Journal of Reproductive Immunology 108 (2015) 2632

Contents lists available at ScienceDirect

Journal of Reproductive Immunology

journal homepage: www.elsevier.com/locate/jreprimm

Maternalfetal interactions, predictive markers for

preeclampsia, and programming
Berthold Huppertz
Institute of Cell Biology, Histology and Embryology, Medical University of Graz, Austria

a r t i c l e

i n f o

Article history:
Received 25 September 2014
Received in revised form 4 November 2014
Accepted 18 November 2014
Keywords:
Preeclampsia
Biomarker
Prediction
Pregnancy
Programming

a b s t r a c t
During pregnancy close interactions between the maternal system and the fetal system
via the placenta exist that result in a powerful crosstalk between both individuals. Looking
for predictive biomarkers in maternal blood is extremely difcult because of this crosstalk
as such markers may be derived from only maternal sources, only placental sources or
both. In particular, the concentrations of markers derived from both sources may vary
because of the huge variety of reasons and sources. During the last decade this has misled
a number of scientists and clinicians who tried to decipher the sources of markers and the
impact of the placenta and/or the maternal vascular system. A few examples for predictive
biomarkers are presented, the placenta-specic marker placental protein 13 (PP13) and the
angiogenic marker PlGF being released from both mother and placenta. Finally, a further
reason why biomarkers may not be successful in predicting all cases of preeclampsia is
that different causative routes lead to the development of preeclampsia. The differences
in the development of preeclampsia not only explain why markers may or may not have a
predictive value, but also why some mothers and/or children may display long-term effects
later in life.
2014 Elsevier Ireland Ltd. All rights reserved.

1. Introduction
During pregnancy in the human, fetal cells come into
direct contact with maternal cells and tissues. This close
contact brings together cells of two genetically different
individuals. While this type of contact is typically associated with rejection processes, during normal pregnancy
there is neither harm to the mother nor rejection of the
baby.
Looking at the sites of contact, it becomes obvious
that contact with the maternal cells is facilitated by fetal

Correspondence to: Institute of Cell Biology, Histology and Embryology, Medical University of Graz, Harrachgasse 21/7, 8010 Graz, Austria.
Tel.: +43 316 380 7604.
E-mail address: bhuppertz@medunigraz.at
http://dx.doi.org/10.1016/j.jri.2014.11.003
0165-0378/ 2014 Elsevier Ireland Ltd. All rights reserved.

trophoblast, which is derived from the trophectoderm

of the blastocyst. The trophoblast develops into two
main subtypes, villous and extravillous trophoblast. The
villous trophoblast develops into the epithelial cover
of all placental villi with the syncytiotrophoblast as the
outermost layer in direct contact with the maternal plasma
in the rst trimester of pregnancy and the maternal blood
during the rest of gestation. The second layer, composed
of villous cytotrophoblasts, does not come into direct
contact with maternal tissues. If this happens accidentally,
e.g., by local damage of the covering syncytiotrophoblast,
then such cells are covered by brin-type brinoid and
start to secrete their own matrix-type brinoid, similar
to extravillous trophoblasts (Kaufmann et al., 1996).
Extravillous trophoblasts invade into maternal uterine
tissues, crossing the decidua and nally reaching the
myometrium. On their way, extravillous trophoblasts

B. Huppertz / Journal of Reproductive Immunology 108 (2015) 2632

also migrate toward decidual arteries (spiral arteries) and

toward uterine glands, opening both systems toward the
intervillous space of the placenta (Burton et al., 2002;
Moser et al., 2010, 2011). Opening of the uterine glands
enables histiotrophic nutrition during the rst trimester of
pregnancy, when spiral arteries are still not opened toward
the placenta or plugged by endovascular trophoblast. With
the onset of maternal blood ow toward the placenta at
the beginning of the second trimester, the opening of the
spiral arteries ensures hemotrophic nutrition of the fetus
until delivery (Burton et al., 2002; Moser et al., 2010).

2. Preeclampsia
Preeclampsia remains one of the major reasons for
maternal, fetal, and neonatal mortality and morbidity.
Worldwide, the rate of preeclampsia is about 28% of
all pregnancies, the higher rates are mostly present in
developing countries (ACOG, 2002; WHO, 2005). Here,
preeclampsia accounts for 1015% of maternal deaths, 12%
of infants born small for gestational age (SGA), and up
to 25% of stillbirths and neonatal mortality rates (Duley,
2009). Although preeclampsia is a pregnancy-specic syndrome, it has long-term consequences for those women
who experience preeclampsia during pregnancy. Such
women are at increased risk of a variety of diseases, including chronic hypertension, diabetes mellitus, ischemic heart
disease, cerebrovascular disease, kidney disease, thromboembolism, hypothyroidism, and even impaired memory
(Williams, 2011).
There is a multitude of pregnancy-related pathological
conditions that cause morbidities and mortality of mothers and children. One of the most common syndromes,
preeclampsia, is still the syndrome of hypotheses as its etiology and progress are still unclear in a number of facets.
At the same time, it is common knowledge today that the
placenta is essential for the development of the clinical
symptoms of preeclampsia, while a fetus is not necessarily needed. Hence, in preeclampsia the normal interplay
between mother and placenta (and thus the fetus) is dysregulated, nally culminating in the maternal symptoms
specic for preeclampsia. While the placenta is releasing
factors even during normal pregnancy, it has been shown
that in most cases of preeclampsia the release of trophoblastic factors from the placenta is altered because of
a dysfunctioning syncytiotrophoblast. On the other hand,
the response of the mother depends on her susceptibility to
factors derived from the syncytiotrophoblast. The complex
interplay between factors released from the placenta and
the response of the maternal vascular system nally denes
whether or not a pregnant woman develops preeclampsia.
Specic features of the subtypes of preeclampsia, including severity, duration of progression, time of onset, and
progress to eclampsia, can be explained by the ne tuning
of the interactions between the maternal and the placental
systems. This very much complicates the search for the etiology of preeclampsia and poses the need to broaden the
view and include the interactions among fetus, placenta,
and mother, even if the origin of preeclampsia can clearly
be attributed to the placenta.

27

3. Predictive biomarkers for preeclampsia

The hype in identifying new biomarkers to predict
preeclampsia is leaving us with not a single biomarker on
the market that is of any predictive value. The last decade
has seen a huge number of different biomarkers coming
and going, leaving only a trace in the scientic literature.
Generally, a marker should only be named predictive and
is only valuable if the detectable changes of this biomarker
occur prior to the onset of clinical symptoms of a disease
or syndrome. It would be best to focus on only those markers that display signicant differences as early as possible
and as specically as possible. In the case of preeclampsia
a biomarker should show such alterations as early as the
rst trimester of pregnancy or even prior to pregnancy.
Early prediction of preeclampsia enables the planning of an
appropriate management strategy and offers close surveillance of pregnant women at risk (Cetin et al., 2011).
Besides showing signicant changes as early as possible,
a predictive biomarker for preeclampsia should fulll the
following criteria (Cetin et al., 2011):
The marker should be specic for the syndrome and should
not show a clear inuence of other syndromes, such as
IUGR or diabetes.
The marker should be obtained following a non- or minimally invasive procedure, such as blood, urine or saliva.
The marker should be stable in the sample or simple protocols should be available to maintain the markers stability.
The marker should be unaffected by changes in other components in the sample such as hemoglobin, uric acid or
lipids.
The test should be accurate and sensitive and recognize
only the marker of interest.
The test should be able to predict preeclampsia before
clinical symptoms are evident.
The test should be specically for preeclampsia and not
interfere with other pathological conditions such as IUGR
or diabetes.
Since most of the biomarkers available today are based
on proteins found in the blood/plasma/serum samples of
pregnant women, kits have been developed to measure
even very low concentrations (up to pg/ml) in such samples. However, what is still lacking for most if not all such
biomarkers are the kinetics and knowledge of the composition of these biomarkers in maternal blood. The markers
may only be of maternal or only of fetal (placental) origin,
or they may be derived from both individuals.
If a marker is only derived from the placenta, a direct
correlation with placental development and physiology
may be possible. Such factors derived from the placenta
may subsequently induce the release of maternal factors,
leading to alterations in their blood levels as well. Such
a maternal biomarker may be used as a biomarker, without anything being known about the signaling pathways
leading to such alterations. The only marker known today
to be of pure placental/fetal origin is placental protein 13
(PP13 or galectin 13), which is expressed in the placenta
and released from the syncytiotrophoblast into maternal
blood (Huppertz et al., 2008, 2013). Recently, it has been

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B. Huppertz / Journal of Reproductive Immunology 108 (2015) 2632

shown that PP13 may induce vasodilation and decrease

blood pressure in pregnant rats (Gizurarson et al., 2013).
If the carbohydrate binding site of PP13 was deleted specic effects of PP13 were no longer present (Sammar et al.,
2014). These data show that a biomarker derived from the
placenta may well have direct biological effects on maternal physiology.
If a factor is only derived from the mother and not
present or released from the placenta, it may give an idea
of the response of the mother to pregnancy. Such markers from maternal sources could be altered because of an
inammatory or metabolic response of the mother to the
changing environment during pregnancy and especially
pregnancy-related pathological conditions. At the same
time, such markers may simply be derived from damaged
and dying maternal cells. To the best of my knowledge, no
such marker is known today.
Most of the markers in use today are derived from
both sides: from the mother and the placenta/fetus. Here,
a direct correlation with mother and/or fetus/placenta is
extremely difcult as it is not clear how much of this marker
is derived from which individual. It also needs to be taken
into account that interactions between maternal and placental factors may lead to an increase or a decrease in
specic markers in the maternal blood. Hence, even if a
marker increases in placental tissues, it may decrease in
maternal blood as most of this serum marker is released
from maternal sources. Below, some examples are shown
to illustrate the joint production of markers.
3.1. Fetal hemoglobin
Fetal hemoglobin has recently been described as a new
predictive biomarker for preeclampsia and has also been
hypothesized to be a causative factor (Olsson et al., 2010;
Hansson et al., 2013). Interestingly, the heme scavenger
and antioxidant alpha(1)-microglobulin increases in parallel with fetal hemoglobin (Olsson et al., 2010). Hence, it
has been shown in a rat model that the deleterious effects
provoked by fetal hemoglobin can be reduced by adding
alpha(1)-microglobulin (Sverrisson et al., 2014). The term
indicates the sole expression of this protein in the fetus.
However, as early as 20 years ago it was shown that a
small amount of fetal hemoglobin can be detected in most
adults. Rochette et al. (1994) found that in 85% of the normal adult population the synthesis of fetal hemoglobin is
reduced to 0.6% of total hemoglobin. At the same time,
these authors found that the rate of erythrocytes containing
fetal hemoglobin is 0.34.4% in 85% of the adult population.
Looking at recent literature in which fetal hemoglobin was
identied as a putative rst- and early second-trimester
predictive biomarker for preeclampsia reveals the following (Anderson et al., 2011). In the control group the total
hemoglobin concentration was 198.34 g/ml, while in the
preeclampsia group it was 177.90 g/ml. Fetal hemoglobin
in the control and preeclampsia groups was 0.45 g/ml
and 1.38 g/ml respectively. Calculating the rate of fetal
hemoglobin to total hemoglobin, in controls the rate was
0.23%, while in the preeclampsia groups it was 0.78%.
Both values do not differ much from the normal value of
fetal hemoglobin synthesis in adults of 0.6% and may lead

to two different explanations. First, in preeclampsia fetal

hemoglobin from fetal sources enters the maternal blood
stream and can be detected in maternal serum. Second,
in preeclampsia factors derived from the placenta damage maternal blood cells leading to the release of fetal
hemoglobin from erythrocytes. So far, it is unclear which
explanation is correct or if both are valid.
3.2. Angiogenic factors
Quite a number of pro- and anti-angiogenic factors together with their receptors are expressed and
active in the placenta throughout gestation. These factors include vascular endothelial growth factor (VEGF),
placental growth factor (PlGF), and endoglin as well as
VEGF-receptor 1 (Flt-1) and VEGF-receptor 2 (Flk-1). The
normal action of these factors and receptors in the placenta
is mandatory for normal development and changes in placental vessels throughout pregnancy (Clark et al., 1998). To
use such factors as predictive markers of preeclampsia they
need to be released into maternal blood rather than into
fetal blood, where they act on placental angiogenesis. However, only a fraction of angiogenic factors and receptors are
released from the placenta into the maternal circulation,
and only those being released can be used as markers in
maternal blood, such as PlGF.
PlGF is expressed by all populations of trophoblast,
including villous and extravillous trophoblast (Clark et al.,
1998). Mostly neglected but important to note is that PlGF
is also expressed in endothelial cells and smooth muscle
cells of healthy adults (Pan et al., 2010). Hence, the concentration of PlGF detected in the blood of pregnant women is
the summation of the release from placental sources plus
the release from different maternal sources.
Unfortunately, the concentration of PlGF in maternal
blood is not only the summation of the release from placental and maternal sources, but rather becomes even more
complex since the soluble form of a receptor to PlGF and
VEGF (soluble Flt-1, sFlt-1) is released (again from placental
and maternal sources) into maternal blood and is circulating in the blood of pregnant women. This scavenging
receptor binds to VEGF and PlGF circulating in maternal
blood and thus decreases the fraction of PlGF that is freely
oating in maternal blood. The assays available today only
bind to and recognize nonbound and freely available PlGF.
Hence, even in the presence of a stable release of PlGF from
maternal and placental sources, simply an increase in the
release of sFlt-1 (Levine et al., 2004) will lead to a virtual
reduction of PlGF (Akolekar et al., 2008) owing to the binding of PlGF to sFlt-1.
As can be seen from the above, predicting the levels
of a predictive marker such as PlGF in maternal blood is
extremely difcult and may lead to incorrect assumptions
and hypotheses (Staff et al., 2013). These authors assumed
that PlGF is solely expressed in the placenta and built their
hypotheses on these grounds, always referring to PlGF as a
placenta-derived factor. However, there are at least two
reasons why this cannot be as easy as the authors proposed. First, comparing PlGF levels in non-pregnant cancer
patients with those in pregnant women revealed the following picture. In pregnant women PlGF levels before 28

B. Huppertz / Journal of Reproductive Immunology 108 (2015) 2632

29

Fig. 1. Serum biomarkers for preeclampsia during pregnancy. Schematic representation of the placenta with its villous part, its part within the placental
bed, and the systemic maternal vascular system represented by a single vessel. Markers released from the placenta (PlGF, sFlt-1, PP13) enter the maternal
blood and can be detected there. Markers released from maternal sources (endothelial cells, smooth muscle cells) enter the maternal blood and can be
detected there as well. Both markers bind to their receptors on maternal endothelial cells as well as villous trophoblast.

weeks gestation were 18.4 pg/ml (Meler et al., 2014), while

in patients with oral squamous cell carcinoma the levels
increased from 10.1 pg/ml in healthy non-pregnant controls to 19.1 in cancer patients prior to surgery (Cheng
et al., 2012). Second, it has been shown that the protein
expression of PlGF in the placenta and that in CD105- and
CD34-positive endothelial cells are very similar (Su et al.,
2004). Assuming a similar release of PlGF from the two
sources expressing PlGF, the surface area of these sources
comes into play. The surface area of a term placenta was
estimated to be 1215 m2 (Benirschke et al., 2006), while
the endothelial surface area of blood vessels in an adult
was estimated to be about 40007000 m2 (Aird, 2005). Both
reasons make it very unlikely that the sole source for PlGF in
maternal blood is the placenta. However, so far it is totally
unclear what the placental and maternal contributions of
PlGF are to the total pool of PlGF in maternal blood.
The angiogenic markers, including PlGF, suffer from
another major disadvantage. It has become clear during the
last few years that angiogenic factors are not at all specic
for preeclampsia (Robinson et al., 2006), but rather show
an even better predictive value for patients suffering from
pure IUGR (Stepan et al., 2007; Cowans et al., 2010). This is
why angiogenic markers have a good predictive value for
early onset patients suffering from preeclampsia and IUGR,
while they have no predictive value for more than 80% of

all preeclampsia cases, i.e., those at term without growth

restriction (Smith et al., 2007) (Fig. 1).
4. Etiology of preeclampsia
After dening the needs for predictive biomarkers, the
nal chapter will clarify why a single marker or even a
combination of markers may still fail to explicitly predict
preeclampsia. We know that the placenta is mandatory for
the development of preeclampsia; however, only the interplay between mother and fetus/placenta nally decides
whether or not the mother develops clinical symptoms.
Hence, the impact of each side on the clinical onset of the
syndrome needs to be considered (Huppertz, 2008).
Taking into account the close interactions between
maternal and feto-placental factors, at least three different
scenarios can be developed to explain the different types
and times of the onset of preeclampsia as well as the different effects on the health of the mother and fetus later in
life (Fig. 2):
1. Cases consisting of a normal mother before pregnancy
and a dysfunctioning placenta
Normally, the syncytiotrophoblast releases factors by
controlled secretion and apoptotic shedding. In this
set of cases developing preeclampsia, necrosis, and

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B. Huppertz / Journal of Reproductive Immunology 108 (2015) 2632

Normal or predisposed mother

+
Abnormal placenta
Villous trophoblast
Aected

Extravillous trophoblast

Normal

Normal

Preeclampsia Preeclampsia & IUGR

Aected

IUGR

Normal growth of fetus

(no IUGR)

Reduced growth of fetus

(IUGR)

Normal levels of
angiogenic factors
(due to absence of IUGR)

Altered levels of
angiogenic factors
(due to presence of IUGR)

Altered levels of PP13

(due to presence of PE)

Higher risk to woman

later in life
(due to PE if predisposed)

Normal levels of PP13

(due to absence of PE)

Higher risk to newborn

later in life
(due to IUGR)

Fig. 2. Effect of preeclampsia and IUGR later in life. Depending on the predisposition of the mother and the development of the placenta different
scenarios are presented showing the pathways leading to healthy pregnancy, pure preeclampsia, pure intrauterine growth retardation (IUGR),
or the combination of preeclampsia and IUGR. Also, the effects on health
later in life are depicted.

aponecrosis of the syncytiotrophoblast (Huppertz et al.,

2006; Huppertz, 2008, 2010) lead to the release of subcellular fragments as well as micro- and nanoparticles
(Johansen et al., 1999; Redman and Sargent, 2000) that
affect the maternal endothelium systemically (Goswami
et al., 2006). Hence, a dysfunctioning placenta and especially a maldeveloped syncytiotrophoblast continuously
release factors that systematically activate and harm
the maternal vascular system during pregnancy. It may
depend on the villous surface as to when the maternal scavenging systems are nally overloaded and the
clinical symptoms of preeclampsia appear.
The scavenging system of the still healthy mother
can deal with these deleterious changes for a specic
time period. If this is true for a longer time period,
clinical symptoms may only develop later in pregnancy
(late onset preeclampsia). Concurrently, the maternal
endothelium is affected only late in pregnancy and thus,
changes of predictive angiogenic markers such as PlGF
and sFlt-1 do not develop, since these are mostly related
to IUGR rather than preeclampsia (Nicolaides et al.,
2006; Pilalis et al., 2007). However, placenta-specic

markers such as PP13 can identify such cases already

during the rst trimester of pregnancy (Huppertz et al.,
2008). In this scenario, the fetus mostly develops into a
normally grown baby (no growth restriction).
After pregnancy, the mother may recover completely
without any deleterious effects later in life.
2. Cases consisting of a predisposed mother and a normal
placenta
This time, the placenta releases the normal portfolio
of fragments, factors, and molecules into the maternal blood. However, the mothers scavenging system,
her vascular system or any other signaling pathway
involved in regulating maternal blood pressure and kidney function may not work properly. This may lead to
an inadequate response of these systems, resulting in an
overload and defect even by the normal quantity and
quality of factors released from the placenta. This scenario may be predicted by a number of factors known to
predispose a woman to developing preeclampsia, such
as chronic hypertension or renal disease.
Since the placenta has normal growth and development and the malfunctions of the maternal systems
slowly develop into preeclampsia, this scenario results
in the appearance of clinical symptoms late during pregnancy (late onset preeclampsia). Also, the fetus may not
be affected, resulting in a baby with no growth restriction. Again, changes in predictive angiogenic markers
such as PlGF and sFlt-1 prior to the onset of symptoms
are mostly absent (Ohkuchi et al., 2007), and due to
a normally developed placenta, also placenta-specic
markers may not be able to predict such cases.
Since women in this scenario already suffer from
mostly subliminal defects of their vascular system, they
may well be at a higher risk of developing cardiovascular
diseases later in life.
3. Cases consisting of a predisposed mother and a dysfunctioning placenta
This scenario includes the most severe cases as the
combination of defects on the maternal and on the placental side will denitely lead to more severe symptoms
in the mother.
Looking at the placenta, there may be a subpopulation only showing alterations of the villous trophoblast,
especially the syncytiotrophoblast. Here, the syncytiotrophoblast displays necrotic and aponecrotic
shedding of subcellular fragments, resulting in a systemic deterioration of the maternal vascular system,
which is already impaired. The damage to the maternal system will develop quickly and clinical symptoms
will appear early in pregnancy (early onset preeclampsia) with no effect on the growth of the fetus (no
growth restriction). Such cases will be easily predicted
by placenta-derived markers such as PP13; however,
since fetal growth is not affected these cases will not
be able to be predicted by angiogenic markers such as
sFlt-1and PlGF.
There may be a larger subpopulation of cases with
a maldeveloped placenta that also show defects in the
development of the extravillous trophoblast and thus
will display impaired trophoblast invasion (Huppertz,
2011). In those cases the syncytiotrophoblast is affected

B. Huppertz / Journal of Reproductive Immunology 108 (2015) 2632

and releases factors by necrotic and aponecrotic shedding, while the maldeveloped extravillous trophoblast
will alter maternal blood ow toward the placenta
(Burton et al., 2009), subsequently impairing fetal
growth. Again, the damage to the maternal system will
develop early in pregnancy (early onset preeclampsia)
and growth of the fetus will be impaired as well (growth
restriction). Such cases will be easily detectable by all
markers, placenta-specic (Chafetz et al., 2007) and
angiogenic markers (Schaarschmidt et al., 2013).
In this scenario, women may well be at a higher risk of
developing cardiovascular diseases and other morbidities later in life. In cases with IUGR the babies may show
fetal programming as well (Longtine and Nelson, 2011;
Hogg et al., 2013).
5. Conclusions and outlook
The very tight interactions between the maternal system and the fetal system via the placenta enable an intense
crosstalk of both individuals during pregnancy. The disadvantage for science is that the calculation of any biomarker
detected in maternal blood is extremely difcult as too
many parameters need to be taken into account. This has
misled quite a number of scientists and clinicians who have
tried to hypothesize how markers might be derived and
what the impact of the placenta and/or the maternal vascular system might be. Finally, depending on the causative
routes leading to the development of preeclampsia, markers may or may not have a predictive value and mother
and/or child may display long-term effects later in life.
What can be done to promote a better understanding of
the etiology of preeclampsia? There are several answers to
this question. Only a few are listed here:
1. The scientic community needs to be more openminded and to accept more hypotheses, even if they may
sound unusual in the rst instance. Accepting only the
current model has not led to success or progress in the
last two decades.
2. Scientists working on biomarkers for preeclampsia
depend on high-quality samples from pregnant women.
During the last decade a number of publications have
been published using bad-quality samples and/or assays.
This may even lead to a good biomarker being disregarded because the wrong samples have been used.
Here, a better understanding of the importance of sample and assay quality is needed.
3. Finally, high-quality samples need to be collected and
stored at multiple sites with a comparable quality
standard and respective governance structures. It is not
sufcient to set up a consortium of existing collections
without controlling and harmonizing sample quality
and without developing transparent governance mechanisms to access such samples.
Conict of interest
None declared.

31

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