Placental Origins of Preeclampsia: Challenging the Current Hypothesis

Berthold Huppertz

Hypertension. 2008;51:970-975; originally published online February 7, 2008;

doi: 10.1161/HYPERTENSIONAHA.107.107607
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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
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
5% to 7% of pregnant women worldwide.3,4 respective clinical relevance. The typical features of this
type of preeclampsia can be summarized as follows:
The precise etiopathogenesis of preeclampsia remains to be
a subject of extensive research, but it is believed that it is ● An inadequate and incomplete trophoblast invasion
likely to be multifactorial. Nevertheless, it is accepted that it of maternal spiral arteries;
is the presence of the placenta rather than the fetus, which is ● Changes of the blood flow within the placental bed
responsible for development of preeclampsia. Although the spiral arteries and thus in the uterine arteries
(notches and other changes [increased PI] of the
placenta plays a crucial role in the development of pre-
Doppler waveforms);
eclampsia, the onset, severity, and progression is significantly ● An increased peripheral resistance of the placental
affected by the maternal response to placentally derived vessels may be one cause of an abnormal blood flow
factors and proteins. Therefore, mother and fetus should be of the umbilical arteries (increased systolis/diastolis
taken into account when calculating the risk for preeclampsia. (S/D) ratio in still preserved flow or absent and even
Preeclampsia is generally defined as the development of reversed end diastolic blood flow velocity in these
hypertension and proteinuria after 20 weeks of gestation in a arteries);
previously normotensive woman,3,4 although different varia- ● Clear signs of a fetal growth restriction.
tions of this have been proposed by different groups and It needs to be clarified that all the above features of the early
organizations. (ACOG, ISSHP, Australian college). It has onset type of preeclampsia are not specific for this type of
also been further subdivided into mild, moderate, and severe pregnancy pathology. Most of the cases with early onset
preeclampsia as well as early and late onset preeclampsia, of preeclampsia are associated with another major pregnancy
which the latter is a more contemporary concept.5 It has been pathology, intrauterine growth restriction (IUGR). The typi-
suggested that early (before 34⫹0 weeks) and late (after cal features of early onset IUGR cases are an inadequate
34⫹0 weeks) onset preeclampsia have different etiologies trophoblast invasion, an inadequate transformation of spiral
and therefore a different clinical expression, but it is still a arteries, followed by respective changes in the blood flow of
subject of considerable research. There are, however, some the uterine arteries, alterations of the umbilical blood flow,
basic differences between the 2 groups: and restrictions of fetal growth.
Because the subgroup with early onset of preeclampsia is
A. The late onset type of preeclampsia comprises more associated with relatively severe complications, it has been
than 80% of all preeclampsia cases worldwide. Most of the focus of basic and clinical research. The combination of
these late onset cases are associated with: the 2 syndromes (preeclampsia and IUGR) in these cases may
have lead to the presumption that the early onset type of
● A normally grown baby with no signs of any growth preeclampsia is caused by alterations described to be caus-
restriction;
ative for IUGR, such as changes in the blood flow of the
● A normal or only slightly altered behavior of the
uterine as well as the umbilical arteries and growth restriction
uterine spiral arteries (no changes in the Doppler
waveforms or slight increase of the pulsatility index of the baby. But “pure” early onset IUGR cases show exactly
[PI]); the features listed above. Thus it is doubtful whether such
● No changes in the blood flow of the umbilical alterations are indeed related to preeclampsia at all.
arteries; This is supported by studies trying to use uterine artery
● An increased risk for pregnant women displaying an Doppler as a predictor of preeclampsia. In a study with 10
enlarged placental mass or surface (diabetes, multi- early onset preeclampsia cases and 423 controls Nicolaides et
ple pregnancies, anemia, high altitude). al used uterine artery Doppler at 11⫹0 to 13⫹6 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 [email protected]
(Hypertension. 2008;51:970-975.)
© 2008 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org DOI: 10.1161/HYPERTENSIONAHA.107.107607

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 Huppertz Placental Origins of Preeclampsia 971

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
Figure 1. The diagram presents an overview of early trophoblast
development. The first development of the trophoblast lineage at 1 p.c., whereas the definition of the 2 pathways (villous and
the blastocyst stage is followed by the separation of cytotropho- extravillous) gets in place in week 3 p.c. This temporal differ-
blast and syncytiotrophoblast, which subsequently is followed by ence may become important in terms of the placental origins of
the differentiation of the 2 pathways of trophoblast differentiation,
pregnancy pathologies such as preeclampsia and IUGR.
villous and extravillous. On the right, the time course of develop-
ment after fertilization (p.c., post coitum) is shown.
Serum Markers to Predict Preeclampsia
predictor. But although the uterine artery PI was increased in
6 There is a general trend in clinical sciences to focus on early
the preeclampsia cases, for a 10% false-positive rate, the predictive markers. This is probably because of the fact that
detection rate would only have been 40%. In a larger study early prediction/detection allows for planning appropriate
Pilalis et al measured the uterine artery blood flow in 1123 management, early detection of complications, and in some
pregnant women at 11 to 14 weeks of gestation.7 The cases instituting preventative measures thus eventually im-
outcome of this study was unambiguous: The sensitivity of proving overall outcome. Pregnancy is limited to 40 weeks,
uterine artery Doppler for all cases of preeclampsia was only and because preeclampsia is defined as new onset of hyper-
21%, and it was 33.3% for early onset preeclampsia cases. tension and proteinuria in the second half of pregnancy, ie,
The sensitivity for detection of early onset of fetal growth after 20 weeks of gestation, there are at least 20 weeks (from
restriction in this study, however, was 100%. implantation to week 20 of pregnancy) left for prediction.
This data raises the question whether a clear difference Today women who develop preeclampsia can only be de-
between early and late onset cases of preeclampsia is really tected by the appearance of clinical symptoms such as hyper-
existent. Maybe it is the combination with IUGR that makes tension and proteinuria.3,4,10,11 No predictive test is available to
the early onset cases so severe. In terms of symptoms of identify pregnant women who will subsequently develop pre-
preeclampsia (hypertension and proteinuria) in both groups eclampsia and moreover, which of those may develop the early
there are severe cases with maximal blood pressure values or late type of the syndrome, the mild or severe type, even
and maximal protein concentrations in the urine. turning into eclampsia. This is opposed by the high prevalence
of preeclampsia (5%), which is associated with a high risk for
What Then Is the Origin of Preeclampsia? life threatening events of the mother (18% of all maternal deaths
during pregnancy). Furthermore, it has become clear that there
Trophoblast Development are short- and long-term complications for those babies who
Taking a look at early human development (Figure 1) the tropho- have been born early, with low birth weight, or after exposure to
blast is the first cell lineage to differentiate at the stage of the a stressful environment such as during preeclampsia. Also the
blastocyst at about day 6 postconception (p.c.). Further differ- women who experienced preeclampsia are known to have a
entiation steps result in the formation of the 2 different pathways higher risk for health problems later in life such as a higher
of trophoblast, the villous and the extravillous pathway. prevalence of cardiovascular diseases. As preeclampsia has such
At the time of implantation the early syncytiotrophoblast is a high impact on maternal and neonatal morbidity and mortality,
generated,8 which increases in size by a continuous feeding it has been and still continues to be a subject of intensive clinical
mechanism of mononucleated cytotrophoblast cells. The and basic research aimed at identifying new and effective serum
latter cells continuously proliferate, differentiate, and syncy- markers for risk assessment and reducing complications attrib-
tially fuse with the syncytiotrophoblast, thus increasing and utable to it.
maintaining this multinucleated layer throughout gestation. In 2004 the new era of serum markers for the prediction of
During the very early stages of syncytiotrophoblast develop- preeclampsia began. Soluble VEGF receptor-1 (soluble fms-
ment this layer is invasive and helps penetrating the uterine like tyrosine kinase 1, sFlt-1) and soluble placental growth
epithelium. Only after some days the first fluid filled space, factor (PIGF) were identified as potential serum markers for
the so called lacunae develop that coalesce and are the preeclampsia.12,13 In the following years it became clear that
forerunners of the intervillous space.9 these markers have some disadvantages such as:
At about day 12 p.c. the cytotrophoblast cells start to
penetrate through the syncytiotrophoblastic mass, moving ● They can be used to predict preeclampsia only a few weeks
toward the first branches that extend into the intervillous before the onset of clinical symptoms.14
space, thus resulting in the formation of villous trophoblast ● They are not specific for preeclampsia but show similar
cells. Only a few days later (day 15 p.c.) the cytotrophoblast changes in pure IUGR as well. Even worse a recent study
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972 Hypertension April 2008 Part II

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- Figure 2. The diagram depicts the 2 different pathways leading
doglin concentrations were significantly different already 2 to to preeclampsia or IUGR. An insult in the villous trophoblast can
3 months before onset of clinical symptoms. Thus early onset be traced already in the first trimester and is indicative for pre-
eclampsia. An insult in the extravillous trophoblast can only be
cases could be detected at about week 20, whereas late onset detected in the second trimester and is indicative for IUGR.
cases could be detected at about week 28 of gestation.17
The above markers may be able to predict the development of
The current hypothesis to describe the origin and stages
preeclampsia, but only later in gestation. The time window that
toward the clinical symptoms of preeclampsia can be sum-
will be given by such markers may not be wide enough for a
marized as follows:
successful treatment, especially if an early administration of
putative medications is needed and effective only if started in the
1. Any deleterious effect on the extravillous trophoblast;
first trimester. As a consequence there are enormous efforts on 2. Failure of the extravillous trophoblast to adequately
the way that are directed toward identifying new and noninva- transform the uterine spiral arteries;
sive serum markers for the early and accurate prediction of 3. Reduced flow of maternal blood into the intervillous
preeclampsia in the first trimester of pregnancy. This would space;
enable the use of effective prophylactic or preventive therapies 4. Hypoxia or intervals of hypoxia followed by reoxygen-
starting as early as possible during pregnancy.18,19 ation of the placenta;
Such new serum markers showing significant differences 5. Hypoxic damage of the villous trophoblast;
already in the first trimester of pregnancy include placental 6. Release of STBM (syncytiotrophoblast membrane frag-
protein 13 (PP13),6,20,21,22 placenta associated plasma protein ments;34 into the maternal blood stream;
7. Maternal inflammatory response to the STBM resulting
A (PAPP-A),21,23 long pentraxin 3 (PTX3),24,25 as well as a
in the development of the clinical symptoms of
revival of sFlt-1.26 Taking PP13 as an example of one of the preeclampsia.
new and early serum markers, it has been shown very recently
that this marker may be able to detect even late onset Challenging the Current Hypothesis
preeclampsia cases as early as 7 to 8 weeks of gestation.22 The current concept on the placental origin of preeclampsia
The discovery of serum markers capable of predicting starts with a failure to transform the maternal spiral arteries,
preeclampsia with good detection rates and low false-positive subsequently followed by alterations of the villous trophoblast
rates will pave the way for improved antenatal and perinatal and its release of material. Figure 2 brings these 2 events into a
care. This will also allow introducing these markers into time frame during pregnancy and clearly shows that the tempo-
routine testing in the first or second trimester similar to the ral sequence of events does not fit with the current hypothesis.
markers currently used in screening for trisomy 21. If such A few years ago it has been very clearly demonstrated that
markers enable prediction around the end of the first trimes- during the first trimester of pregnancy there is no flow of
ter, this will open a long time window to tailor medications maternal blood cells into the intervillous space of the placen-
and respective prevention strategies.3,4,10,11,18,27 Hence, such ta.35 Only at around 11 to 12 weeks of gestation the plugs of
markers and implementations for the early detection and extravillous trophoblast cells blocking the lumen of the spiral
prediction of preeclampsia are urgently required. arteries are dislocated and open the flow of maternal blood
toward the placenta. This can be traced by the increase of
Current Hypothesis: Placental Origins oxygen from the first to the second trimester.
of Preeclampsia In parallel, the last few years have witnessed an enormous
During the last decades a variety of hypotheses has been increase in the knowledge of serum markers for preeclampsia,
generated aiming to explain the placental origins of pre- especially those showing significant alterations in their con-
eclampsia.28 –31 Most of them disappeared soon, although a centrations as early as 7 weeks.22 Thus, these alterations can
few are still discussed and need approval.32 The last few years be measured weeks before the onset of flow of maternal blood
there was a shift in defining the placental origin of preeclamp- cells through the intervillous space.
sia from midgestation, just before onset of clinical symptoms A failure of transforming the spiral arteries may lead to a
more toward very early stages of pregnancy.33 This shift was reduced diameter and thus will affect the blood volume
further substantiated by the detection of new and early flowing toward the intervillous space. Because blood flow is
biomarkers as described above. only established at the beginning of the second trimester, such
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 Huppertz Placental Origins of Preeclampsia 973

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 fetus—if 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, which— on the placental side— ultimately
Figure 3. The diagram represents the early development of the leads to an abnormal release of trophoblast material into the
trophoblast lineage. The decisive differentiation steps are high- maternal circulation.
lighted with gray boxes. The dark gray boxes indicate the very
early differentiation steps. If there is a failure during this time of The different scenarios are (Figure 4):
development the pregnancy may result in a combination of pre-
eclampsia (PE) and IUGR. If only the villous pathway is affected, 1. Normal Pregnancy
it may result in a preeclampsia (lower left). And if only the extra- During normal pregnancy aged and late apoptotic syncy-
villous pathway is affected it may result in an IUGR (lower right).
tiotrophoblast nuclei are packed into apical protrusions of the
syncytiotrophoblast,36,37 called syncytial knots9 (Figure 4,
a failure in transformation can only be effective after onset of
light gray). These membrane-sealed corpuscular structures
blood flow, ie, after week 12 of gestation (Figure 2).
are apoptotically generated and released from the apical
How can a failure that is effective only at the beginning of the
syncytiotrophoblast membrane into the maternal circulation.
second trimester lead to alterations of the release of proteins
They are transported through the maternal venous system
from the villous trophoblast already in mid first trimester?
behind the placenta and reach the first capillary bed behind
the placenta, the lungs.38 Here these huge apoptotic struc-
New Hypothesis: Placental Origins
tures, containing multiple nuclei, are engulfed by lung mac-
of Preeclampsia rophages (Figure 4, light gray) and thus cannot be detected in
The very early alterations in the concentrations of serum
peripheral maternal blood behind the lungs.39 In peripheral
markers point out that preeclampsia seems to develop already
blood of healthy pregnant woman these structures are virtu-
at the onset of placentation, somewhere around implantation
ally absent.40 It has recently been described that the engulf-
or even earlier. As shown in Figure 3, at these early stages of
ment of apoptotic material by macrophages leads to a
human development there may be several differentiation
silencing of such macrophages, thus reducing the secretion of
steps and developmental stages, where any insult on tropho-
proinflammatory cytokines.41,42
blast differentiation could result in preeclampsia or IUGR or
any other pregnancy pathology up to spontaneous abortion:
2. Preeclampsia, Induced by Intrinsic
Placental Factors
1. If the very first differentiation of the trophoblast cell
During preeclampsia the release of the syncytiotrophoblast
lineage is affected during development from morula to
blastocyst (Figure 3), this may result in a severe defect of material does no longer follow the normal rules. Because of
the trophoblast cell lineage in general. This may result in a an alteration in villous trophoblast differentiation early in
combination of IUGR and preeclampsia or even more pregnancy, the release of syncytial knots is no longer the
severe outcomes such as spontaneous abortions. main mechanism of disposal. Now other mechanisms take
2. If the insult takes place slightly afterward, when the over such as necrosis and aponecrosis43 (Figure 4, dark gray).
blastocyst trophoblast differentiates into the first cy- The latter term has been introduced by Formigli et al43 and
totrophoblast and syncytiotrophoblast (Figure 3), the describes the start of the apoptosis cascade followed by a
same dramatic outcome as described above may result. failure of the program to end normally. This then results in a
3. Afterward, if only the differentiation of the extravillous necrotic release of already apoptotically cleaved material.
trophoblast pathway is affected, this may result in pure
The 2 mechanisms, necrosis and aponecrosis, give rise to the
IUGR (Figure 3) with all the typical characteristics such
as failed invasion and abnormal uterine artery Doppler. necrotic and cell-free release of trophoblast material. Such
4. If only the villous pathway is affected, then a pre- necrotic trophoblast fragments can be detected in high num-
eclampsia may result (Figure 3) with its typical charac- bers only in preeclampsia whereas in pure IUGR they are not
teristics such as release of STBM and a maternal elevated above normal levels.40 The trophoblastic fragments,
inflammatory response. termed STBM,34 are nonapoptotic and thus no longer
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974 Hypertension April 2008 Part II

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.

membrane-sealed structures. They are small (200 to 600 Specific conditions increase placental mass (diabetes or
nm;44) and can pass the lungs; therefore they can easily be multiple pregnancies) or placental surface (hypoxic condi-
detected in peripheral blood and may cause systemic alter- tions of the mother: anemia, high altitude; Figure 4, gray
ations of the maternal endothelium and inflammatory system. pathway on the left, extrinsic factors). This increase will be
Although early serum markers may predict preeclampsia paralleled by an increase in the release of syncytial knots. If
already in the first trimester of pregnancy, the respective clinical the maternal clearance system cannot cope with this increased
manifestation of preeclampsia only occurs after midgestation. number of apoptotic fragments, they may undergo secondary
This discrepancy can be explained as follows: During the first necrosis within the blood and thus may lead to the clinical
trimester of pregnancy trophoblast turnover is different to the symptoms of preeclampsia as well.
turnover later in gestation. In the first trimester most of the The same may be true if the maternal disposal or inflam-
fusion events of cytotrophoblast cells with the syncytiotropho- matory systems are not working properly and react inappro-
blast are needed for growth of the syncytiotrophoblast rather priately to the release of apoptotic trophoblast fragments
than for the maintenance of this layer.37 Only later in gestation a (Figure 4, gray pathway on the left, maternal factors). Again,
steady-state between input of new material by cytotrophoblast this may lead to an overload of the disposal machinery, thus
fusion and release of syncytial knots is established. During the inducing a systemic activation and damage of endothelial
first trimester the release of trophoblast material is much lower cells, resulting in preeclampsia.
than later in gestation. This is not only true because of the lower
total placental mass and surface early in gestation but also Conclusion
because of the differences in trophoblast turnover at the two Ultimately, preeclampsia is a syndrome of early placentation. An
different stages of trophoblast development. insult resulting in an aberrant development and differentiation of
the villous syncytiotrophoblast causes an impaired maintenance
3. Preeclampsia, Induced by Extrinsic and of the placental barrier. This will subsequently lead to the release
Maternal Factors of necrotic and aponecrotic trophoblast fragments culminating in
The origin of preeclampsia may not be restricted to an a systemic inflammatory response of the mother. By contrast, a
intrinsic alteration of the villous trophoblast alone. Looking at failure of extravillous trophoblast invasion is correlated with the
the conditions with an increased risk to develop preeclampsia, pathophysiology of IUGR. The new concept brought forward
they may be divided into those that increase placental mass or here clearly separates the origins of preeclampsia and IUGR and
surface and those that alter the response of the mother to what proposes alterations in different trophoblast differentiation path-
is released by the placenta. ways as origins for both syndromes.
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 Huppertz Placental Origins of Preeclampsia 975

Source of Funding 21. Spencer K, Cowans NJ, Chefetz I, Tal J, Kuhnreich I, Meiri H. First-
trimester maternal serum PP-13, PAPP-A and second-trimester uterine
This work was supported by the EU Grant #37244, project title
artery Doppler pulsatility index as markers of pre-eclampsia. Ultrasound
Pregenesys.
Obstet Gynecol. 2007;29:128 –134.
22. Huppertz B, Sammar M, Chefetz I, Neumaier-Wagner P, Bartz C, Meiri
Disclosures H. Longitudinal determination of serum PP13 during development of
None. preeclampsia. Fetal Diagn Therapy. In press.
23. Ong CY, Liao AW, Spencer K, Munim S, Nicolaides KH. First trimester
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