Randomized control trials show beneficial effects of heparin in high-risk pregnancies to prevent preeclampsia and intrauterine growth restriction. However, the lack of placental pathology data in these trials challenges the assumption that heparin is a placental anticoagulant. Recent data show that placental infarction is probably associated with abnormalities in development of the placenta, characterized by poor maternal perfusion and an abnormal villous trophoblast compartment in contact with maternal blood, than with maternal thrombophilia. At-risk pregnancies may therefore be predicted by noninvasive prenatal testing of placental function in mid-pregnancy. Heparin has diverse cellular functions that include direct actions on the trophoblast. Dissecting the non–anticoagulant actions of heparin may indicate novel and safer therapeutic targets to prevent the major placental complications of pregnancy.

A small subset of reproductive-aged women require anticoagulation in the context of a mechanical heart valve1  or to prevent recurrent venous thromboembolism as in women with antiphospholipid syndrome.2  When planning pregnancy, they mostly convert from an oral anticoagulant such as Coumadin to subcutaneous injections of heparin to avoid the potential embryopathy induced by transplacental passage of Coumadin.3  By doing so, they expose themselves to relatively minor side effects such as skin bruising and, because heparin promotes bone loss, to the rare possibility of vertebral bone compression fractures and neurologic complications.4  In this context heparin is a success story for women whose predecessors were counseled to avoid attempts at motherhood. More than 35 years ago the concept of placental anticoagulation was proposed for women in subsequent pregnancies after recurrent placental infarction.5  Since then we have witnessed an exponential increase in the prescription of heparin to pregnant women for a wide variety of indications, based on a common theme that superior placental function can be attained via its anticoagulant properties. The fashion has spread widely according to claims that heparin promotes successful implantation after in vitro fertilization,6,7  prevents recurrent miscarriages,8  promotes better outcomes in the perinatal period,9  and, finally, may be used vaginally to induce labor in full-term pregnancies.10  A common aspect of these studies is the use of safer low molecular weight heparins (LMWHs) in prophylactic regimes that have a low risk of serious side effects when used over a relatively short duration of time in pregnancy. However, the current cost per pregnancy to prescribe prophylactic LMWH is ∼ $3000, a significant burden to uninsured women in countries, such as Canada, with variable employer-based drug plans. Ongoing use of such drugs for these indications in pregnancy therefore deserves more rigorous evidence. Recent impressive but negative trials are making progress by limiting the scope of use in women with recurrent miscarriage. Heparins are complex macromolecules with diverse actions extending beyond the classic anticoagulant role.11  Likewise diseases, such as severe preeclampsia (PE), that may be prevented by LMWH are equally complex in their pathogenesis. It is important to fully appreciate the mechanisms by which LMWH may favorably interact with the human placenta.

In 2009-2010, 3 well-designed trials reported a lack of efficacy of subcutaneous LMWH in the prevention of recurrent miscarriages, across both thrombophilia-positive and -negative women.12-14  A subsequent review of the management of recurrent miscarriage concluded that LMWH is not indicated in thrombophilia-negative women but that the evidence remains insufficient to make the same conclusion in thrombophilia-positive women pending the results of ongoing registered randomized control trials (listed in the review).15  From a pathologic standpoint these data are not surprising, because placental bed biopsies from a large series of euploid first-trimester miscarriages show no histologic evidence of disease (abnormal spiral artery transformation or lumen thrombosis) that might theoretically be prevented by heparin.16 

The evidence that LMWH may promote improved perinatal outcomes is more promising but is confined to smaller underpowered trials in thrombophilia screen–negative women.17  The recent Canadian pilot trial18  randomly assigned 114 perceived high-risk women without thrombophilia to LMWH or no drug, mostly on the basis of either previous severe PE or placental infarction. LMWH was commenced in the first trimester. All 3 perinatal deaths (at 21-24 weeks) were potentially because of placental complications, but no placental pathology was reported. A composite outcome was significantly different that favored LMWH, mostly comprising a reduction (1 vs 8) in severe PE. A subsequent similarly designed pilot trial, not yet included in the Cochrane Review,17  randomly assigned 160 women with previous pathologically proven placental abruption and no antiphospholipid antibodies equally to receive LMWH or no drug.19  The study design apparently excluded pregnancies with placental pathologies despite the stated inclusion criteria. LMWH was commenced as soon as pregnancy was chemically diagnosed in the first trimester. As in the Rey trial, a composite outcome was significantly different favoring LMWH and interestingly had a similar (2 vs 12) reduction in severe PE. Neither trial reported placental pathology, yet both trials required placental pathology as an entry criterion. More recently, an Israeli group published 2 retrospective case-control studies of LMWH in women with previous severe perinatal complications of pregnancy with20  and without21  thrombophilia. Because of trial design no meaningful clinical conclusions can be drawn, although data in women without thrombophilia21  merits closer scrutiny because the publication included detailed placental pathology. Of 32 LMWH-treated women, 50% had placental infarcts and 25% had multiple placental infarcts, strikingly similar to their control arm. These high rates of infarction rates suggest that LMWH in the doses used are incapable of preventing placental infarction in clinically high-risk women.

The human placenta is termed hemochorial because the maternal vascular integrity is disrupted by the invasive extravillous cytotrophoblast cells (EVTs) to bring maternal blood directly in contact with placental villi (Figure 1). Although this anatomical arrangement dominates at the end of the first trimester, it is attained cautiously during embryogenesis, so as to avoid oxygen toxicity.22  The growth requirements of the postimplantation blastocyst are provided by the endometrial glands secreting their contents into the primitive intervillous space until 10 weeks of gestation.23  Cytotrophoblasts form an outer shell with the intention of occluding capillaries breached within the decidualized gland stroma.24  These interact with decidual cells that express tissue factor (TF) the potent initiator of the rapid external pathway of hemostasis via thrombin generation (reviewed in Lockwood et al25 ). Deletion of TF in mice is lethal with abnormal vascular development and hemorrhage.26  TF is also expressed in placental trophoblast, but is normal effectively counterbalanced by protein C activation via the endothelial cell protein receptor.27  Human embryogenesis is therefore characterized by low oxygen tension because of effective but controlled local hemostasis.

Figure 1

Normal placental development. Extravillous cytotrophoblasts proliferate in anchoring columns to successful invade through the decidua (1) and transform the distal spiral arteries (2). These changes mediate high volume flow at low pressure into the intervillous space (3). The placental villi are covered by the villous trophoblast compartment (4), comprising cytotrophoblasts that proliferate to generate the outer syncytiotrophoblast in direct contact with maternal blood.

Figure 1

Normal placental development. Extravillous cytotrophoblasts proliferate in anchoring columns to successful invade through the decidua (1) and transform the distal spiral arteries (2). These changes mediate high volume flow at low pressure into the intervillous space (3). The placental villi are covered by the villous trophoblast compartment (4), comprising cytotrophoblasts that proliferate to generate the outer syncytiotrophoblast in direct contact with maternal blood.

Close modal

EVTs subsequently dilate the distal spiral arterioles by removing the muscular walls,28  and, where exposed to maternal blood, they switch to a pseudoendothelial phenotype.29  Under normal circumstances, EVTs are able to suppress proinflammatory responses (complement C3 activation and IL-6 expression).30  Uteroplacental blood flow then increases exponentially in the second trimester, to a much greater extent that is required for transplacental transfer of oxygen and nutrients; this spraying the villi evenly at low pressure31  may be an important contributor to hemostasis from the principles of Virchov triad.32 

Pregnancy is associated with significant changes in circulating proteins that participate in hemostasis (increased procoagulant proteins,33  decreased anticoagulant proteins34  presumably designed to limit blood loss at birth; reviewed in Thornton and Douglas35  and Sarig and Brenner36 ). This shift to a procoagulant state is counterbalanced, in the systemic circulation, by reduced hematocrit37  and increased cardiac output,38  whereas rises in tissue factor pathway inhibitors (TFPI1 and TFPI2) counteract the elevated circulating and placental TF activity.39 

From the second trimester onward, maternal blood is in contact with the outer syncytiotrophoblast surface of the developing placental villi, analogous to the labyrinth trophoblast in mice.40  In both species, this is a terminally differentiated postmitotic structure. In contrast with mice the human placenta retains its population of proliferating villous cytotrophoblasts until term.41  Although a limited degree of transcription can be detected in the outer syncytiotrophoblast,42  it is mostly confined to the underlying cytotrophoblasts; continuous syncytial fusion thus maintains the transcriptional machinery of functionality of the outer syncytiotrophoblast. Syncytial fusion also donates antiapoptotic proteins to focally restrict syncytiotrophoblast apoptosis under normal conditions (reviewed in Huppertz et al43 ). The dual requirements of continuous syncytial fusion and the need to retain a population of proliferating progenitor cells require that cytotrophoblast division is asymmetric; this is achieved via expression of the transcription factor glial cell missing-1 (GCM1) in the daughter cell destined for syncytial fusion.44  GCM1 is similarly required for the formation of extravillous trophoblast such that defective GCM1 expression is a common molecular explanation for the dual defect in both extravillous and villous trophoblast lineages observed in placentas from severe preeclamptic pregnancies.44  GCM1 is promoted by peroxisome proliferator-activated receptor-γ45  and in turn promotes expression of the fusogenic protein Syncytin1 required to effect fusion.46 

This differentiated outer syncytiotrophoblast layer expresses a number of regulators of hemostasis normally found in the systemic endothelium (summarized in Sood et al47 ). These include the procoagulant proteins TF, VWF, factor VIII,48  and tissue plasminogen activator inhibitor type 1. Inhibitory proteins of the cascade include TFPI1 and TFPI2,49,50  thrombomodulin,51,52  annexin V,53  and tissue plasminogen activators such as urokinase. The placenta is theoretically vulnerable to thrombosis because TF is constitutively expressed, although as trophoblast cells differentiate, they adopt a thromboresistant phenotype.47  As an example, differentiating cytotrophoblast cells in the first-trimester placenta strongly express endothelial cell protein receptor that, after syncytial fusion, will participate in hemostasis within the intervillous space.47 

PE is a potentially life-threatening hypertensive disorder affecting ∼ 2%-7% of all pregnancies.54  Approximately 1% of cases are severe, causing stillbirth or the need for extreme preterm delivery.55  The pathogenesis of the disease is a variable blend of host risk factors (metabolic syndrome, maternal age, medical comorbidities)55,56  and severe defects in placental development (M. Walker, B. Fitzgerald, S. Keating, J. Ray, and J.C.P.K., manuscript submitted, 2011) and pathology, most commonly villous infarction.57-59  Host susceptibility alone more commonly induces near-term disease that is safely managed by delivery,60  whereas the early severe forms of the disease are more challenging to manage because of the early gestational age and coexistent IUGR.61  Although host factors contribute to the susceptibility of late-gestation PE,55  early/severe disease is strikingly predicted by abnormal uterine artery Doppler (area under the receiver operator curve, 0.922) with no significant added value by incorporating maternal characteristics.62  This ultrasound-based test is easily integrated into the standard 20-week fetal anatomical ultrasound scan and can be combined with an assessment of placental dimensions and texture.63 

The maternal disease is characterized by hypertension because of vascular dysfunction. The consequent high systemic vascular resistance and depressed cardiac output can be observed during the second trimester64  and is associated with the release, from the placental villi into maternal venous blood, of splice-variant decoy receptor proteins, such as soluble fms-like tyrosine kinase (sFLT1), that competitively antagonizes the actions of proangiogenic growth factors (vascular endothelial growth factor [VEGF] and placenta-like growth factor) that contribute to the physiologic angiogenesis and systemic vasodilation characteristic of normal pregnancy65  (for review see Powe et al66 ). Animal models in both rats67  and mice68  support a pathogenic role for sFlt1 in the pathogenesis of severe PE. Despite this evidence for a pathogenic role for sFLT1, other investigators have found conflicting evidence. First, in a nested case-control study of ∼ 2000 women, high levels of sFLT1 at 10-14 weeks predicted lower risks for a range of adverse perinatal outcomes and did not associate with PE.69  Second, when LMWH is administered to pregnant women, it elevates circulating sFlt1 levels ∼ 3-fold.70  sFLT1 has physiologic actions, for example to arrest de novo blood vessel formation in the cornea.71  sFlt1 is locally retained on the surface of placental villi, where it can be released via the heparanase action of LMWH.70,72  Interestingly, LMWH induces transcription and translation of sFlt1 in floating first-trimester villous explants, further contributing to the LMWH-induced secretion in a manner that antagonizes VEGF receptor phosphorylation.73  This disparity in clinical and in vitro observations suggests more complex interactions between the placenta and LMWH to mediate a preventive role of heparin in women at high risk of severe PE.

The placental disease is characterized by maternal underperfusion. As such, bilateral abnormal waveforms strongly predict early placental disease and are associated with pathology of the maternal-fetal interface and the placental villi shown in Figure 2. Physiologic transformation of the spiral arteries is impaired, resulting in decidual vasculopathy and an unstable perfusion of the placenta by maternal blood (for detailed review see Burton et al31 ). Note this is not primarily a thrombotic vasculopathy; rather, it is characterized mostly by lack of transformation of the distal spiral arterioles because of maternal macrophage-mediated cell death of the invading extravillous cytotrophoblasts,74  recruited by local complement activation and generation of IL-6, resulting in acute atherosis.30  The lesion of focus in the context of heparin and anticoagulation is infarction of placental villi. Large or central placental infarction is the dominant lesion, in one cohort affecting > 50% of pregnancies delivering before 32 weeks.57  Placental infarction associates with abnormal uterine artery Doppler, suggesting that reduced uteroplacental perfusion as a contributory factor.75  We recently explored the relative importance of maternal thrombophilia and structural disorders of the placenta in a single center 10-year cohort study of 180 singleton pregnancies with histologic-confirmed placental infarction.59  High rates of mostly severe PE (61%), HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome (39%), small for gestational age (70%) and stillbirth (39%) among the 108 screened for thrombophilia show the serious implications of placental infarction. Thrombophilia (defined as > 1 factor V Leiden or prothrombin gene mutations or antiphospholipid antibodies) was found in only 14 of 108 (13%), whereas a range of underlying structural abnormalities of the placenta (small placenta, decidual vasculopathy, abnormal development of the placental villi), collectively classified as abnormal placental development, were found in ∼ 70% of cases, > 7-fold more common than thrombophilia. Of the 108 cases with thrombophilia testing, only 4 placentas had infarcts in an otherwise structurally normal placenta. These findings suggest that, from early pregnancy, there are defects in the development of placental structure that prevents normal hemostasis and somehow confers a risk of infarction. Heparin is unlikely to be capable of reversing these early developmental changes in placental structure, and the high rates of infarction (50%) observed recently by Kupfermic et al21  in high-risk women treated with LMWH supports this conclusion.

Figure 2

Uteroplacental vascular insufficiency. Extravillous cytotrophoblasts are less successful in invading the maternal decidua and may be removed by the maternal immune system (1). Consequently the distal spiral arteries are narrower (2) and diseased, accompanied by atherosis or local fibrin deposition (3) and reduced endovascular invasion (4). Hypoxia or hypoxia-reoxygenation injury (5) has direct effects on the villous trophoblast compartment, reducing syncytial fusion (6) that may trigger the formation of syncytial knots (7). These accumulate but may fragment and shed into maternal blood (8), whereas areas deficient in syncytial fusion may exhibit focal necrosis (9).

Figure 2

Uteroplacental vascular insufficiency. Extravillous cytotrophoblasts are less successful in invading the maternal decidua and may be removed by the maternal immune system (1). Consequently the distal spiral arteries are narrower (2) and diseased, accompanied by atherosis or local fibrin deposition (3) and reduced endovascular invasion (4). Hypoxia or hypoxia-reoxygenation injury (5) has direct effects on the villous trophoblast compartment, reducing syncytial fusion (6) that may trigger the formation of syncytial knots (7). These accumulate but may fragment and shed into maternal blood (8), whereas areas deficient in syncytial fusion may exhibit focal necrosis (9).

Close modal

Placental infarcts alone do not cause the maternal vascular injury of severe PE; rather they mediate the coexistent IUGR because of defective global transplacental transfer. How, therefore, does the placenta induce the maternal syndrome and at the same time become prone to thrombosis? The key is abnormal differentiation of the placental villi, summarized in Figure 3. The underlying decidual vasculopathy, established in early pregnancy, renders the placental villi poorly perfused, inducing static local hypoxia76  or more likely a dynamic process of ischemia-reperfusion injury.77  The GCM1 axis, which controls differentiation of both types of trophoblasts, is disrupted in severely preeclamptic placental villi to favor a reduction in syncytial fusion78-81  and is accentuated by hypoxia-mediated degradation of GCM1.82  Patchy areas of apoptosis, excess syncytial knot formation, and areas of necrosis are found in severe preeclamptic placental villi83  and can be reproduced in vitro, respectively, by hypoxic culture84  or hypoxia-reoxygenation77  in cultured first-trimester placental villous explants. Large syncytial knots secrete sFlt1 into maternal blood in severely preeclamptic women.85 

Figure 3

Abnormal villus trophoblast differentiation and placental thrombosis. Progenitor cytotrophoblasts proliferate (1) and divide asymmetrically (2 and 3) so that the progenitor is conserved (4) for subsequent rounds of syncytial fusion. The daughter cytotrophoblast prepares for syncytial fusion (5), focally donating transcriptional machinery and antiapoptotic proteins into the outer syncytiotrophoblast (6). Syncytial nuclei gradually progress toward apoptosis and aggregate in syncytial knots (7 and 8). Syncytial fusion is restricted in severe PE, increasing the number and size of syncytial knots (9 and 10). Some knots may fragment into the intervillous space, whereas other parts of the abnormal villi have exposed cytotrophoblasts and basal lamina (11) that trigger local thrombosis (see inset). Syncytiotrophoblast fragments are filtered in the maternal lungs, whereas microparticles pass through and may exert systemic effects in the maternal vasculature.

Figure 3

Abnormal villus trophoblast differentiation and placental thrombosis. Progenitor cytotrophoblasts proliferate (1) and divide asymmetrically (2 and 3) so that the progenitor is conserved (4) for subsequent rounds of syncytial fusion. The daughter cytotrophoblast prepares for syncytial fusion (5), focally donating transcriptional machinery and antiapoptotic proteins into the outer syncytiotrophoblast (6). Syncytial nuclei gradually progress toward apoptosis and aggregate in syncytial knots (7 and 8). Syncytial fusion is restricted in severe PE, increasing the number and size of syncytial knots (9 and 10). Some knots may fragment into the intervillous space, whereas other parts of the abnormal villi have exposed cytotrophoblasts and basal lamina (11) that trigger local thrombosis (see inset). Syncytiotrophoblast fragments are filtered in the maternal lungs, whereas microparticles pass through and may exert systemic effects in the maternal vasculature.

Close modal

These alterations in trophoblast cell biology are directly relevant to hemostasis because normal trophoblast differentiation, in both mice and humans, is accompanied by the adoption of an endothelial-like anticoagulant phenotype.47  The extensive literature supporting an arrest of syncytial fusion in severe PE disrupts surface regulation of hemostasis to favor local thrombosis; as an example, isolated first trimester villous cytotrophoblasts subjected to either hypoxia and hypoxia-reoxygenation were recently shown to double TF gene expression.86  TF is also released by the placenta into the maternal circulation in microparticles87  that are shed excessively in severe PE.88 

In the nonpregnant state, LMWH prolongs survival in metastatic cancer.89  These effects are supported by in vitro data90  and are retained in truncated forms of heparin that lack anti–thrombin-3 binding sites.11  These clinical effects seem paradoxical, because heparin promotes dimerization of basic growth factors such as fibroblast growth factor (FGF) and VEGF and to enhance their cell signaling. The explanation may be that smaller LMWH, especially < 6 kDa,91  are unable to facilitate growth factor-receptor interactions that promote angiogenesis. In the context of the trophoblast layer (Figure 4), heparin is required along with FGF4 to maintain murine trophoblast stem cells.92  Withdrawal of FGF4/heparin allows spontaneous differentiation to extravillous trophoblast.93  Some of these murine effects can be observed in human placental villi. Denuded of the outer syncytiotrophoblast to expose villous cytotrophoblasts in first-trimester placental villi to FGF4 and heparin, they proliferate to form lumps of cells expressing the receptor FGFR2.94  Lower doses of LMWH alone (0.25 IU/mL) in such experiments promote villous cytotrophoblast mitosis and syncytiotrophoblast formation in first-trimester villi.94  Heparin also induces cytotrophoblast proliferation in trophoblast-derived cell lines.94,95  These observations are consistent with previous data, suggesting that heparin reverses the proapoptotic effects in villous explant syncytiotrophoblast induced by serum from antiphospholipid antibody syndrome,96  presumably by promoting mitosis in the trophoblast progenitors within the explants that express FGFR2. We recently demonstrated a more direct and beneficial effect of heparin on placental villi in the context of preventing severe PE. We demonstrated that both unfractionated heparin (UFH) and LMWH, in comparable doses used clinically in pregnancy, are capable of reversing the natural antiangiogenic tendency of first-trimester placental villi.97  These heparins exert this proangiogenic effect despite increasing secretion of sFLT170,72  that at least in vitro impairs VEGF receptor signaling.75  This paradox between in vitro and in vivo data in the context of sFLT1 may be because of the restoration additional functions of the outer syncytiotrophoblast that override the endothelial-specific effects of excess sFLT1. First, in the context of hemostasis regulation, restoration of syncytial fusion in severe preeclamptic placental villi is predicted to promote improved expression of anticoagulant proteins on the syncytiotrophoblast surface. Second, this restoration may promote other important signaling systems, such as hemoxygenase-1, to reverse disease progression toward the vasculopathy and end-organ damage that characterizes severe PE.98 

Figure 4

Heparin promotes cytotrophoblast proliferation. Heparin facilitates dimerization of FGFs to enhance mitotic signaling. This action of heparin may reduce the risk of severe PE by promoting the production of cytotrophoblasts for syncytial fusion and maintenance of a healthy outer syncytiotrophoblast in contact with maternal blood.

Figure 4

Heparin promotes cytotrophoblast proliferation. Heparin facilitates dimerization of FGFs to enhance mitotic signaling. This action of heparin may reduce the risk of severe PE by promoting the production of cytotrophoblasts for syncytial fusion and maintenance of a healthy outer syncytiotrophoblast in contact with maternal blood.

Close modal

Heparin may also play a substantial non-anticoagulant role in the prevention of severe PE via suppression of complement pathway activation. Women destined to develop PE have elevated circulating levels of complement-activation factor Bb, but not C3a or sC5b-9.99  Because Bb levels are associated with maternal obesity, complement activation may be a dominant pathway in the maternal phenotype of PE. Interestingly, a mutation (MCP/A304V) in the complement regulatory protein MCP was recently shown in 4 of 59 maternal DNA samples of women who had developed severe PE/HELLP syndrome.100  Although antiphospholipid syndrome is deliberately excluded from this review, there is good experimental evidence to suggest that heparin inhibits complement activation in this context.101  Noninfectious leukocyte infiltration of both the maternal-fetal interface (deciduitis) and villi (villitis) is a feature in both severe PE and IUGR that, interestingly, is more common with male than female fetuses. Heparin may limit the adverse effects of this type of pathology via suppression of T-cell adhesion and migration.102 

The consistency of the data in 2 recent trials of LMWH to prevent severe PE, together with an awareness of their limitations, should be influential for future definitive trial designs.18,19  There has been a substantial interest in developing algorithms to screen pregnancies for severe PE, variously combining maternal characteristics,55  uterine artery Doppler,62  and a variety of maternal blood tests,103  a group of which are used primarily to screen at 12-16 weeks of pregnancy for Down syndrome104  and are therefore available “free” for real-time prediction of PE and IUGR. Because > 70% of infarcted placentas are small-for-dates59  and small dysmorphic placentas on ultrasound scanning (< 10 cm long at 19-22 weeks' gestation),58  increase the risk of severe PE and IUGR,105  we have combined these tests in high-risk clinical practice routinely since 2007, when we demonstrated that normal tests substantially reduce the risk extreme preterm birth from severe PE/HELLP syndrome (odds ratio, 0.2; 95% CI, 0.1-0.4) and severe early-onset IUGR (odds ratio, 0).106  With the use of this concept we subsequently screened our high-risk population for multiparameter placental dysfunction to recruit to our pilot HEPRIN (HEparin for the PRevention of placental INsufficiency) trial that was recently reported.107  Of ∼ 250 women screened, we randomly assigned 32 of 41 eligible women to either 7500 IU of UFH twice daily or no drug. Despite the much smaller sample size, we had more perinatal deaths (3; 9.3%) and deliveries < 32 weeks (9 of 32; 28.1%) than either recent trial of LMWH to prevent adverse perinatal outcomes18,19  that recruited on clinical risk factors alone. Only 5 of 31 examined placentas (16.1%) were normal. UFH did not reduce the risk of placental infarction (UFH, 3 of 16, 18.8% vs standard care, 4 of 15, 26.7%), consistent with recent Israeli observational data.21 

Given the exciting potential of prophylactic LMWH to prevent recurrent severe PE, it is important to step back from the assumption that it acts as a direct placental anticoagulant. Consequently, investigators will focus on the more diverse biologic actions of heparins and the potential that non-anticoagulant forms of heparin, without their attendant obstetric/delivery risks, might conserve beneficial actions that may operate more directly at the level of the syncytiotrophoblast layer covering the placental villi. Future trial designs, focusing on a smaller subset of women at most risk of severe PE, is now possible by embracing tools that permit a prenatal diagnosis of “placental insufficiency” in the early second trimester; this strategy is logical because at-risk women can be identified before the maternal vasculopathy becomes established. Given the diversity of potential actions of heparin together with the heterogeneity of cell-specific pathologies in the pathologic placenta, it is imperative that all future LMWH trials capture the placenta. A good start is the determination of gross and microscopic pathologies, but the subtle molecular actions of heparin will only become understood in a clinical context if immediate sampling is done that preserves the snapshot of cellular functions and protein transcription/translation. Our understanding of the molecular control of villous syncytiotrophoblast formation already offers several additional therapeutic possibilities that might restore placental self-anticoagulation via restoration of syncytial fusion. The future for the prevention of severe PE therefore has a new focus.

This work was supported by the PSI (11-02, J.C.P.K.) and Rose Torno, Chair, Mount Sinai Hospital (J.C.P.K.), and a Molly Towell Perinatal Research Foundation Fellowship (S.D.).

Contribution: J.C.P.K. and S.D. designed and wrote the manuscript.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: John Kingdom, Department of Obstetrics & Gynecology, Rm 3265, Mount Sinai Hospital, 600 University Ave, Toronto, ON, Canada M5G 1X5; e-mail: [email protected].

1
Yinon
 
Y
Siu
 
SC
Warshafsky
 
C
et al. 
Use of low molecular weight heparin in pregnant women with mechanical heart valves.
Am J Cardiol
2009
, vol. 
104
 
9
(pg. 
1259
-
1263
)
2
Bates
 
SM
Greer
 
IA
Pabinger
 
I
Sofaer
 
S
Hirsh
 
J
Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition).
Chest
2008
, vol. 
133
 
6 Suppl
(pg. 
844S
-
886S
)
3
Hirsh
 
J
Cade
 
JF
Gallus
 
AS
Fetal effects of Coumadin administered during pregnancy.
Blood
1970
, vol. 
36
 
5
(pg. 
623
-
627
)
4
Lefkou
 
E
Khamashta
 
M
Hampson
 
G
Hunt
 
BJ
Review: low-molecular-weight heparin-induced osteoporosis and osteoporotic fractures: a myth or an existing entity?
Lupus
2010
, vol. 
19
 
1
(pg. 
3
-
12
)
5
Buyse
 
FG
Wormgoor
 
BH
Bernard
 
JT
Koudstaal
 
J
Anticoagulant therapy of patients with repeated placental infarction.
Obstet Gynecol
1974
, vol. 
43
 
6
(pg. 
844
-
848
)
6
Nelson
 
SM
Greer
 
IA
The potential role of heparin in assisted conception.
Hum Reprod Update
2008
, vol. 
14
 
6
(pg. 
623
-
645
)
7
Urman
 
B
Ata
 
B
Yakin
 
K
et al. 
Luteal phase empirical low molecular weight heparin administration in patients with failed ICSI embryo transfer cycles: a randomized open-labeled pilot trial.
Hum Reprod
2009
, vol. 
24
 
7
(pg. 
1640
-
1647
)
8
Rai
 
R
Cohen
 
H
Dave
 
M
Regan
 
L
Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies).
BMJ
1997
, vol. 
314
 
7076
(pg. 
253
-
257
)
9
Gris
 
JC
Mercier
 
E
Quere
 
I
et al. 
Low-molecular-weight heparin versus low-dose aspirin in women with one fetal loss and a constitutional thrombophilic disorder.
Blood
2004
, vol. 
103
 
10
(pg. 
3695
-
3699
)
10
Ekman-Ordeberg
 
G
Akerud
 
A
Dubicke
 
A
Malmstrom
 
A
Hellgren
 
M
Does low molecular weight heparin shorten term labor?
Acta Obstet Gynecol Scand
2010
, vol. 
89
 
1
(pg. 
147
-
150
)
11
Casu
 
B
Vlodavsky
 
I
Sanderson
 
RD
Nonanticoagulant heparins and inhibition of cancer.
Pathophysiol Haemost Thromb
2008
, vol. 
36
 
3-4
(pg. 
195
-
203
)
12
Laskin
 
CA
Spitzer
 
KA
Clark
 
CA
et al. 
Low molecular weight heparin and aspirin for recurrent pregnancy loss: results from the randomized, controlled HepASA Trial.
J Rheumatol
2009
, vol. 
36
 
2
(pg. 
279
-
287
)
13
Clark
 
P
Walker
 
ID
Langhorne
 
P
et al. 
SPIN (Scottish Pregnancy Intervention) study: a multicenter, randomized controlled trial of low-molecular-weight heparin and low-dose aspirin in women with recurrent miscarriage.
Blood
2010
, vol. 
115
 
21
(pg. 
4162
-
4167
)
14
Kaandorp
 
SP
Goddijn
 
M
van der Post
 
JA
et al. 
Aspirin plus heparin or aspirin alone in women with recurrent miscarriage.
N Engl J Med
2010
, vol. 
362
 
17
(pg. 
1586
-
1596
)
15
Branch
 
DW
Gibson
 
M
Silver
 
RM
Clinical practice. Recurrent miscarriage.
N Engl J Med
2010
, vol. 
363
 
18
(pg. 
1740
-
1747
)
16
Ball
 
E
Robson
 
SC
Ayis
 
S
Lyall
 
F
Bulmer
 
JN
Early embryonic demise: no evidence of abnormal spiral artery transformation or trophoblast invasion.
J Pathol
2006
, vol. 
208
 
4
(pg. 
528
-
534
)
17
Dodd
 
JM
McLeod
 
A
Windrim
 
RC
Kingdom
 
J
Antithrombotic therapy for improving maternal or infant health outcomes in women considered at risk of placental dysfunction.
Cochrane Database Syst Rev
2010
6
pg. 
CD006780
 
18
Rey
 
E
Garneau
 
P
David
 
M
et al. 
Dalteparin for the prevention of recurrence of placental-mediated complications of pregnancy in women without thrombophilia: a pilot randomized controlled trial.
J Thromb Haemost
2009
, vol. 
7
 
1
(pg. 
58
-
64
)
19
Gris
 
JC
Chauleur
 
C
Faillie
 
JL
et al. 
Enoxaparin for the secondary prevention of placental vascular complications in women with abruptio placentae. The pilot randomised controlled NOH-AP trial.
Thromb Haemost
2010
, vol. 
104
 
4
(pg. 
771
-
779
)
20
Kupferminc
 
MJ
Rimon
 
E
Many
 
A
et al. 
Low molecular weight heparin treatment during subsequent pregnancies of women with inherited thrombophilia and previous severe pregnancy complications.
J Matern Fetal Neonat Med
2011
, vol. 
24
 
8
(pg. 
1042
-
1045
)
21
Kupferminc
 
M
Rimon
 
E
Many
 
A
et al. 
Low molecular weight heparin versus no treatment in women with previous severe pregnancy complications and placental findings without thrombophilia.
Blood Coagul Fibrinolysis
2011
, vol. 
22
 
2
(pg. 
123
-
126
)
22
Jauniaux
 
E
Gulbis
 
B
Burton
 
GJ
The human first trimester gestational sac limits rather than facilitates oxygen transfer to the foetus–a review.
Placenta
2003
, vol. 
24
 
Suppl A
(pg. 
S86
-
S93
)
23
Burton
 
GJ
Watson
 
AL
Hempstock
 
J
Skepper
 
JN
Jauniaux
 
E
Uterine glands provide histiotrophic nutrition for the human fetus during the first trimester of pregnancy.
J Clin Endocrinol Metab
2002
, vol. 
87
 
6
(pg. 
2954
-
2959
)
24
Burton
 
GJ
Jauniaux
 
E
Watson
 
AL
Maternal arterial connections to the placental intervillous space during the first trimester of human pregnancy: the Boyd collection revisited.
Am J Obstet Gynecol
1999
, vol. 
181
 
3
(pg. 
718
-
724
)
25
Lockwood
 
CJ
Huang
 
SJ
Krikun
 
G
et al. 
Decidual hemostasis, inflammation, and angiogenesis in pre-eclampsia.
Semin Thromb Hemost
2011
, vol. 
37
 
2
(pg. 
158
-
164
)
26
Carmeliet
 
P
Mackman
 
N
Moons
 
L
et al. 
Role of tissue factor in embryonic blood vessel development.
Nature
1996
, vol. 
383
 
6595
(pg. 
73
-
75
)
27
Isermann
 
B
Sood
 
R
Pawlinski
 
R
et al. 
The thrombomodulin-protein C system is essential for the maintenance of pregnancy.
Nat Med
2003
, vol. 
9
 
3
(pg. 
331
-
337
)
28
Robson
 
SC
Simpson
 
H
Ball
 
E
Lyall
 
F
Bulmer
 
JN
Punch biopsy of the human placental bed.
Am J Obstet Gynecol
2002
, vol. 
187
 
5
(pg. 
1349
-
1355
)
29
Zhou
 
Y
Fisher
 
SJ
Janatpour
 
M
et al. 
Human cytotrophoblasts adopt a vascular phenotype as they differentiate. A strategy for successful endovascular invasion?
J Clin Invest
1997
, vol. 
99
 
9
(pg. 
2139
-
2151
)
30
Hering
 
L
Herse
 
F
Verlohren
 
S
et al. 
Trophoblasts reduce the vascular smooth muscle cell proatherogenic response.
Hypertension
2008
, vol. 
51
 
2
(pg. 
554
-
559
)
31
Burton
 
GJ
Woods
 
AW
Jauniaux
 
E
Kingdom
 
JC
Rheological and physiological consequences of conversion of the maternal spiral arteries for uteroplacental blood flow during human pregnancy.
Placenta
2009
, vol. 
30
 
6
(pg. 
473
-
482
)
32
Bagot
 
CN
Arya
 
R
Virchow and his triad: a question of attribution.
Br J Haematol
2008
, vol. 
143
 
2
(pg. 
180
-
190
)
33
O'Riordan
 
MN
Higgins
 
JR
Haemostasis in normal and abnormal pregnancy.
Best Pract Res Clin Obstet Gynaecol
2003
, vol. 
17
 
3
(pg. 
385
-
396
)
34
Uchikova
 
EH
Ledjev
 
II
Changes in haemostasis during normal pregnancy.
Eur J Obstet Gynecol Reprod Biol
2005
, vol. 
119
 
2
(pg. 
185
-
188
)
35
Thornton
 
P
Douglas
 
J
Coagulation in pregnancy.
Best Pract Res Clin Obstet Gynaecol
2010
, vol. 
24
 
3
(pg. 
339
-
352
)
36
Sarig
 
G
Brenner
 
B
Coagulation, inflammation, and pregnancy complications.
Lancet
2004
, vol. 
363
 
9403
(pg. 
96
-
97
)
37
van Buul
 
EJ
Steegers
 
EA
Jongsma
 
HW
et al. 
Haematological and biochemical profile of uncomplicated pregnancy in nulliparous women; a longitudinal study.
Neth J Med
1995
, vol. 
46
 
2
(pg. 
73
-
85
)
38
Robson
 
SC
Hunter
 
S
Boys
 
RJ
Dunlop
 
W
Serial study of factors influencing changes in cardiac output during human pregnancy.
Am J Physiol
1989
, vol. 
256
 
4 Pt 2
(pg. 
H1060
-
H1065
)
39
Ittel
 
A
Bretelle
 
F
Gris
 
JC
et al. 
Increased risk of gestational vascular complications in women with low free tissue factor pathway inhibitor plasma levels out of pregnancy.
Thromb Haemost
2011
, vol. 
105
 
1
(pg. 
66
-
71
)
40
Simmons
 
DG
Natale
 
DR
Begay
 
V
et al. 
Early patterning of the chorion leads to the trilaminar trophoblast cell structure in the placental labyrinth.
Development
2008
, vol. 
135
 
12
(pg. 
2083
-
2091
)
41
Mayhew
 
TM
Simpson
 
RA
Quantitative evidence for the spatial dispersal of trophoblast nuclei in human placental villi during gestation.
Placenta
1994
, vol. 
15
 
8
(pg. 
837
-
844
)
42
Ellery
 
PM
Cindrova-Davies
 
T
Jauniaux
 
E
Ferguson-Smith
 
AC
Burton
 
GJ
Evidence for transcriptional activity in the syncytiotrophoblast of the human placenta.
Placenta
2009
, vol. 
30
 
4
(pg. 
329
-
334
)
43
Huppertz
 
B
Kadyrov
 
M
Kingdom
 
JC
Apoptosis and its role in the trophoblast.
Am J Obstet Gynecol
2006
, vol. 
195
 
1
(pg. 
29
-
39
)
44
Baczyk
 
D
Drewlo
 
S
Proctor
 
L
et al. 
Glial cell missing-1 transcription factor is required for the differentiation of the human trophoblast.
Cell Death Differ
2009
, vol. 
16
 
5
(pg. 
719
-
727
)
45
Parast
 
MM
Yu
 
H
Ciric
 
A
et al. 
PPARgamma regulates trophoblast proliferation and promotes labyrinthine trilineage differentiation.
PLoS One
2009
, vol. 
4
 
11
pg. 
e8055
 
46
Mi
 
S
Lee
 
X
Li
 
X
et al. 
Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis.
Nature
2000
, vol. 
403
 
6771
(pg. 
785
-
789
)
47
Sood
 
R
Kalloway
 
S
Mast
 
AE
Hillard
 
CJ
Weiler
 
H
Fetomaternal cross talk in the placental vascular bed: control of coagulation by trophoblast cells.
Blood
2006
, vol. 
107
 
8
(pg. 
3173
-
3180
)
48
Kadhom
 
N
Wolfrom
 
C
Gautier
 
M
Allain
 
JP
Frommel
 
D
Factor VIII procoagulant antigen in human tissues.
Thromb Haemost
1988
, vol. 
59
 
2
(pg. 
289
-
294
)
49
Mast
 
AE
Acharya
 
N
Malecha
 
MJ
Hall
 
CL
Dietzen
 
DJ
Characterization of the association of tissue factor pathway inhibitor with human placenta.
Arterioscler Thromb Vasc Biol
2002
, vol. 
22
 
12
(pg. 
2099
-
2104
)
50
Sprecher
 
CA
Kisiel
 
W
Mathewes
 
S
Foster
 
DC
Molecular cloning, expression, and partial characterization of a second human tissue-factor-pathway inhibitor.
Proc Natl Acad Sci U S A
1994
, vol. 
91
 
8
(pg. 
3353
-
3357
)
51
Freyssinet
 
JM
Brami
 
B
Gauchy
 
J
Cazenave
 
JP
Coextraction of thrombomodulin and tissue factor from human placenta: effects of concanavalin A and phospholipid environment on activity.
Thromb Haemost
1986
, vol. 
55
 
1
(pg. 
112
-
118
)
52
Salem
 
HH
Maruyama
 
I
Ishii
 
H
Majerus
 
PW
Isolation and characterization of thrombomodulin from human placenta.
J Biol Chem
1984
, vol. 
259
 
19
(pg. 
12246
-
12251
)
53
Krikun
 
G
Lockwood
 
CJ
Wu
 
XX
et al. 
The expression of the placental anticoagulant protein, annexin V, by villous trophoblasts: immunolocalization and in vitro regulation.
Placenta
1994
, vol. 
15
 
6
(pg. 
601
-
612
)
54
Steegers
 
EA
von Dadelszen
 
P
Duvekot
 
JJ
Pijnenborg
 
R
Pre-eclampsia.
Lancet
2010
, vol. 
376
 
9741
(pg. 
631
-
644
)
55
North
 
RA
McCowan
 
LM
Dekker
 
GA
et al. 
Clinical risk prediction for pre-eclampsia in nulliparous women: development of model in international prospective cohort.
BMJ
2011
, vol. 
342
 pg. 
d1875
 
56
Redman
 
CW
Sargent
 
IL
Latest advances in understanding preeclampsia.
Science
2005
, vol. 
308
 
5728
(pg. 
1592
-
1594
)
57
Moldenhauer
 
JS
Stanek
 
J
Warshak
 
C
Khoury
 
J
Sibai
 
B
The frequency and severity of placental findings in women with preeclampsia are gestational age dependent.
Am J Obstet Gynecol
2003
, vol. 
189
 
4
(pg. 
1173
-
1177
)
58
Toal
 
M
Keating
 
S
Machin
 
G
et al. 
Determinants of adverse perinatal outcome in high-risk women with abnormal uterine artery Doppler images.
Am J Obstet Gynecol
2008
, vol. 
198
 
3
(pg. 
330
(pg. 
e331
-
337
)
59
Franco
 
C
Walker
 
M
Robertson
 
J
et al. 
Placental infarction and thrombophilia.
Obstet Gynecol
2011
, vol. 
117
 
4
(pg. 
929
-
934
)
60
Koopmans
 
CM
Bijlenga
 
D
Groen
 
H
et al. 
Induction of labour versus expectant monitoring for gestational hypertension or mild pre-eclampsia after 36 weeks' gestation (HYPITAT): a multicentre, open-label randomised controlled trial.
Lancet
2009
, vol. 
374
 
9694
(pg. 
979
-
988
)
61
von Dadelszen
 
P
Payne
 
B
Li
 
J
et al. 
Prediction of adverse maternal outcomes in pre-eclampsia: development and validation of the fullPIERS model.
Lancet
2011
, vol. 
377
 
9761
(pg. 
219
-
227
)
62
Yu
 
CK
Smith
 
GC
Papageorghiou
 
AT
Cacho
 
AM
Nicolaides
 
KH
An integrated model for the prediction of preeclampsia using maternal factors and uterine artery Doppler velocimetry in unselected low-risk women.
Am J Obstet Gynecol
2005
, vol. 
193
 
2
(pg. 
429
-
436
)
63
Toal
 
M
Chaddha
 
V
Windrim
 
R
Kingdom
 
J
Ultrasound detection of placental insufficiency in women with elevated second trimester serum alpha-fetoprotein or human chorionic gonadotropin.
J Obstet Gynaecol Can
2008
, vol. 
30
 
3
(pg. 
198
-
206
)
64
Sep
 
S
Schreurs
 
M
Bekkers
 
S
et al. 
Early-pregnancy changes in cardiac diastolic function in women with recurrent pre-eclampsia and in previously pre-eclamptic women without recurrent disease.
BJOG
2011
, vol. 
118
 
9
(pg. 
1112
-
1119
)
65
Levine
 
RJ
Maynard
 
SE
Qian
 
C
et al. 
Circulating angiogenic factors and the risk of preeclampsia.
N Engl J Med
2004
, vol. 
350
 
7
(pg. 
672
-
683
)
66
Powe
 
CE
Levine
 
RJ
Karumanchi
 
SA
Preeclampsia, a disease of the maternal endothelium: the role of antiangiogenic factors and implications for later cardiovascular disease.
Circulation
2011
, vol. 
123
 
24
(pg. 
2856
-
2869
)
67
Murphy
 
SR
LaMarca
 
BB
Cockrell
 
K
Granger
 
JP
Role of endothelin in mediating soluble fms-like tyrosine kinase 1-induced hypertension in pregnant rats.
Hypertension
2010
, vol. 
55
 
2
(pg. 
394
-
398
)
68
Bergmann
 
A
Ahmad
 
S
Cudmore
 
M
et al. 
Reduction of circulating soluble Flt-1 alleviates preeclampsia-like symptoms in a mouse model.
J Cell Mol Med
2010
, vol. 
14
 
6B
(pg. 
1857
-
1867
)
69
Smith
 
GC
Crossley
 
JA
Aitken
 
DA
et al. 
Circulating angiogenic factors in early pregnancy and the risk of preeclampsia, intrauterine growth restriction, spontaneous preterm birth, and stillbirth.
Obstet Gynecol
2007
, vol. 
109
 
6
(pg. 
1316
-
1324
)
70
Sela
 
S
Natanson-Yaron
 
S
Zcharia
 
E
et al. 
Local retention versus systemic release of soluble VEGF receptor-1 are mediated by heparin-binding and regulated by heparanase.
Circ Res
2011
, vol. 
108
 
9
(pg. 
1063
-
1070
)
71
Ambati
 
BK
Nozaki
 
M
Singh
 
N
et al. 
Corneal avascularity is due to soluble VEGF receptor-1.
Nature
2006
, vol. 
443
 
7114
(pg. 
993
-
997
)
72
Carroll
 
TY
Mulla
 
MJ
Han
 
CS
et al. 
Modulation of trophoblast angiogenic factor secretion by antiphospholipid antibodies is not reversed by heparin [published online ahead of print May 7, 2011].
Am J Reprod Immunol
 
73
Drewlo
 
S
Levytska
 
K
Sobal
 
M
et al. 
Heparin promotes soluble VEGF receptor expression in human placental villi to impair endothelial VEGF signaling [published online ahead of print October 10, 2011].
J Thromb Hemost
 
74
Reister
 
F
Frank
 
HG
Kingdom
 
JC
et al. 
Macrophage-induced apoptosis limits endovascular trophoblast invasion in the uterine wall of preeclamptic women.
Lab Invest
2001
, vol. 
81
 
8
(pg. 
1143
-
1152
)
75
Ferrazzi
 
E
Bulfamante
 
G
Mezzopane
 
R
et al. 
Uterine Doppler velocimetry and placental hypoxic-ischemic lesion in pregnancies with fetal intrauterine growth restriction.
Placenta
1999
, vol. 
20
 
5-6
(pg. 
389
-
394
)
76
Soleymanlou
 
N
Jurisica
 
I
Nevo
 
O
et al. 
Molecular evidence of placental hypoxia in preeclampsia.
J Clin Endocrinol Metab
2005
, vol. 
90
 
7
(pg. 
4299
-
4308
)
77
Hung
 
TH
Skepper
 
JN
Charnock-Jones
 
DS
Burton
 
GJ
Hypoxia-reoxygenation: a potent inducer of apoptotic changes in the human placenta and possible etiological factor in preeclampsia.
Circ Res
2002
, vol. 
90
 
12
(pg. 
1274
-
1281
)
78
McCarthy
 
FP
Drewlo
 
S
Kingdom
 
J
et al. 
Peroxisome proliferator-activated receptor-{gamma} as a potential therapeutic target in the treatment of preeclampsia.
Hypertension
2011
, vol. 
58
 
2
(pg. 
280
-
286
)
79
Chen
 
CP
Chen
 
CY
Yang
 
YC
Su
 
TH
Chen
 
H
Decreased placental GCM1 (glial cells missing) gene expression in pre-eclampsia.
Placenta
2004
, vol. 
25
 
5
(pg. 
413
-
421
)
80
Vargas
 
A
Toufaily
 
C
Lebellego
 
F
et al. 
Reduced expression of both Syncytin 1 and Syncytin 2 correlates with severity of preeclampsia [published online ahead of print April 14, 2011].
Reprod Sci
 
81
Wich
 
C
Kausler
 
S
Dotsch
 
J
Rascher
 
W
Knerr
 
I
Syncytin-1 and glial cells missing a: hypoxia-induced deregulated gene expression along with disordered cell fusion in primary term human trophoblasts.
Gynecol Obstet Invest
2009
, vol. 
68
 
1
(pg. 
9
-
18
)
82
Chiang
 
MH
Liang
 
FY
Chen
 
CP
et al. 
Mechanism of hypoxia-induced GCM1 degradation: implications for the pathogenesis of preeclampsia.
J Biol Chem
2009
, vol. 
284
 
26
(pg. 
17411
-
17419
)
83
Fitzgerald
 
B
Levytska
 
K
Kingdom
 
J
et al. 
Villous trophoblast abnormalities in extremely preterm deliveries with elevated second trimester maternal serum hCG or inhibin-A.
Placenta
2011
, vol. 
32
 
4
(pg. 
339
-
345
)
84
Huppertz
 
B
Kingdom
 
J
Caniggia
 
I
et al. 
Hypoxia favours necrotic versus apoptotic shedding of placental syncytiotrophoblast into the maternal circulation.
Placenta
2003
, vol. 
24
 
2-3
(pg. 
181
-
190
)
85
Tache
 
V
Lacoursiere
 
DY
Saleemuddin
 
A
Parast
 
MM
Placental expression of vascular endothelial growth factor receptor-1/soluble vascular endothelial growth factor receptor-1 correlates with severity of clinical preeclampsia and villous hypermaturity.
Hum Pathol
2011
, vol. 
42
 
9
(pg. 
1283
-
1288
)
86
Teng
 
YC
Lin
 
QD
Lin
 
JH
Ding
 
CW
Zuo
 
Y
Coagulation and fibrinolysis related cytokine imbalance in preeclampsia: the role of placental trophoblasts.
J Perinat Med
2009
, vol. 
37
 
4
(pg. 
343
-
348
)
87
Aharon
 
A
Brenner
 
B
Microparticles and pregnancy complications.
Thromb Res
2011
, vol. 
127
 
suppl 3
(pg. 
S67
-
S71
)
88
Knight
 
M
Redman
 
CW
Linton
 
EA
Sargent
 
IL
Shedding of syncytiotrophoblast microvilli into the maternal circulation in pre-eclamptic pregnancies.
Br J Obstet Gynaecol
1998
, vol. 
105
 
6
(pg. 
632
-
640
)
89
Lazo-Langner
 
A
Goss
 
GD
Spaans
 
JN
Rodger
 
MA
The effect of low-molecular-weight heparin on cancer survival. A systematic review and meta-analysis of randomized trials.
J Thromb Haemost
2007
, vol. 
5
 
4
(pg. 
729
-
737
)
90
Marchetti
 
M
Vignoli
 
A
Russo
 
L
et al. 
Endothelial capillary tube formation and cell proliferation induced by tumor cells are affected by low molecular weight heparins and unfractionated heparin.
Thromb Res
2008
, vol. 
121
 
5
(pg. 
637
-
645
)
91
Khorana
 
AA
Sahni
 
A
Altland
 
OD
Francis
 
CW
Heparin inhibition of endothelial cell proliferation and organization is dependent on molecular weight.
Arterioscler Thromb Vasc Biol
2003
, vol. 
23
 
11
(pg. 
2110
-
2115
)
92
Tanaka
 
S
Kunath
 
T
Hadjantonakis
 
AK
Nagy
 
A
Rossant
 
J
Promotion of trophoblast stem cell proliferation by FGF4.
Science
1998
, vol. 
282
 
5396
(pg. 
2072
-
2075
)
93
Hughes
 
M
Dobric
 
N
Scott
 
IC
et al. 
The Hand1, Stra13 and Gcm1 transcription factors override FGF signaling to promote terminal differentiation of trophoblast stem cells.
Dev Biol
2004
, vol. 
271
 
1
(pg. 
26
-
37
)
94
Baczyk
 
D
Dunk
 
C
Huppertz
 
B
et al. 
Bi-potential behaviour of cytotrophoblasts in first trimester chorionic villi.
Placenta
2006
, vol. 
27
 
4-5
(pg. 
367
-
374
)
95
Hills
 
FA
Abrahams
 
VM
Gonzalez-Timon
 
B
et al. 
Heparin prevents programmed cell death in human trophoblast.
Mol Hum Reprod
2006
, vol. 
12
 
4
(pg. 
237
-
243
)
96
Bose
 
P
Black
 
S
Kadyrov
 
M
et al. 
Adverse effects of lupus anticoagulant positive blood sera on placental viability can be prevented by heparin in vitro.
Am J Obstet Gynecol
2004
, vol. 
191
 
6
(pg. 
2125
-
2131
)
97
Sobel
 
ML
Kingdom
 
J
Drewlo
 
S
angiogenic response of placental villi to heparin.
Obst Gynecol
2011
, vol. 
117
 
6
(pg. 
1375
-
1383
)
98
George
 
EM
Cockrell
 
K
Aranay
 
M
et al. 
Induction of heme oxygenase 1 attenuates placental ischemia-induced hypertension.
Hypertension
2011
, vol. 
57
 
5
(pg. 
941
-
948
)
99
Lynch
 
AM
Murphy
 
JR
Gibbs
 
RS
et al. 
The interrelationship of complement-activation fragments and angiogenesis-related factors in early pregnancy and their association with pre-eclampsia.
BJOG
2010
, vol. 
117
 
4
(pg. 
456
-
462
)
100
Salmon
 
JE
Heuser
 
C
Triebwasser
 
M
et al. 
Mutations in complement regulatory proteins predispose to preeclampsia: a genetic analysis of the PROMISSE cohort.
PLoS Med
2011
, vol. 
8
 
3
pg. 
e1001013
 
101
Girardi
 
G
Redecha
 
P
Salmon
 
JE
Heparin prevents antiphospholipid antibody-induced fetal loss by inhibiting complement activation.
Nat Med
2004
, vol. 
10
 
11
(pg. 
1222
-
1226
)
102
Christopherson
 
KW
Campbell
 
JJ
Travers
 
JB
Hromas
 
RA
Low-molecular-weight heparins inhibit CCL21-induced T cell adhesion and migration.
J Pharmacol Exp Ther
2002
, vol. 
302
 
1
(pg. 
290
-
295
)
103
Kuc
 
S
Wortelboer
 
EJ
van Rijn
 
BB
et al. 
Evaluation of 7 serum biomarkers and uterine artery Doppler ultrasound for first-trimester prediction of preeclampsia: a systematic review.
Obstet Gynecol Surv
2011
, vol. 
66
 
4
(pg. 
225
-
239
)
104
Dugoff
 
L
First- and second-trimester maternal serum markers for aneuploidy and adverse obstetric outcomes.
Obstet Gynecol
2010
, vol. 
115
 
5
(pg. 
1052
-
1061
)
105
Proctor
 
L
Toal
 
M
Drewlo
 
S
et al. 
Role of placental ultrasound to predict adverse pregnancy outcomes in women with low PAPP-A at 11-13 weeks.
Placenta
2007
, vol. 
28
 
8-9
(pg. 
A41
-
A41
)
106
Toal
 
M
Chan
 
C
Fallah
 
S
et al. 
Usefulness of a placental profile in high-risk pregnancies.
Am J Obstet Gynecol
2007
, vol. 
196
 
4
(pg. 
363
(pg. 
e361
-
367
)
107
Kingdom
 
JC
Walker
 
M
Proctor
 
LK
et al. 
Unfractionated heparin for second trimester placental insufficiency: a pilot randomized trial.
J Thromb Haemost
2011
, vol. 
9
 
8
(pg. 
1783
-
1492
)
Sign in via your Institution