Berthold Huppertz

Placental Origins of Preeclampsia: Challenging the Current Hypothesis

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doi: 10.1161/HYPERTENSIONAHA.107.107607
2008;51:970-975; originally published online February 7, 2008; Hypertension.
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Placental Origins of Preeclampsia
Challenging the Current Hypothesis
Berthold Huppertz
P
reeclampsia is a major contributor to the maternal and
neonatal mortality and morbidity.
1,2
It is the 2nd
largest cause of maternal mortality worldwide and affects
5% to 7% of pregnant women worldwide.
3,4
The precise etiopathogenesis of preeclampsia remains to be
a subject of extensive research, but it is believed that it is
likely to be multifactorial. Nevertheless, it is accepted that it
is the presence of the placenta rather than the fetus, which is
responsible for development of preeclampsia. Although the
placenta plays a crucial role in the development of pre-
eclampsia, the onset, severity, and progression is significantly
affected by the maternal response to placentally derived
factors and proteins. Therefore, mother and fetus should be
taken into account when calculating the risk for preeclampsia.
Preeclampsia is generally defined as the development of
hypertension and proteinuria after 20 weeks of gestation in a
previously normotensive woman,
3,4
although different varia-
tions of this have been proposed by different groups and
organizations. (ACOG, ISSHP, Australian college). It has
also been further subdivided into mild, moderate, and severe
preeclampsia as well as early and late onset preeclampsia, of
which the latter is a more contemporary concept.
5
It has been
suggested that early (before 340 weeks) and late (after
340 weeks) onset preeclampsia have different etiologies
and therefore a different clinical expression, but it is still a
subject of considerable research. There are, however, some
basic differences between the 2 groups:
A. The late onset type of preeclampsia comprises more
than 80% of all preeclampsia cases worldwide. Most of
these late onset cases are associated with:
A normally grown baby with no signs of any growth
restriction;
A normal or only slightly altered behavior of the
uterine spiral arteries (no changes in the Doppler
waveforms or slight increase of the pulsatility index
[PI]);
No changes in the blood flow of the umbilical
arteries;
An increased risk for pregnant women displaying an
enlarged placental mass or surface (diabetes, multi-
ple pregnancies, anemia, high altitude).
B. The early onset type of preeclampsia comprises a small
subset of all preeclampsia cases (5% to 20%, depending
on the statistics), but comprises the most severe cases of
respective clinical relevance. The typical features of this
type of preeclampsia can be summarized as follows:
An inadequate and incomplete trophoblast invasion
of maternal spiral arteries;
Changes of the blood flow within the placental bed
spiral arteries and thus in the uterine arteries
(notches and other changes [increased PI] of the
Doppler waveforms);
An increased peripheral resistance of the placental
vessels may be one cause of an abnormal blood flow
of the umbilical arteries (increased systolis/diastolis
(S/D) ratio in still preserved flow or absent and even
reversed end diastolic blood flow velocity in these
arteries);
Clear signs of a fetal growth restriction.
It needs to be clarified that all the above features of the early
onset type of preeclampsia are not specific for this type of
pregnancy pathology. Most of the cases with early onset
preeclampsia are associated with another major pregnancy
pathology, intrauterine growth restriction (IUGR). The typi-
cal features of early onset IUGR cases are an inadequate
trophoblast invasion, an inadequate transformation of spiral
arteries, followed by respective changes in the blood flow of
the uterine arteries, alterations of the umbilical blood flow,
and restrictions of fetal growth.
Because the subgroup with early onset of preeclampsia is
associated with relatively severe complications, it has been
the focus of basic and clinical research. The combination of
the 2 syndromes (preeclampsia and IUGR) in these cases may
have lead to the presumption that the early onset type of
preeclampsia is caused by alterations described to be caus-
ative for IUGR, such as changes in the blood flow of the
uterine as well as the umbilical arteries and growth restriction
of the baby. But pure early onset IUGR cases show exactly
the features listed above. Thus it is doubtful whether such
alterations are indeed related to preeclampsia at all.
This is supported by studies trying to use uterine artery
Doppler as a predictor of preeclampsia. In a study with 10
early onset preeclampsia cases and 423 controls Nicolaides et
al used uterine artery Doppler at 110 to 136 weeks as a
Received December 4, 2007; first decision December 31, 2007; revision accepted January 8, 2008.
From the Institute of Cell Biology, Histology and Embryology, Center of Molecular Medicine, Medical University Graz, Austria.
Correspondence to Dr Berthold Huppertz, PhD, Professor of Cell Biology, Institute of Cell Biology, Histology and Embryology, Center of Molecular
Medicine, Medical University Graz, Harrachgasse 21/7, 8010 Graz, Austria. E-mail berthold.huppertz@meduni-graz.at
(Hypertension. 2008;51:970-975.)
2008 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org DOI: 10.1161/HYPERTENSIONAHA.107.107607
970 by guest on June 1, 2014 http://hyper.ahajournals.org/ Downloaded from
predictor.
6
But although the uterine artery PI was increased in
the preeclampsia cases, for a 10% false-positive rate, the
detection rate would only have been 40%. In a larger study
Pilalis et al measured the uterine artery blood flow in 1123
pregnant women at 11 to 14 weeks of gestation.
7
The
outcome of this study was unambiguous: The sensitivity of
uterine artery Doppler for all cases of preeclampsia was only
21%, and it was 33.3% for early onset preeclampsia cases.
The sensitivity for detection of early onset of fetal growth
restriction in this study, however, was 100%.
This data raises the question whether a clear difference
between early and late onset cases of preeclampsia is really
existent. Maybe it is the combination with IUGR that makes
the early onset cases so severe. In terms of symptoms of
preeclampsia (hypertension and proteinuria) in both groups
there are severe cases with maximal blood pressure values
and maximal protein concentrations in the urine.
What Then Is the Origin of Preeclampsia?
Trophoblast Development
Taking a look at early human development (Figure 1) the tropho-
blast is the first cell lineage to differentiate at the stage of the
blastocyst at about day 6 postconception (p.c.). Further differ-
entiation steps result in the formation of the 2 different pathways
of trophoblast, the villous and the extravillous pathway.
At the time of implantation the early syncytiotrophoblast is
generated,
8
which increases in size by a continuous feeding
mechanism of mononucleated cytotrophoblast cells. The
latter cells continuously proliferate, differentiate, and syncy-
tially fuse with the syncytiotrophoblast, thus increasing and
maintaining this multinucleated layer throughout gestation.
During the very early stages of syncytiotrophoblast develop-
ment this layer is invasive and helps penetrating the uterine
epithelium. Only after some days the first fluid filled space,
the so called lacunae develop that coalesce and are the
forerunners of the intervillous space.
9
At about day 12 p.c. the cytotrophoblast cells start to
penetrate through the syncytiotrophoblastic mass, moving
toward the first branches that extend into the intervillous
space, thus resulting in the formation of villous trophoblast
cells. Only a few days later (day 15 p.c.) the cytotrophoblast
cells have reached the maternal side of the syncytiotropho-
blast mass. This is the time of the first contact of mononucle-
ated trophoblast cells with the maternal decidual stroma. Thus
only in week 5 postmenstruation (p.m.) the subtype of
extravillous trophoblast cells is established.
At this stage of human development the 2 major subtypes of
trophoblast, villous and extravillous, are established and their
further subpopulations (villous cytotrophoblast and syncytiotro-
phoblast versus interstitial [mono- and multinuclear], endomu-
ral, and endovascular extravillous trophoblast) are developing.
The development of the trophoblast lineage takes place in week
1 p.c., whereas the definition of the 2 pathways (villous and
extravillous) gets in place in week 3 p.c. This temporal differ-
ence may become important in terms of the placental origins of
pregnancy pathologies such as preeclampsia and IUGR.
Serum Markers to Predict Preeclampsia
There is a general trend in clinical sciences to focus on early
predictive markers. This is probably because of the fact that
early prediction/detection allows for planning appropriate
management, early detection of complications, and in some
cases instituting preventative measures thus eventually im-
proving overall outcome. Pregnancy is limited to 40 weeks,
and because preeclampsia is defined as new onset of hyper-
tension and proteinuria in the second half of pregnancy, ie,
after 20 weeks of gestation, there are at least 20 weeks (from
implantation to week 20 of pregnancy) left for prediction.
Today women who develop preeclampsia can only be de-
tected by the appearance of clinical symptoms such as hyper-
tension and proteinuria.
3,4,10,11
No predictive test is available to
identify pregnant women who will subsequently develop pre-
eclampsia and moreover, which of those may develop the early
or late type of the syndrome, the mild or severe type, even
turning into eclampsia. This is opposed by the high prevalence
of preeclampsia (5%), which is associated with a high risk for
life threatening events of the mother (18% of all maternal deaths
during pregnancy). Furthermore, it has become clear that there
are short- and long-term complications for those babies who
have been born early, with low birth weight, or after exposure to
a stressful environment such as during preeclampsia. Also the
women who experienced preeclampsia are known to have a
higher risk for health problems later in life such as a higher
prevalence of cardiovascular diseases. As preeclampsia has such
a high impact on maternal and neonatal morbidity and mortality,
it has been and still continues to be a subject of intensive clinical
and basic research aimed at identifying new and effective serum
markers for risk assessment and reducing complications attrib-
utable to it.
In 2004 the new era of serum markers for the prediction of
preeclampsia began. Soluble VEGF receptor-1 (soluble fms-
like tyrosine kinase 1, sFlt-1) and soluble placental growth
factor (PIGF) were identified as potential serum markers for
preeclampsia.
12,13
In the following years it became clear that
these markers have some disadvantages such as:

They can be used to predict preeclampsia only a few weeks

before the onset of clinical symptoms.
14

They are not specific for preeclampsia but show similar

changes in pure IUGR as well. Even worse a recent study
Figure 1. The diagram presents an overview of early trophoblast
development. The rst development of the trophoblast lineage at
the blastocyst stage is followed by the separation of cytotropho-
blast and syncytiotrophoblast, which subsequently is followed by
the differentiation of the 2 pathways of trophoblast differentiation,
villous and extravillous. On the right, the time course of develop-
ment after fertilization (p.c., post coitum) is shown.
Huppertz Placental Origins of Preeclampsia 971
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has shown that higher levels of sFlt-1 at 11 to 14 weeks of
gestation were not associated with the risk of preeclampsia
but were associated with a reduced risk of delivery of a
small for gestational age infant.
15

A large number of women developing preeclampsia will not

be detected by elevated sFlt-1 or decreased VEGF. In a study
of Savvidou et al only 3 of 16 preeclampsia cases were
detected by measuring sFlt-1 and VEGF at 23 to 25 weeks.
16
More recently, soluble endoglin, an antiangiogenic protein,
was raised as a new marker with increasing levels in women
who subsequently will develop preeclampsia.
17
Soluble en-
doglin concentrations were significantly different already 2 to
3 months before onset of clinical symptoms. Thus early onset
cases could be detected at about week 20, whereas late onset
cases could be detected at about week 28 of gestation.
17
The above markers may be able to predict the development of
preeclampsia, but only later in gestation. The time window that
will be given by such markers may not be wide enough for a
successful treatment, especially if an early administration of
putative medications is needed and effective only if started in the
first trimester. As a consequence there are enormous efforts on
the way that are directed toward identifying new and noninva-
sive serum markers for the early and accurate prediction of
preeclampsia in the first trimester of pregnancy. This would
enable the use of effective prophylactic or preventive therapies
starting as early as possible during pregnancy.
18,19
Such new serum markers showing significant differences
already in the first trimester of pregnancy include placental
protein 13 (PP13),
6,20,21,22
placenta associated plasma protein
A (PAPP-A),
21,23
long pentraxin 3 (PTX3),
24,25
as well as a
revival of sFlt-1.
26
Taking PP13 as an example of one of the
new and early serum markers, it has been shown very recently
that this marker may be able to detect even late onset
preeclampsia cases as early as 7 to 8 weeks of gestation.
22
The discovery of serum markers capable of predicting
preeclampsia with good detection rates and low false-positive
rates will pave the way for improved antenatal and perinatal
care. This will also allow introducing these markers into
routine testing in the first or second trimester similar to the
markers currently used in screening for trisomy 21. If such
markers enable prediction around the end of the first trimes-
ter, this will open a long time window to tailor medications
and respective prevention strategies.
3,4,10,11,18,27
Hence, such
markers and implementations for the early detection and
prediction of preeclampsia are urgently required.
Current Hypothesis: Placental Origins
of Preeclampsia
During the last decades a variety of hypotheses has been
generated aiming to explain the placental origins of pre-
eclampsia.
2831
Most of them disappeared soon, although a
few are still discussed and need approval.
32
The last few years
there was a shift in defining the placental origin of preeclamp-
sia from midgestation, just before onset of clinical symptoms
more toward very early stages of pregnancy.
33
This shift was
further substantiated by the detection of new and early
biomarkers as described above.
The current hypothesis to describe the origin and stages
toward the clinical symptoms of preeclampsia can be sum-
marized as follows:
1. Any deleterious effect on the extravillous trophoblast;
2. Failure of the extravillous trophoblast to adequately
transform the uterine spiral arteries;
3. Reduced flow of maternal blood into the intervillous
space;
4. Hypoxia or intervals of hypoxia followed by reoxygen-
ation of the placenta;
5. Hypoxic damage of the villous trophoblast;
6. Release of STBM (syncytiotrophoblast membrane frag-
ments;
34
into the maternal blood stream;
7. Maternal inflammatory response to the STBM resulting
in the development of the clinical symptoms of
preeclampsia.
Challenging the Current Hypothesis
The current concept on the placental origin of preeclampsia
starts with a failure to transform the maternal spiral arteries,
subsequently followed by alterations of the villous trophoblast
and its release of material. Figure 2 brings these 2 events into a
time frame during pregnancy and clearly shows that the tempo-
ral sequence of events does not fit with the current hypothesis.
A few years ago it has been very clearly demonstrated that
during the first trimester of pregnancy there is no flow of
maternal blood cells into the intervillous space of the placen-
ta.
35
Only at around 11 to 12 weeks of gestation the plugs of
extravillous trophoblast cells blocking the lumen of the spiral
arteries are dislocated and open the flow of maternal blood
toward the placenta. This can be traced by the increase of
oxygen from the first to the second trimester.
In parallel, the last few years have witnessed an enormous
increase in the knowledge of serum markers for preeclampsia,
especially those showing significant alterations in their con-
centrations as early as 7 weeks.
22
Thus, these alterations can
be measured weeks before the onset of flow of maternal blood
cells through the intervillous space.
A failure of transforming the spiral arteries may lead to a
reduced diameter and thus will affect the blood volume
flowing toward the intervillous space. Because blood flow is
only established at the beginning of the second trimester, such
Figure 2. The diagram depicts the 2 different pathways leading
to preeclampsia or IUGR. An insult in the villous trophoblast can
be traced already in the rst trimester and is indicative for pre-
eclampsia. An insult in the extravillous trophoblast can only be
detected in the second trimester and is indicative for IUGR.
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a failure in transformation can only be effective after onset of
blood flow, ie, after week 12 of gestation (Figure 2).
How can a failure that is effective only at the beginning of the
second trimester lead to alterations of the release of proteins
from the villous trophoblast already in mid first trimester?
New Hypothesis: Placental Origins
of Preeclampsia
The very early alterations in the concentrations of serum
markers point out that preeclampsia seems to develop already
at the onset of placentation, somewhere around implantation
or even earlier. As shown in Figure 3, at these early stages of
human development there may be several differentiation
steps and developmental stages, where any insult on tropho-
blast differentiation could result in preeclampsia or IUGR or
any other pregnancy pathology up to spontaneous abortion:
1. If the very first differentiation of the trophoblast cell
lineage is affected during development from morula to
blastocyst (Figure 3), this may result in a severe defect of
the trophoblast cell lineage in general. This may result in a
combination of IUGR and preeclampsia or even more
severe outcomes such as spontaneous abortions.
2. If the insult takes place slightly afterward, when the
blastocyst trophoblast differentiates into the first cy-
totrophoblast and syncytiotrophoblast (Figure 3), the
same dramatic outcome as described above may result.
3. Afterward, if only the differentiation of the extravillous
trophoblast pathway is affected, this may result in pure
IUGR (Figure 3) with all the typical characteristics such
as failed invasion and abnormal uterine artery Doppler.
4. If only the villous pathway is affected, then a pre-
eclampsia may result (Figure 3) with its typical charac-
teristics such as release of STBM and a maternal
inflammatory response.
An insult occurring very early during trophoblast develop-
ment, before or at the blastocyst stage, may affect the villous
as well as the extravillous pathways of trophoblast differen-
tiation thus leading to a combination of preeclampsia and
IUGR. Such very early insults are often the most severe ones,
thus the resulting combination of early onset preeclampsia
and IUGR is the most frightening situation for both mother
and child. If the insult is too strong it may even result in a
spontaneous abortion of the baby.
It may even be true that an insult leading to alterations of
the villous trophoblast and thus causing preeclampsia may in
a second stage also affect the growth of the fetusif the
villous trophoblast is no longer able to maintain its transport
capacities to adequately feed the fetus.
Thus the new hypothesis brought forward here reads as
follows:
Preeclampsia is the result of a failure of villous trophoblast
differentiation, whichon the placental sideultimately
leads to an abnormal release of trophoblast material into the
maternal circulation.
The different scenarios are (Figure 4):
1. Normal Pregnancy
During normal pregnancy aged and late apoptotic syncy-
tiotrophoblast nuclei are packed into apical protrusions of the
syncytiotrophoblast,
36,37
called syncytial knots
9
(Figure 4,
light gray). These membrane-sealed corpuscular structures
are apoptotically generated and released from the apical
syncytiotrophoblast membrane into the maternal circulation.
They are transported through the maternal venous system
behind the placenta and reach the first capillary bed behind
the placenta, the lungs.
38
Here these huge apoptotic struc-
tures, containing multiple nuclei, are engulfed by lung mac-
rophages (Figure 4, light gray) and thus cannot be detected in
peripheral maternal blood behind the lungs.
39
In peripheral
blood of healthy pregnant woman these structures are virtu-
ally absent.
40
It has recently been described that the engulf-
ment of apoptotic material by macrophages leads to a
silencing of such macrophages, thus reducing the secretion of
proinflammatory cytokines.
41,42
2. Preeclampsia, Induced by Intrinsic
Placental Factors
During preeclampsia the release of the syncytiotrophoblast
material does no longer follow the normal rules. Because of
an alteration in villous trophoblast differentiation early in
pregnancy, the release of syncytial knots is no longer the
main mechanism of disposal. Now other mechanisms take
over such as necrosis and aponecrosis
43
(Figure 4, dark gray).
The latter term has been introduced by Formigli et al
43
and
describes the start of the apoptosis cascade followed by a
failure of the program to end normally. This then results in a
necrotic release of already apoptotically cleaved material.
The 2 mechanisms, necrosis and aponecrosis, give rise to the
necrotic and cell-free release of trophoblast material. Such
necrotic trophoblast fragments can be detected in high num-
bers only in preeclampsia whereas in pure IUGR they are not
elevated above normal levels.
40
The trophoblastic fragments,
termed STBM,
34
are nonapoptotic and thus no longer
Figure 3. The diagram represents the early development of the
trophoblast lineage. The decisive differentiation steps are high-
lighted with gray boxes. The dark gray boxes indicate the very
early differentiation steps. If there is a failure during this time of
development the pregnancy may result in a combination of pre-
eclampsia (PE) and IUGR. If only the villous pathway is affected,
it may result in a preeclampsia (lower left). And if only the extra-
villous pathway is affected it may result in an IUGR (lower right).
Huppertz Placental Origins of Preeclampsia 973
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membrane-sealed structures. They are small (200 to 600
nm;
44
) and can pass the lungs; therefore they can easily be
detected in peripheral blood and may cause systemic alter-
ations of the maternal endothelium and inflammatory system.
Although early serum markers may predict preeclampsia
already in the first trimester of pregnancy, the respective clinical
manifestation of preeclampsia only occurs after midgestation.
This discrepancy can be explained as follows: During the first
trimester of pregnancy trophoblast turnover is different to the
turnover later in gestation. In the first trimester most of the
fusion events of cytotrophoblast cells with the syncytiotropho-
blast are needed for growth of the syncytiotrophoblast rather
than for the maintenance of this layer.
37
Only later in gestation a
steady-state between input of new material by cytotrophoblast
fusion and release of syncytial knots is established. During the
first trimester the release of trophoblast material is much lower
than later in gestation. This is not only true because of the lower
total placental mass and surface early in gestation but also
because of the differences in trophoblast turnover at the two
different stages of trophoblast development.
3. Preeclampsia, Induced by Extrinsic and
Maternal Factors
The origin of preeclampsia may not be restricted to an
intrinsic alteration of the villous trophoblast alone. Looking at
the conditions with an increased risk to develop preeclampsia,
they may be divided into those that increase placental mass or
surface and those that alter the response of the mother to what
is released by the placenta.
Specific conditions increase placental mass (diabetes or
multiple pregnancies) or placental surface (hypoxic condi-
tions of the mother: anemia, high altitude; Figure 4, gray
pathway on the left, extrinsic factors). This increase will be
paralleled by an increase in the release of syncytial knots. If
the maternal clearance system cannot cope with this increased
number of apoptotic fragments, they may undergo secondary
necrosis within the blood and thus may lead to the clinical
symptoms of preeclampsia as well.
The same may be true if the maternal disposal or inflam-
matory systems are not working properly and react inappro-
priately to the release of apoptotic trophoblast fragments
(Figure 4, gray pathway on the left, maternal factors). Again,
this may lead to an overload of the disposal machinery, thus
inducing a systemic activation and damage of endothelial
cells, resulting in preeclampsia.
Conclusion
Ultimately, preeclampsia is a syndrome of early placentation. An
insult resulting in an aberrant development and differentiation of
the villous syncytiotrophoblast causes an impaired maintenance
of the placental barrier. This will subsequently lead to the release
of necrotic and aponecrotic trophoblast fragments culminating in
a systemic inflammatory response of the mother. By contrast, a
failure of extravillous trophoblast invasion is correlated with the
pathophysiology of IUGR. The new concept brought forward
here clearly separates the origins of preeclampsia and IUGR and
proposes alterations in different trophoblast differentiation path-
ways as origins for both syndromes.
Figure 4. The diagram represents an overview of the events occurring during normal pregnancy and leading to the development of pre-
eclampsia. The normal pathway (in light gray) starts with normal cytotrophoblast differentiation and ends with the engulfment of apo-
ptotic syncytial knots in the lungs. If preeclampsia is initiated by intrinsic placental factors there is a shift toward nonapoptotic release
of trophoblastic fragments resulting in preeclampsia (in dark gray). Because of extrinsic factors the maternal disposal system to remove
apoptotic syncytial knots may be overloaded resulting in secondary necrosis of syncytial knots and subsequently in preeclampsia (in
gray). Because of maternal factors the mother may not respond adequately to the presence of placental material in maternal blood (in
gray) and may have the same outcome as the presence of extrinsic factors: preeclampsia.
974 Hypertension April 2008 Part II
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Source of Funding
This work was supported by the EU Grant #37244, project title
Pregenesys.
Disclosures
None.
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