-
tension are frequently associated with fetal growth restric-
tion; similarly, preterm parturition is commonly asso-
ciated with fetal growth abnormalities
3840
. Moreover,
gestational hypertension and gestational proteinuria
15
are
considered part of the spectrum of pre-eclampsia because
between 25%and 50%of patients with gestational hyper-
tension develop pre-eclampsia
41
. Thus, not surprisingly,
abnormal UtADV in the second trimester is also an
important risk factor for the development of gestational
hypertension (OR, 1.6 (95% CI, 1.182.25)) and for
the delivery of a small-for-gestational age neonate in the
absence of pre-eclampsia (OR, 2.3 (95% CI, 1.722.97))
after adjusting for maternal age, previous pre-eclampsia,
nulliparity, maternal obesity and smoking status
29
.
Abnormalities in the placental bed and subsequent fail-
ure of physiologic transformation of the spiral arteries in
the rst or early second trimester limit the blood ow to
the uteroplacental unit
42,43
. Indeed, high impedance to
blood ow in both uterine arteries, a surrogate marker
of uteroplacental ischemia
44,45
, is associated with
failure of physiologic transformation of the spi-
ral arteries in placental bed biopsies from patients
with pre-eclampsia
4649
and those with fetal growth
restriction
46,4850
. However, not all patients with these
pregnancy complications have evidence of failure of phys-
iologic transformation of the spiral arteries
46,47,49,50
.
Moreover, this pathological nding is not limited to
patients with pre-eclampsia or fetal growth restriction; it
has also been described in a subset of patients with preterm
parturition
51
, and fetal death
52
. Thus, abnormal UtADV
in the rst or second trimester as well as failure of physio-
logic transformation of the spiral arteries are not limited to
patients with pre-eclampsia. Therefore, the application of
Hills criterion of specicity to sonographic or patholog-
ical evidence is inadequate because the abovementioned
pregnancy complications tend to coexist or overlap.
Temporal relationship
Sonographic evidence of reduced uteroplacental perfu-
sion in the rst and second trimester is a risk factor
for the development of pre-eclampsia in the index preg-
nancy. Thus, by denition, abnormal UtADV precedes
the clinical manifestation of pre-eclampsia. However, the
positive predictive value of abnormal UtADV in the sec-
ond trimester for the development of pre-eclampsia is only
between 8% and 33%
53
, indicating that the vast major-
ity of patients with second-trimester abnormal UtADV
will not develop this pregnancy complication. Therefore,
abnormal UtADV has a limited value in the screening
of patients for pre-eclampsia. In spite of this, a study
comparing second-trimester abnormal UtADV with other
biochemical parameters, including angiogenic-related fac-
tors, markers of oxidative stress and markers of endothe-
lial dysfunction, indicated that second-trimester abnormal
UtADVperformed better than did all the other parameters
in the identication of patients at risk for pre-eclampsia
54
.
We believe that the actual value of second-trimester
UtADV is in the assessment of risk for the develop-
ment of pre-eclampsia in individual patients, particularly
in combination with other biochemical markers
55,56
. This
has important clinical implications, because the typical
practitioner provides health services to individual patients
and is not involved in population screening.
The conventional view is that physiological transfor-
mation of the spiral artery occurs in the rst and early
second trimester of pregnancy
42,43
. Thus, the observations
that a higher proportion of spiral arteries have failure
of physiologic transformation in placental bed biopsies
from patients with pre-eclampsia than do those from nor-
mal pregnancies
4649
suggest that reduced uteroplacental
owprecedes the clinical manifestations of pre-eclampsia.
Collectively, this sonographic and pathological evidence
suggests that uteroplacental ischemia in pre-eclampsia is
chronic in nature.
Consistency
This Hills criterion requires that the observation of an
association between chronic uteroplacental ischemia and
Copyright 2012 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2012; 40: 373382.
376 Espinoza
pre-eclampsia has been replicated in different settings
using different methods. The evidence reviewed above
indicates that abnormal UtADV is a surrogate marker for
chronic uteroplacental ischemia, and that it is an impor-
tant risk factor for the development of pre-eclampsia
in the index pregnancy. Other methods used to provide
additional evidence of chronic uteroplacental ischemia
in pre-eclamptic women include studies with functional
placental scintigraphy with Iridium-113m
57
, demonstrat-
ing that patients with pre-eclampsia have reduced blood
ow in the uteroplacental circulation, as well as more
recent studies using magnetic resonance imaging (MRI)
and intravoxel incoherent motion, demonstrating that
pre-eclamptic patients have lower blood ow in the basal
plate of the placenta compared with normal controls
58
.
Animal models of pre-eclampsia provide additional evi-
dence of the association between uteroplacental ischemia
and this pregnancy complication. These models were
designed to reduce the blood ow in the aorta and/or
both uterine arteries in an attempt to mimic the reduced
blood ow due to abnormal physiological transforma-
tion of the spiral arteries, and include the following:
1) placement of a clamp in the aorta below the renal
arteries in pregnant animals, aiming to reduce the femoral
pressure by half, led to a gradual increase in the carotid
blood pressure
1
; 2) partial occlusion of both uterine arter-
ies in baboons, before pregnancy or in the mid-trimester,
induced hypertension and proteinuria and renal lesions
that resemble glomerular endotheliosis
59
; 3) partial occlu-
sion of the aorta below the renal arteries in 11 Rhesus
monkeys produced hypertension and proteinuria in four
of the seven animals who continued pregnancy to term
60
;
4) more recently, unilateral uterine artery ligation in preg-
nant baboons resulted in hypertension, proteinuria and
renal histological changes, including endotheliosis and
deposition of brin and brinoid, as well as, a reduced
platelet count and increased circulating concentrations of
sFlt-1
61
; 5) perhaps one of the most reproducible animal
models of pre-eclampsia, the reduced uterine perfusion
(RUPP) model in pregnant rats
6266
, in which uteropla-
cental perfusion is reduced by 40% by placement of
silver clips in the aorta and both right and left uterine
arteries; this leads to increased mean arterial blood pres-
sure, proteinuria and fetal growth restriction as well as
angiogenic imbalances characterized by an increase in the
placental expression of sFlt-1 and sEng as well as reduced
expression of VEGF and PlGF
67,68
.
Additional evidence of the consistency of the associa-
tion between uteroplacental ischemia and pre-eclampsia
is provided by the observations that different placental
lesions may lead to chronic trophoblast ischemia and
angiogenic imbalances
15
. For example, decidual arteri-
olopathy, central villi infarction and hypermaturity of
villi are frequently seen in classical pre-eclampsia, par-
ticularly at early gestational ages
36
. Whereas in mirror
syndrome associated with pre-eclampsia, the main his-
tological feature of the placenta is severe villous edema,
the placental villi in molar pregnancies are considered
avascular
15
. In mirror syndrome, the impaired oxygen
exchange in the fetal maternal interface is most likely
due to compression of the villous blood vessels and/or a
thicker interface. However, swollen edematous villi may
also reduce the intervillous space and the intervillous
blood ow, with subsequent reduction in the fetal oxygen
supply
15
. Thus, severe villous edema in hydropic fetuses
may be associated with trophoblast ischemia leading
to placental overexpression and release of antiangio-
genic factors. It is possible that chronic uteroplacental
ischemia and subsequent angiogenic imbalance may rep-
resent a common pathway in the mechanisms of disease
of pre-eclampsia associated with partial mole and mirror
syndrome as well as that of classical pre-eclampsia
15
.
Collectively, the observations reviewed above indicate
that animal models of uteroplacental ischemia and
non-invasive imaging techniques in humans as well as
studies of placental pathology in patients with pre-
eclampsia are supportive of the association between
chronic uteroplacental ischemia and pre-eclampsia.
Biological plausibility
This Hills criterion of causation refers to the need for
some theoretical basis for positing an association between
chronic uteroplacental ischemia and pre-eclampsia and
for this association to agree with the currently accepted
understanding of pathological processes. Recent evidence
indicates that a combination of different mechanisms of
disease may be operative in pre-eclampsia. For example,
uteroplacental ischemia may lead to increased circulating
concentrations of antiangiogenic factors, as demonstrated
by the following observations: 1) reduced uterine perfu-
sion in non-human primates
61
and rats
67
is associated
with hypertension and increased placental expression
of antiangiogenic factors; 2) cytotrophoblasts cultured
under hypoxic conditions upregulate mRNA expression
and production of sFlt-1 in the supernatant
69
; 3) increased
expression of sFlt-1 in the human placenta is medi-
ated by hypoxia inducible factor-1 (HIF-1)
70
; 4) among
patients with pre-eclampsia, the higher the impedance to
blood ow in the uterine arteries (a surrogate marker of
chronic uteroplacental ischemia), the higher the mater-
nal plasma concentration of antiangiogenic factors
71
; and
5) histological lesions suggestive of chronic trophoblast
ischemia have been associated with hypertension, pro-
teinuria and angiogenic imbalances, including lesions
consistent with maternal underperfusion in classic pre-
eclampsia
72
, severe villous edema in mirror syndrome
and avascular villi in mole and partial mole
15
. Thus, the
evidence reviewed herein provides theoretical support for
the association between chronic uteroplacental ischemia
and pre-eclampsia.
One of the main limitations of in-vitro studies trying
to simulate trophoblast ischemia in the laboratory is the
common misconception that tissue ischemia equates to
tissue hypoxia. Ischemia can be dened as a decrease in
the blood supply to a bodily organ, tissue or part caused
by constriction or obstruction of the blood vessels, while
hypoxia is dened as a deciency in the amount of oxygen
Copyright 2012 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2012; 40: 373382.
Opinion 377
reaching body tissues. The conventional view is that the
degree of tissue ischemia is what determines the presence
or absence of tissue hypoxia. Yet, many in-vitro studies
used hypoxia or hypoxemia as a surrogate marker of
tissue ischemia; not surprisingly, these studies reported
conicting results, indicating an association of tissue
hypoxia
7377
or even hyperoxia
7884
with pre-eclampsia.
Many of these studies used changes in the expression of
HIF as a surrogate indicator of tissue hypoxia. However,
recent evidence indicates that non-hypoxic stimuli can
lead to increased expression of HIF in the placenta
76,85,86
and other tissues
87,88
. For example, normoxic induction
of HIF can be mediated by adenosine A2a receptor in
macrophages
87
. Improvements in non-invasive methods
to evaluate tissue ischemia in animal models and better
methods to evaluate tissue ischemia in-vitro, apart from
the evaluation of oxygen content, may provide important
insight into the mechanisms of injury in pre-eclampsia.
Coherence
This Hills criterion refers to the idea that a cause-and-
effect interpretation should not seriously conict with the
generally known facts of the natural history and biology
of the disease.
17
Some attempts have been made to assess
in vivo the changes in blood ow secondary to failure
of physiological transformation of the spiral arteries,
indicating that this failure leads to placental rheological
consequences rather than chronic hypoxia
89
. However,
this idea is based on mathematical modeling and has not
been conrmed by empirical data. Moreover, these results
are not consistent with studies using functional MRI
which found reduced blood ow in the basal plate of
pre-eclamptic women, an anatomic area that corresponds
to the spiral arteries
58
, compared with that of normal
controls. The evidence reviewed thus far indicates that
chronic uteroplacental ischemia plays a central role in
the pathogenesis of pre-eclampsia and that this possible
cause-and-effect association does not conict with the
natural history and biology of the disease.
Experiment (reversibility)
In the experimental uteroplacental ischemia described
by Ogden, Hildebrand and Page in 1940
1
, the authors
reported that placement of a clamp in the aorta below
the renal arteries in pregnant dogs produced a gradual
increase in the carotid blood pressure and that release
of the aortic clamp was followed by a return to the
previous blood pressure sometimes immediately, some-
times gradually during 20 minutes.
1
The observation that
this effect was prevented when a pregnant animal under-
went hysterectomy indicates that uteroplacental ischemia
is not sufcient to lead to systemic hypertension, but
that it requires the presence of the fetus (or fetal sig-
naling) and the uteroplacental unit; in the words of the
authors: Since in our 4 control animals. . . compression
of the aorta below the renal artery produces no such
prolonged rise as we have here described, we are forced
to conclude that the products of conception (i.e. fetus,
placenta, or gravid uterus) are fundamentally responsible
for these slow blood pressure rises. This observation is
consistent with the notion that a combination of utero-
placental ischemia and some of the other mechanisms
of injury discussed in the introduction of this Opinion
may be operative in pre-eclampsia. For example, accu-
mulating clinical
15,72
and experimental
61,67,69,70
evidence
indicates that uteroplacental ischemia leads to angiogenic
imbalances
15
, which appears to play a central role in the
pathogenesis of pre-eclampsia.
In their original report, Ogden, Hildebrand and Page
wrote: These rises of blood pressure could be produced
repeatedly in the same animal except after a long period
on unduly severe constriction when it may be supposed
that prolonged anoxemia had caused irreversible changes
in the uterus or its contents.
1
This observation has
transcendental implications, because, if fetal signaling, in
response to uteroplacental ischemia, leads to an elevation
in the maternal systemic blood pressure, initial increases
in the maternal blood pressure might compensate for
the reduced blood ow to the fetal and placental
tissues. However, because of its chronic nature, persistent
ischemia to the uteroplacental unit may lead to further
increase in maternal blood pressure even if the reduced
blood supply to the uteroplacental unit was initially
compensated by an elevation in the maternal systemic
blood pressure. Thus, there is a tendency for pre-eclampsia
to become more severe if the patient remains pregnant.
Moreover, a hypothetical intervention that could correct
reduced uteroplacental owmay not be able to reverse the
disease process if the irreversible changes in the uterus or
its contents
1
are already in place.
Analogy (consideration of alternate explanations)
Other animal models of pre-eclampsia have been
described
90
, based on: 1) genetic manipulation of enzymes
and pathways involved in the pathogenesis of pre-
eclampsia; 2) administration of various agents, includ-
ing N-omega-nitro-L-arginine (L-NAME), insulin, Adria-
mycin (a nephrotoxin agent) and autoantibodies against
angiotensin II type 1a receptors (AT
1
) obtained from
women with pre-eclampsia; of note, in this latter model,
coadministration of AT
1
and Losartan prevented man-
ifestation of pre-eclamptic features; 3) manipulation of
innate or adaptive immunity; 4) manipulation of pro-
and anti-inammatory cytokines; 5) ultra-low-dose endo-
toxin infusion; 5) chronic stress; and 6) sympathetic
hyperactivity
90
. A detailed description of these models is
beyond the scope of this Opinion and the reader is referred
to a recent review on the topic
90
. All of these models are
based on the manipulation of different pathways involved
in the pathogenesis of pre-eclampsia; they do not disprove
the possible causal association between chronic uteropla-
cental ischemia and pre-eclampsia, because they simply
demonstrate that different pathways may be operative in
the pathogenesis of this pregnancy complication. This is
consistent with the results of a proteomic study indicating
Copyright 2012 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2012; 40: 373382.
378 Espinoza
divergent molecular mechanisms in pre-eclampsia, includ-
ing: 1) angiogenesis; 2) mitogen-activated protein kinases
(MAPK) signaling; and 3) hormone biosynthesis and
metabolism
91
. Future studies will determine if there is
an association between chronic uteroplacental ischemia
and these molecular pathways.
A possible role of the fetus in the pathogenesis of
pre-eclampsia
Clinical and sonographic observations in patients with
pre-eclampsia suggest that the fetus may play a
role in the maternal manifestations of this pregnancy
complication
92,93
. A striking example of the role of the
fetus is remission of pre-eclampsia following the death
of the growth-restricted fetus in discordant twins, or
after correction of fetal hydrops in mirror syndrome
associated with parvovirus infection
15
. In the latter
case, improvement in the fetal status and presumably
subsequent improvement in fetal perfusion of the placenta
led to the resolution of pre-eclampsia without the need
for placental delivery.
The fetal endothelium is continuous with that of the
villous capillaries and it is possible that, in response
to ischemia, endothelial signaling in villous capillaries
may lead to placental overexpression and secretion of
an excess of antiangiogenic factors. This is supported
by studies using placental explants, in which the fetal
compartment and the intervillous space are perfused
under controlled conditions. In one study the authors
determined the adenosine concentrations in fetal venous
perfusates using isolated dual-perfused human placental
cotyledons. They reported that cessation of maternal
perfusion was associated with a two- to six-fold increase in
fetal venous perfusate concentrations of adenosine and a
concomitant increase in fetoplacental perfusion pressure.
Furthermore, perfusate pressure and the concentration of
adenosine in the fetal compartment returned to baseline
levels on reperfusion of the maternal circuit
94
. Thus,
even in the absence of a fetus, the fetal endothelium in the
placental villi is capable of increasing the concentration
of adenosine in response to reduced perfusion. Adenosine
is a nucleoside that has been implicated in the placental
expression of sFlt-1 under both normoxic and hypoxic
conditions
95
. Moreover, recent reports suggest that the
fetus may use adenosine signaling in an attempt to improve
the uteroplacental circulation in pre-eclamptic women
with sonographic evidence of chronic uteroplacental
ischemia
93
.
Abnormal fetoplacental circulation may also lead to
uteroplacental ischemia and pre-eclampsia. A striking
example of this is the development of pre-eclampsia
before 20 weeks of gestation in patients with mole or
partial mole. The conventional view is that placental villi
in partial and complete mole are avascular or limited
to villous capillary remnants
15
. However, this notion
was recently challenged by the observation that vascular
endothelial cells are present in the villous stroma of
complete mole
15
. By denition, these vascular endothelial
cells are of fetal origin. Thus, it is possible that the lack of
fetoplacental circulation in complete mole leads to severe
ischemia of endothelial and trophoblast cells and excessive
placental production of antiangiogenic factors. In molar
pregnancies, the prevalence of pre-eclampsia is much
higher when a fetus is present, suggesting a role for the
fetus in pre-eclampsia. Indeed, pre-eclampsia is present in
41.9%of pregnancies with partial mole
15
. In contrast, the
prevalence of pre-eclampsia in complete mole signicantly
decreased, from 12% (41/347) in the period 19661972
to 1.3% (1/74) in the period 19881993, presumably
due to earlier diagnosis and uterine evacuation, which
may have prevented the subsequent development of pre-
eclampsia
15
. The absence of a fetus in complete mole
does not disprove the fetal role in pre-eclampsia
96
.
On the contrary, the lack of fetal perfusion of the
placenta in complete mole may represent an extreme
in the spectrum of ischemic disease of the uteroplacenta,
leading to angiogenic imbalances and early-onset pre-
eclampsia. This is supported by the observation that
the serum concentration of sFlt-1 in the rst trimester
among patients with complete mole is signicantly higher
than that of patients with normal pregnancies and that
of patients who develop pre-eclampsia in the index
pregnancy
97
.
Late-onset pre-eclampsia: relative uteroplacental
ischemia?
Late-onset pre-eclampsia (>34 weeks) accounts for the
vast majority of pre-eclamptic cases. However, absolute
uteroplacental ischemia appears to be less relevant in the
pathogenesis of late-onset compared with early-onset pre-
eclampsia
15
. Evidence in support of this view includes the
recent observation that more than half of patients with
late-onset pre-eclampsia do not have placental histological
lesions consistent with maternal underperfusion
72
. In
addition, among patients with late-onset pre-eclampsia,
those without placental lesions consistent with maternal
underperfusion have evidence of angiogenic imbalances
when compared with women with normal pregnancies
but of a lower magnitude than in pre-eclamptic women
with vascular placental lesions
72
. Furthermore, late-onset
pre-eclampsia is frequently associated with fetuses that
are appropriate- or large-for-gestational age
15
. Thus, in
these cases an increased fetal demand for substrates that
surpasses the placental ability to sustain fetal growth
may induce fetal signaling for placental overproduction
of antiangiogenic factors and subsequent compensatory
maternal hypertension. It is possible that relative
uteroplacental ischemia due to a mismatch between
limited uteroplacental blood ow and increased fetal
demand for nutrients may be central to the development of
late-onset pre-eclampsia. Not surprisingly, the prediction
of late-onset pre-eclampsia using rst- and second-
trimester biochemical or biophysical (UtADV) parameters
or a combination of them has been less effective than
has the prediction of early-onset pre-eclampsia
15
. This is
probably because a trophoblast ischemic threshold leading
Copyright 2012 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2012; 40: 373382.
Opinion 379
to pre-eclampsia is crossed late in pregnancy or due to
a more acute nature of the insults to the fetal supply
line in late-onset pre-eclampsia. The latter suggestion is
supported by the results of a longitudinal study reporting
that there is a subset of patients who have sonographic
evidence of limited uteroplacental blood ow in the
third but not in the second trimester, presumably due
to early regression of the physiologic transformation of
the spiral arteries. These patients have a higher frequency
of pre-eclampsia than do patients without sonographic
evidence of uteroplacental ischemia in the second or third
trimester
29
.
A recent population-based study indicated that gesta-
tional diabetes (GDM) is an independent factor for the
development of pre-eclampsia after controlling for con-
founding factors including maternal age, parity, BMI,
smoking as well as chronic hypertension or renal disease
(adjusted OR, 1.61 (95% CI, 1.391.86))
98
. Moreover,
a large retrospective study demonstrated that the rate
of pre-eclampsia among women with GDM with poor
glycemic control was twice as high as that among women
with better glycemic control (18% vs 9.8%; OR, 2.56
(95% CI, 1.54.3))
99
. However, there is limited literature
regarding the timing of onset of pre-eclampsia among
women with GDM. Of note, a recent study involving
45 consecutive patients with GDM demonstrated normal
placental histology in 80% of them
100
; thus, placental
vascular lesions are not common in women with GDM.
Since this pregnancy complication is associated with large-
for-gestational age neonates, it is possible that, in women
with GDM who develop pre-eclampsia, an increased fetal
demand for substrates that surpass the placental ability
to sustain fetal growth may induce fetal signaling for
placental overproduction of antiangiogenic factors and
subsequent compensatory maternal hypertension. How-
ever, additional studies are required to explore the role of
angiogenic imbalances in these patients. To the extent that
these studies conrm angiogenic imbalances in GMD, rel-
ative uteroplacental ischemia due to a mismatch between
uteroplacental blood ow and increased fetal demand
for nutrients may be central to the development of pre-
eclampsia associated with GDM. Thus, better methods
to identify large-for-gestational age neonates may pro-
vide important insight into the pathogenesis of late-onset
pre-eclampsia.
In view of the limited pathological and sonographic
evidence of uteroplacental ischemia in late-onset pre-
eclampsia, fetal signaling may provide a unifying
conceptual framework in the pathogenesis of both early-
and late-onset pre-eclampsia.
Summary
Pre-eclampsia
101
and eclampsia
102
are a leading cause
of maternal morbidity and mortality. Understanding
the subjacent mechanisms of injury in this pregnancy
complication may help in the design of new prophy-
lactic and therapeutic interventions. Absolute uteropla-
cental ischemia appears to be more relevant in early-
onset pre-eclampsia. In contrast, relative uteroplacental
ischemia due to a mismatch between uteroplacental blood
ow and increased fetal demand for nutrients may be cen-
tral to the development of late-onset pre-eclampsia. Hills
criteria are still widely accepted as a logical structure
for investigating and dening causality in epidemiolog-
ical studies. However, their method of application is
debated. For example, some authors propose using a
counterfactual consideration as the basis to apply each
criterion. Moreover, a revision of the criteria was recently
proposed in the context of evidence-based medicine, sub-
dividing them into three categories: direct, mechanistic
and parallel evidence
103
. Also, some authors argue that
the basic mechanism of proving causality is in scientic
common sense deduction
104
. However, it is important
to remember that Sir Austin Bradford Hill himself indi-
cated that none of these nine criteria of causality can
bring indisputable evidence for or against the cause-and-
effect hypothesis and none can be required as a sine qua
non.
17
While recognizing these limitations, the balance of
observations reviewed herein indicate that Hills criteria
suggest a causal association between chronic uteropla-
cental ischemia and pre-eclampsia. The conventional
denition of pre-eclampsia has important limitations
105
,
and recent modications continue to be based on conven-
tion rather than on maternal and/or perinatal outcome.
Novel conceptual frameworks may contribute to a more
objective denition of this obstetric syndrome.
J. Espinoza
Department of Obstetrics and Gynecology,
Texas Childrens Hospital Pavilion for Women,
Baylor College of Medicine,
6651 Main Street, Suite 1020,
Houston, TX 77030, USA
(e-mail: jimmy.espinoza@bcm.edu)
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