Beruflich Dokumente
Kultur Dokumente
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 340 weeks) and late (after cal features of early onset IUGR cases are an inadequate
340 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 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
Huppertz Placental Origins of Preeclampsia 971
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
972 Hypertension April 2008 Part II
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
974 Hypertension April 2008 Part II
Downloaded from http://hyper.ahajournals.org/ by guest on October 18, 2017
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.
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
References maternal serum free beta human chorionic gonadotropin and pregnancy
1. Sibai BN, Caritis SN, Thom E, Klebanoff M, McNellis D, Rocco L, Paul associated plasma protein A as indicators of pregnancy complications.
RH, Romero R, Witter F, Rosen M, Depp R. Prevention of preeclampsia Br J Obstet Gynecol. 2000;107:12651270.
with low-dose aspirin in health. Nulliparous pregnant women. N Engl 24. Cetin I, Cozzi V, Pasqualini F, Nebuloni M, Garlanda C, Vago L, Pardi
J Med. 1993;329:12131218. G, Mantovani A. Elevated maternal levels of the long pentraxin 3 (PTX3)
2. Levine RJ, Hauth JC, Curet LB, Sibai BM, Catalano PM, Morris CD, in preeclampsia and intrauterine growth restriction. Am J Obstet Gynecol.
DerSimonian R, Esterlitz JR, Raymond EG, Bild DE, Clemens JD, Cutler 2006;194:13471353.
JA. Trial of calcium to prevent preeclampsia. N Engl J Med. 1997;337: 25. Rovere-Querini P, Antonacci S, DellAntonio G, Angeli A, Almirante G, Cin
6976. ED, Valsecchi L, Lanzani C, Sabbadini MG, Doglioni C, Manfredi AA,
3. Walker JJ. Preeclampsia. Lancet. 2000;356:1260 1265. Castiglioni MT. Plasma and tissue expression of the long pentraxin 3 during
4. Roberts JM, Cooper DW. Pathogenesis and genetics of preeclampsia. normal pregnancy and preeclampsia. Obstet Gynecol. 2006;108:148155.
Lancet. 2001;357:5356. 26. Vatten LJ, Eskild A, Nilsen TI, Jeansson S, Jenum PA, Staff AC. Changes in
5. Von Dadelszen P, Magee LA, Roberts JM. Subclassification of pre- circulating level of angiogenic factors from the first to second trimester as
eclampsia. Hypertens Pregnancy. 2003;22:143148. predictors of preeclampsia. Am J Obstet Gynecol. 2007;196:239.e1239.e6.
6. Nicolaides KH, Bindra R, Turan OM, Chefetz I, Sammar M, Meiri H, Tal 27. Chiaffarino F, Parazzini F, Paladini D, Acaia B, Ossola W, Marozio L,
Downloaded from http://hyper.ahajournals.org/ by guest on October 18, 2017
J, Cuckle HS. A novel approach to first-trimester screening for early Facchinetti F, Del Giudice A. A small randomised trial of low-dose
pre-eclampsia combining serum PP-13 and Doppler ultrasound. aspirin in women at high risk of preeclampsia. Eur J Obstet Gynecol
Ultrasound Obstet Gynecol. 2006;27:1317. Reprod Biol. 2004;112:142144.
7. Pilalis A, Souka AP, Antsaklis P, Basayiannis K, Benardis P, Haidopoulos D, 28. Dekker GA, Sibai BM. Etiology and pathogenesis of preeclampsia:
Papantoniou N, Mesogitis S, Antsaklis A. Screening for pre-eclampsia and current concepts. Am J Obstet Gynecol. 1998;179:1359 1375.
small for gestational age fetuses at the 1114 weeks scan by uterine artery 29. Kenny L, Baker PN. Maternal pathophysiology in pre-eclampsia. Baillieres
Dopplers. Acta Obstet Gynecol Scand. 2007;86:530534. Best Pract Res Clin Obstet Gynaecol. 1999;13:5975.
8. Huppertz B, Herrler A. Regulation of proliferation and apoptosis during 30. Sekotory A, Ahmed M. Pre-eclampsia: hypotheses. J R Soc Health.
development of the preimplantation embryo and the placenta. Birth 2001;121:76 78.
Defects Res C Embryo Today. 2005;75:249 261. 31. Wilson ML, Goodwin TM, Pan VL, Ingles SA. Molecular epidemiology
9. Benirschke K, Kaufmann P, Baergen R. Pathology of the Human of preeclampsia. Obstet Gynecol Surv. 2003;58:39 66.
Placenta. 5th ed., Springer New York, 2006. 32. Redman CW, Sargent IL. Latest advances in understanding preeclampsia.
10. Miodovnik M, Myatt L. Prediction of preeclampsia. Semin Perinatol. Science. 2005;308:15921594.
1999;25:4557. 33. Burton GJ, Jauniaux E. Placental oxidative stress: From miscarriage to
11. Lyell DJ, Lambert-Messerlian M, Giudice LC. Prenatal screening, epid- preeclampsia. J Soc Gynecol Investig. 2004;11:342352.
miology, diagnosis and management of preeclampsia. Clin Lab Med. 34. Knight M, Redman CW, Linton EA, Sargent IL. Shedding of syncytiotro-
2003;23:413 442. phoblast microvilli into the maternal circulation in pre-eclamptic preg-
12. Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, nancies. Br J Obstet Gynaecol. 1998;105:632 640.
Schisterman EF, Thadhani R, Sachs BP, Epstein FH, Sibai BM, Sukhatme 35. Jauniaux E, Watson AL, Hempstock J, Bao YP, Skepper JN, Burton GJ.
VP, Karumanchi SA. Circulating antigenic factors and the risk for pre- Onset of maternal arterial blood flow and placental oxidative stress.
eclampsia. N Engl J Med. 2004;350:672 683. A possible factor in human early pregnancy failure. Am J Pathol. 2000;
13. Thadhani H, Mutter WP, Wolf M, Levine RJ, Taylor RN, Sukhatme VP, 157:21112122.
Ecker J, Karumanchi SA. First trimester placental growth factor and 36. Huppertz B, Kingdom JC. Apoptosis in the trophoblastrole of apoptosis
soluble fms-like tyrosine kinase 1 and risk for preeclampsia. J Clin in placental morphogenesis. J Soc Gynecol Investig. 2004;11:353362.
Endocrinol Metab. 2004;89:770 775. 37. Huppertz B, Frank HG, Kingdom JC, Reister F, Kaufmann P. Villous
14. Hertig A, Berkane N, Lefevre G, Toumi K, Marti HP, Capeau J, Uzan S, cytotrophoblast regulation of the syncytial apoptotic cascade in the
Rondeau E. Maternal serum sFlt1 concentration is an early and reliable human placenta. Histochem Cell Biol. 1998;110:495508.
predictive marker of preeclampsia. Clin Chem. 2004;50:17021703. 38. Ikle FA. Trophoblastzellen im stromenden Blut. Schweiz Med
15. Smith GC, Crossley JA, Aitken DA, Jenkins N, Lyall F, Cameron AD, Wochenschr. 1964;91:934 945.
Connor JM, Dobbie R. Circulating angiogenic factors in early pregnancy 39. Johansen M, Redman CW, Wilkins T, Sargent IL. Trophoblast depor-
and the risk of preeclampsia, intrauterine growth restriction, spontaneous tation in human pregnancyits relevance for pre-eclampsia. Placenta.
preterm birth, and stillbirth. Obstet Gynecol. 2007;109:1316 1324. 1999;20:531539.
16. Savvidou MD, Yu CK, Harland LC, Hingorani AD, Nicolaides KH. 40. Goswami D, Tannetta DS, Magee LA, Fuchisawa A, Redman CW,
Maternal serum concentration of soluble fms-like tyrosine kinase 1 and Sargent IL, von Dadelszen P. Excess syncytiotrophoblast microparticle
vascular endothelial growth factor in women with abnormal uterine artery shedding is a feature of early-onset pre-eclampsia, but not normotensive
Doppler and in those with fetal growth restriction. Am J Obstet Gynecol. intrauterine growth restriction. Placenta. 2006;27:56 61.
2006;195:1668 1673. 41. Freire-de-Lima CG, Xiao YQ, Gardai SJ, Bratton DL, Schiemann WP,
17. Levine RJ, Lam C, Qian C, Yu KF, Maynard SE, Sachs BP, Sibai BM, Henson PM. Apoptotic cells, through transforming growth factor-beta,
Epstein FH, Romero R, Thadhani R, Karumanchi SA; CPEP Study coordinately induce anti-inflammatory and suppress pro-inflammatory
Group. Soluble endoglin and other circulating antiangiogenic factors in eicosanoid and NO synthesis in murine macrophages. J Biol Chem.
preeclampsia. N Engl J Med. 2006;355:9921005. 2006;281:38376 38384.
18. Chappell LC, Seed PT, Briley AL, Kelly FJ, Lee R, Hunt BJ, Parmar K, 42. Krysko DV, DHerde K, Vandenabeele P. Clearance of apoptotic and
Bewley SJ, Shennan AH, Steer PJ, Poston L. Effects of antioxidants on necrotic cells and its immunological consequences. Apoptosis. 2006;11:
the occurrence of preeclampsia in women at increased risk: a randomized 1709 1726.
trial. Lancet. 1999;354:810 816. 43. Formigli L, Papucci L, Tani A, Schiavone N, Tempestini A, Orlandini
19. Report of the National High Blood Pressure Education Program Working GE, Capaccioli S, Orlandini SZ. Aponecrosis: morphological and bio-
Group on High Blood Pressure in Pregnancy. Am J Obstet Gynecol. chemical exploration of a syncretic process of cell death sharing apoptosis
2000;183:S1S22. and necrosis. J Cell Physiol. 2000;182:41 49.
20. Burger O, Pick E, Zwickel J, Klayman M, Meiri H, Slotky R, Mandel S, 44. Gupta AK, Rusterholz C, Huppertz B, Malek A, Schneider H, Holzgreve
Rabinovitch L, Paltieli Y, Admon A, Gonen R. Placental protein 13 (PP-13): W, Hahn S. A comparative study of the effect of three different syncy-
Effects on cultured trophoblasts, and its detection in human body fluids in tiotrophoblast microparticles preparations on endothelial cells. Placenta.
normal and pathological pregnancies. Placenta. 2004;25:608622. 2005;26:59 66.
Placental Origins of Preeclampsia: Challenging the Current Hypothesis
Berthold Huppertz
Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2008 American Heart Association, Inc. All rights reserved.
Print ISSN: 0194-911X. Online ISSN: 1524-4563
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://hyper.ahajournals.org/content/51/4/970
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Hypertension can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial
Office. Once the online version of the published article for which permission is being requested is located,
click Request Permissions in the middle column of the Web page under Services. Further information about
this process is available in the Permissions and Rights Question and Answer document.