The causes of pre-eclampsia: is it a multifactorial disease or is there one main cause?


This essay discusses the clinical signs and symptoms of pre-eclampsia, and the factors (risk factors and biological molecules) that lead to the aetiology of the disease. The spiral arteries of pre-eclamptic women have high resistance and low flow. This is due to endothelial dysfunction which is caused by the products of oxidative stress, shed particles from membranes, activated neutrophils and plasma lipids. It is also a result of the action of molecules such as vascular endothelial growth factor (VEGF), placental growth factor (PlGF), soluble endoglin (sEng), placental protein 13 (PP13), P Selectin, angiotensin receptor 1 auto antibodies (AT1-AA) and neurokinin B. They all act to affect angiogenesis - the production of new blood vessels - and hence cause hypertension, proteinurea and the other symptoms of pre-eclampsia. I also looked into the risk factors of pre-eclampsia and found that women over the age of 40, those with previous history (personal or family) of preeclampsia, women with multiple pregnancies, insulin dependence, and chronic hypertension all have an increased risk of pre-eclampsia. Also, ladies with renal disease, antiphospholipid dsyndrome, high BMI, those who conceive through reproductive techniques and those from a Caucasian, African or afrocarribean background have an increased risk of pre-eclampsia. I have concluded that pre-eclampsia is a multifactorial disease.


Pre-eclampsia is defined as the presence of hypertension - systolic blood pressure >140mmHg or diastolic blood pressure >90mmHg - and proteinurea - >0.3g/day after the twentieth week of pregnancy in a usually normotensive woman.1 Odema is not part of the definition, but it is a characteristic of the disease. Pre-eclampsia affects 5% - 8% of all pregnancies1, and 3% - 5% of pregnancies in the west2. It is a multi system disorder and is the most common complication of pregnancy, causing high morbidity and mortality in the mother and the foetus. It usually occurs in the last trimester of pregnancy,[1] although it can occur earlier. Maternal risk factors include previous episodes of pre-eclampsia, diabetes or insulin resistance, chronic hypertension (increases risk by 15-25%) multiple gestation, high BMI and age (<20 years or >40 years)1. We know that pre-eclampsia is a disease of origin in the placenta as it only occurs during pregnancy, it is eliminated after the removal of the placenta and it can occur in molar pregnancies (when there is a placenta without a foetus). The mother may also suffer from complications such as liver haemorrhage and necrosis, acture renal failure, HELLP syndrome and eclampsia (convulsions). It is caused by endothelial dysfunction of the spiral arteries supplying the placenta. These arteries become subject to ischeamic attacks, which leads to them becoming low-flow and causing poor placental perfusion. This causes reduced blood supply to the foetus and makes it vulnerable to early onset disease. The mechanism by which endothelial dysfunction occurs is not fully understood, however this review tries to summarise the role of angiogenic factors in the pathophysiology of the disease.

Normal role of the placenta.

The placenta connects the foetus to the uterine wall and allows transfer of gases, nutrients and the removal of waste from the developing baby. The spiral arteries provide the blood and in a healthy woman they will be high flow and low resistance. In a normal pregnancy, there are two stages of cytotrophoblastic invasion - the first being at around 10-12 weeks gestation when the decidual segments of the spiral arteries invade the uterine wall. The second stage is when the myometrial segments are invaded at 15-16 weeks into pregnancy. The epithelium and tunica media of the spiral arteries are damaged, and this leads to remodelling. They turn into high-flow, low-resistance vessels from low-flow and highly resistant ones which are needed for correct placenta formation.2


In preeclampsia, stage one is impaired and the spiral arteries remain low-flow and highly resistant and this significantly reduces the blood supply to the foetus. As pregnancy progresses, the vascular supply to the uterus cannot keep up with the blood and nutrient supply to the foetus and the effects become detrimental. This is due to the fact that the cytotrophoblasts do not invade the myometrial segments correctly.2 This reduced blood supply and repeated hypoxia leads to placental ischemia and oxidative stress. This leads to the release of angiogenic factors, necrosis and apoptosis, which leads to the characteristic generalised endothelium dysfunction of preeclampsia.4 The endothelial cell activation and dysfunction is caused by the products of oxidative stress, the shed membrane particles of leukocytes and platelets, activated neutrophils, elevated plasma lipids, and a range of angiogenic factors. Maternal endothelial dysfunction as the key event leading to pre-eclampsia was first suggested by Roberts et al. and has since been further investigated.

The department of Obstetrics and Gynaecology at John Radcliffe Hospital, Oxford, did a systematic review from literature on the risk factors of pre-eclampsia at antenatal booking. They found that women over the age of 40 had almost double the risk of developing pre-eclmapsia, whether they were primiparous or multiparous. US data shows that for every year of age after 34 years, the risk of pre-eclampsia increases by 30%. Also, if a woman has had pre-eclmapsia in a previous pregnancy, her risk of pre-eclmapsia in a second pregnancy is increased by seven times. Another risk factor is family history of pre-eclampsia. If the woman has a family history of pre-eclampsia, she has almost three times the risk of pre-eclmapsia. If she has severe pre-eclmaptic toxaemia, it is more likely that her mother had pre-eclmapsia than her mother-in-law. Furthermore, the risk of pre-eclmapsia is doubled if the woman is carrying twins, and this is not altered by either the chonionicity or zygosity. They also found one study that showed the risk of pre-eclmapsia is tripled if the woman is carrying triplets. The review also stated that insulin dependent diabetes almost quadruples the risk of pre-eclmapsia. It states that Davies et al shows the prevalence of pre-eclmapsia in women with chronic hypertension is higher (12.1%) compared to women without chronic hypertension (0.3%). Davies et al also show that the prevalence of renal disease in women who develop pre-eclmapsia was 5.3% compared to the 1.8% who do not have renal disease. The review assures that the women with antiphospholipid syndrome (they have lupus anticoagulant or anticardiolipin antibodies) have a 2-3 times increased risk of developing pre-eclmapsia, although those with pre-eclmapsia are no more likely to have lupus anticoagulant or anticardiolipin antibodies. Bianco et al43 showed that women with a BMI [(weight (kg) / height2 (m)] over 35 have twice the risk of pre-eclmapsia compared with women with BMI of 19-27. A high BMI indicates that the woman is at a higher risk of hypertension, and also may be older - both risk factors for pre-eclmapsia. Obesity leads to the increased inflammatory activity, altered adipokines, and higher circulating dimethylarinine - an inhibitor of the vasodilator nitric oxide synthase.36 The review explained that Reiss et al showed that women who developed pre-eclampsia had a raised systolic and diastolic blood pressure compared to those who did not develop the condition. In addition, ladies who conceive through assisted reproduction techniques and those with autoimmune diseases, pre existing renal or vascular diseases have an increased risk of suffering from preeclampsia.4


The symptoms of pre-eclampsia do not occur until about 20 weeks gestation, most occurring during the third trimester (week 27 until the delivery). Early symptoms will include hypertension and proteinurea, the latter being more indicative of the disease. As the disease progresses, the women will develop odema in the feet, ankles, face and hands. This is caused by the increased vascular pressure pushing fluid out into the interstitial space. Odema is a symptom of pregnancy, however its presence in the face and hands indicates pre-eclampsia. Further progression of the disease may lead to severe headaches, vision problems and epigastric pain. The woman may also experience vomiting, excessive weight gain due to fluid retention and a general sense of malaise in the woman. The developing baby will be growing at a slower rate than in a normotesnive pregnancy, and this is known as intra-uterine growth restriction (IUGR). This is due to its reduced oxygen and nutrient supply through the placenta. Extreme complications of pre-eclampsia are eclampsia (convulsions) and the HELLP syndrome (haemolytic anemia, elevated liver enzymes and low platelet count).40 Eclampsia can occur after 20 weeks gestation or post-birth. Unborn babies can suffocate as a result and 1 in 14 may die. The HELLP syndrome is a combined liver and clotting disorder which mostly occurs after delivery. It is slightly more common that eclampsia and the main danger is premature birth. Other complications of pre-eclampsia include cerebral haemorrhage, pulmonary odema, kidney failure, liver failure and disseminated intravascular coagulation.41


Pre-eclampsia is a disease with no single theory. It is associated with multiple organ systems and widespread endothelial dysfunction. There thought to be four main causes of endothelial dysfunction: the products of oxidative stress, leukocytes and platelet derived particles, activated neutrophils and elevated plasma levels.

The products of oxidative stress

Oxidative stress in the placentas of pre-eclamtic women and markers of lipid peroxidation (thiobarbituric reactive substances and 8-isoprostane) are raised in maternal circulation. The oxidised lipids present in low-density lipoproteins (LDLs) increase the expression of cell adhesion molecules and attract monocytes to become foam cells. Once in the endothelium, these foam cells break down and causes vascular dysfunction and reduces vascular smooth muscle tone, resulting in the symptoms of pre-eclampsia. Women with high circulating LDL (high cholesterol) have an increased risk of this. Oxidation of endothelial cells causes them to become leaky, which leads to protein urea as seen in pre-eclampsia.

Shed membrane particles

Leukocyte and platelet derived microparticles are present in the plasma of healthy pregnant women, however they are over expressed in pre-eclamptic women.47 These particles induce vascular inflammation and modulate vascular smooth muscle tone. When investigated, it was seen that the leukocyte membrane particles induce COX-2, which is upregulated in activated macrophages at sites of inflammation. The platelet derived membrane microparticles, were shown to induce nitric oxide synthase and therefore have a protective effect in pre-eclampsia.48

Other membrane particles induce inflammation and activate nuclear factor-kB, nitrotyrosine, superoxide, and 8-isoprostane. Nuclear factor-kB controls transcription of DNA and therefore an imbalance of it causes inflammation; nitrotyrosine is a marker of nitric oxide-dependent oxidative stress and is present in inflammation; superoxide is toxic and causes cell dysfunctionl and 8-isoprostane is a marker of oxidative stress that causes vasoconstriction.44

Membrane particles from the maternal placenta are also a cause of damage. The maternal synctiotrophoblasts break down during normal pregnancy and are replaced by the underlying cytotrophoblasts. The oxidative stress and due to increased lipid peroxidises in pre-eclampsia disrupts the synctiotrophoblast cell balance and this causes a release of membrane microparticles which contain oxidised lipids. These particles have been shown to cause endothelial activation.47

Activated neutrophils

Neutrophil activation is caused by their binding to endothelial adhesion molecules and surface receptors, which requires P-selectin and platelet activating factor. Once the neurophils are activated, neutrophil granules are released and cause vascular dysfunction. There is also synthesis of leukotrienes and superoxides, which also lead to vascular dysfunction. It has been shown that there is increased neutrophil activation and enhanced expression of the markers of this: neutrophil integrin and protease elastase. Increased neutrophil activation causes up-regulation of cellular adhesion molecules on the endothelial surface, increased generation of TNF-α, and endothelial activation from hyperlipidemia.46

Elevated plasma lipids

The main fatty acid increased in pre-eclampsia is linoleic acid. It is an essential found in the cell membrane lipids and is used in the biosynthesis of arachodonic acid and prostaglandins. Excess linoleic acid induces oxidative stress on the endothelial cells and causes endothelial dysfunction.45


An angiogenic factor is ‘a substance that causes the growth of new blood vessels, found in tissues with high metabolic requirements and also released by macrophages to initiate revascularisation in wound healing.'5 Many angiogenic and antiangiogenic factors have been identified in the pathophysiology of pre-eclampsia. The main ones are vascular endothelial growth factor (VEGF), placental growth factor (PlGF), soluble endoglin (sEng), P selectin, placental protein 13 (PP13), AT1 receptor autoantibodies (AT1-AA) and neurokinin B (NKB). Other factors such as ADAM12 and pentraxin 13 (PTX13) also have roles in the aetiology of pre-eclampsia.

Vascular Endothelial Growth Factor / Placental Growth Factor

Placental growth factor (PlGF) and vascular endothelial growth factor (VEGF) are pro-angiogenic factors i.e. they aid the formation of new blood vessels.

VEGF has been found to induce nitric oxide8 - a powerful vasodilator. Nitric oxide (NO) binds to its receptor on a cell and causes an allosteric change in guanylyl cyclise. This produces the secondary messenger, cGMP9, which decreases intracellular calcium concentrations by inhibiting calcium entry into the cell. NO also activates K+ channels, leading to hyperpolarization and relaxation of the vascular smooth muscle. It also stimulates a cGMP-dependent protein kinase that activates myosin light chain phosphatase, the enzyme that dephosphorylates myosin light chains, leading to smooth muscle relaxation.10 In preeclampsia, levels of VEGF are low and therefore there is decreased production of NO, leading to less vasodilatation.

In pre-eclampsia, PlGF and VEGF are inhibited by the soluble form of the VEGF receptor-1 (sVEGFR-1), also known as soluble fms-like tyrosine kinase-1 (sFlt-1). sVEGFR-1 inhibits the interaction between PlGF and VEGF and membrane bound Flt-1, and this leads to vascular endothelial dysfunction.6 It has been shown that in preeclampsia, levels of PlGF and VEGF are lower and serum levels of sFLT-1 are increased.2 This has been shown through rat models in which overexpression of SFLT-1 produced rats with a preeclampsia phenotype. Also, cancer patients who were given anti-VEGF showed signs of hypertension and protienurea.7 These are characteristics of preeclampsia, although they did not have preeclampsia themselves. It just shows that these factors are contributory to the vascular dysfunction. Studies have shown that after pregnancy, levels of sFLT-1 return to normal indicating that preeclampsia is merely a condition that persists during pregnancy.2 It has also been shown that sFLT-1 mRNA is up regulated in the placenta of women with preeclampsia, thus leading to an increase in its production.8

It is believed that renal capillaries are extremely sensitive to VEGF which is essential for the normal function of glomerular endothelial cells. It is usually produced by local podocytes, however in pre-eclampsia, there is a reduction in circulating VEGF which leads to renal dysfunction and the signs of protein urea.42

Soluble endoglin

It has been shown that a novel placena-derived TGFβ coreceptor, soluble endoglin, is elevated during pregnancy and falls after birth. Thus, it is seen as a pre-eclamptic angiogenic factor.15 Endoglin (Eng), also known as CD105, is a transmembrane glycoprotein which is mainly expressed in endothelial cells and copiously in angiogenic endothelium cells.12 It is associated with proliferation and can induce hypoxia. It modulates TGFβ by interacting with with TGFβ receptor subtypes I and II. TGFβ acts as a mediator of proliferation, preventing it in endothelial cells and in the early stages of cancer. It causes apoptosis (programmed cell death) by either activating the mitogen-activated protein kinase 8 pathway or via the DAXX adapter protein. TGFβ also regulate the cell cycle by blocking advancement through the G1 phase of the pathway.11 In pre-eclamptic women, the soluble form of endoglin (sEng) is found to be raised. It is formed by processing of the endothelium bound endothelin and is a product of N-terminal cleavage of the full length Eng.14 This soluble form of endoglin has been found to be at much higher concentrations in pre-eclamptic placentae.

sEng is said to work with sFlt to induce endothelial dysfunction and cause pre-eclampsia. The Karumanchi group has shown that pre-eclamptic placentas have an over expression of mRNA for the gene ENG which encodes for Eng. It has been shown that there is an increase in Eng mRNA by four times in ladies with pre-eclampsia versus normotensive women.1 As sEng is soluble and has the binding site for TGFβ, it binds to circulating TGFβ and decreases its levels.16 It binds to TGFβ1 and TGFβ3 and forms “heterometric association” with the TGFβ receptors I and II.12 This binding prevents the TGFβ1 and TGFβ3 binding to the cell membrane. Therefore, the proangiogenic and vasodilatory affects of these molecules on normal endothelium are not carried out. 13

sEng has been found in the blood of pre-eclamptic women upto 3 months prior to the clinical signs of the disease and its level in maternal blood is proportional to the severity of the diease.16 It has been shown to b raised more in the third trimester compared with the first trimester. 39 This can be seen in Figure 3.

Venkastesha et al. Injected rats with sFLT-1 and sEng and it gave rise to rats with more severe hypertension, protienurea and the HELLP syndrome, than rats with just sEng. Thus it has been hypothesised that these proteins work together to produce the severe clinical signs of pre-eclampsia.1

Serum concentration of sEng and sFlt-1/PlGF ratio in healthy pregnant and nonpregnant women (A). Comparison of sEng and sFlt-1/PlGF ratio between healthy pregnant women and PE patients (B). Values are shown as the mean ± SD. *, P < 0.01. **, P < 0.05.39

P selectin

P selectin, also known as CD62P, is a selectin cell adhesion molecule, the largest of the family. It is expressed in in endothelial cells and in α granules of activated platelets and17 is only transiently upregulated in response to TNF-α and IL-1.18 It has a vital role in inflammatory reactions as it is involved in recruiting and activating leucocytes and in producing the leucocyte-derived tissue factor in coagulation. The soluble form that is found in plasma is shed from the cell membrane of activated platelets. Pre-eclampsia is associated with extreme platelet activation, and therefore there is a great increase in soluble P selectin in the blood of pre-eclamptic women.


ADAM 12 is a member of the ADAM protein family and is involved in cell-cell and cell-matrix interactions during fertilisation, muscle development and neurogenesis. The serum level of ADAM 12 is severely reduced in women who later develop pre-eclampsia.35

Placental P13

Placental protein 13 (PP13) is a protein highly expressed in the maternal placenta and is thought to be involved in maternal vascular remodelling and placental implantation. It is a member of the galectin family of proteins, which are important in cell differentiation and proliferation.34 In a normotensive pregnancy, levels increase throughout all three trimesters, however it has been shown that levels are severely reduced in preeclampsia during the first trimester.32 These reduced levels lead to poor fetal growth33, particularly in early pre eclampsia (<34 weeks gestation). PP13 can therefore be used as a screening tool in early pregnancy for pre eclampsia. It can also be used to differentiate between pre-eclampsia and pregnancy induced hypertension (PIH). PP13 is similar to controls in women with PIH whereas it is reduced during the first trimester in women with preeclampsia.34

PerkinElmer34 did a study on the levels of PP13 in pre-eclmaptic woman (PE), unaffected women (SR) and women who had high risk factors for preeclampsia but were not affected by these or preeclampsia (HR) at different stages of pregnancy. It shows that in a normotensive pregnancy, levels remain steady and decrease slightly at 19-21 weeks. It can be seen that during pre-eclampsia, levels of PP-13 start low during the first trimester but reach normal levels later. Women with risk factors but who did not develop pre-eclampsia had low levels of PP-13 throughout. This is show in figure 5.

AT1 receptor autoantibodies

In normal pregnancy, the renin-angiotensin system (RAS) plays a crucial role in maintaining the homeostatic environment of salts, extracellular fluid volume, vascular resistance, and therefore blood pressure in both the mother and the foetus. It has been shown that in pre-eclampsia, there is an increase in all of the components of the RAS.19 Figure 6 shows the normal renin-angiotensin system:

Renin is produced by the juxtaglomerular cells of the renal arterioles when there is a decrease in blood pressure and circulating sodium chloride (NaCl). This enzyme converts angiotensinogen, which is made in the liver, to angiotensin I and this is the rate limiting step of the RAS. Angiotensin I has no real biological function, and is converted to angiotensin II by the enzyme called angiotensin converting enzyme (ACE). ACE is produced mainly in lung epithelium.20 There are two types of receptors for angiotensin II: AT1 receptors and AT2 receptors. Both are G-coupled receptors but are found in different places.22 Angiotensin II mainly acts through AT1 receptors, which are found predominantly on the surface of smooth muscle cells and the adrenal glands. They act to increase intracellular Ca2+, and when activated causes vasoconstriction and the release of aldosterone. AT2 receptors are found on the foetal kidney and becomes less abundant than AT1 in adult life.21 It is involved in foetal tissue development.19

During pregnancy, the placenta contributes components to the RAS system. Pro-renin, angiotensinogen, ACE, angiotensin I, angiotensin II and AT1 receptors have all been found in placental tissues.19 This is due to the increased oestrogen causing an overexpression of tissue and circulating levels of renin and angiotensinogen. Prorenin also rises two weeks after conception and remains at a high level until delivery.23 Plasma renin and aldosterone are also high during normal pregnancy and as a result, plasma angiotensin II rises. It has been shown that pregnant ladies are resistant to the hypertensive affects of angiotensin II. This reduced sensitivity to components of the RAS is thought to be due to the increased progesterone and prostacyclins, which decrease angiotensin II sensitivity.24 Also, AT1 receptors are inactivated by reactive oxygen species in pregnancy and become monomeric and unsensitive.19 Therefore, a greater stimulus is needed during pregnancy to reach a normotensive state.

However, during pre-eclampsia Merrill et al. have shown that levels of renin, angiotensin I, and aldosterone are lower than in a normotensive pregnancy. ACE are shown to be roughly the same as a normotensive pregnancy. Normally, a reduction in these components of the RAS would cause severe hypotension, however, during pre-eclampsia the AT-I receptors have been shown to increase in sensitivity to angiotensin II. This is thought to be due to the heterodimerisation of the AT-I receptor with the bradykinin receptor, B2. These receptor heterodimers are found in the platelets and in omental vessels of pre-eclamptic women.26 The heterodimers have been shown to increase sensitivity and responsiveness to angiotensin II and increased the resistance to attack and inactivation by reactive oxygen species (ROS).25

In preeclampsia, the levels of angiotensinogen are similar to a normotensive pregnancy.

Pre-clamptic pregnancies have a lower level of renin, angiotensin I, aldosterone and angiotensin II compared to the normotensive pregnant woman. Usually, a decrease in these components of the RAS will cause a decrease in blood pressure, however, the increase in progesterone and prostacyclins during pregnancy decrease angiotensin II sensitivity. It has been shown by Assali et al. that a pregnant woman needs twice as much intravenous angiotensin II to get the same vasomotor response.19

Wallukat et al. in 1999 discovered that women with pre-eclampsia also have an autoantibody that stimulates the AT-1 receptor. It is known as the AT-1 receptor agonist antibody (AT1-AA). The AT1-AA has three main effects: it increases amounts of sFlt-1 and impairs angiogenesis; it stimulates PAI-1 secretion and shallow trophoblast invasion; and it increases ROS production.

As I have said above, sFlt-1 binds to VEGF and PIGF and inhibits their angiogenic actions. During normal pregnancy, sFlt-1 is produced through ANG II stimulation of trophoblast cells via the calcineurin-NFAT pathway.19 In pre-eclampsia, there is a two to five times increase in the amount of placental sFlt-1. VEGF has been shown to increase during pregnancy, however the increase in sFlt-1 production by cytotrophoblasts will reduce its actions and therefore cause a significant reduction in angiogenensis. Therefore, the overall increase in sFlt-1 results in lower VEGF and PIGF, which results in a lower angiogenic state and the presentation of small and hypoxic placentas that are seen in pre-eclamptic placentas. The increase in sFlt-1 may be due to the overexpression of TGFβ3,28 which is due to the upregulation of hypoxia-inducible factor 1-α (HIF-1α). The increase in TGFβ3 limits the trophoblast invasion into the maternal spinal arteries and the deciduas, and this exacerbates the hypoxic state. Cannigia explain that this early trophoblast retardation alters placental gene expression and inhibits the formation of a normal, healthy placenta.

Another hypothesis for the increase in sFlt-1 is due to the production of AT1-AA. It is an agonist to the AT1 receptor and therefore over stimulation of this receptor will lead to an increase in sFlt-1. This oversecretion of sFlt-1 as well as the increase in At-1AA and the placental hypoxia produce a feed forward cycle: the increase in sFlt-1 significantly inhibits angiogenensis and leads to further hypoxia, which in turn produces more sFlt-1.19

Another effect of AT1-AA is that it has been shown to increase PAI-1 secretion, causing shallow trophoblast invasion. AT1-AA activated the AT1 receptors on trophoblast cells, and through the calcineurin-NFAT signaling pathway29, causes release of PAI-1. PAI-1 inhibits urokinas-like plasminogen activator (uPA) which results in reduces conversion of plasminogen to plasmin. As a result, fibrinolysis is decreased, the extracellular matrix doesn't decrease which leads to shallow trophoblast invasion.19 The decreased fibrinolysis and increase fibrosis and the reduced plasmin has been shown to contribute to maternal kidney damage. This is due to the decreased extracellular degradation and the deposition of fibrin which decreases the kidney's permeability.

The third effect of AT1-AA is that it increases reactive oxygen species (ROS) production. ROS are a normal by-product of aerobic respiration, however, when in excess they decrease a cell's anti-oxidant defences and lead to non-specific damage to DNA, proteins ad lipids. This leads to placental damage in pregnancy. The ROS produced are especially harmful to the organogenesis of the developing foetus.30 The ROS is formed in the trophoblasts and vascular smooth muscle cells via NADPH oxidase, which has been shown to be elevated in pre-eclampsia.

Pentraxin 3

Pentraxin 3 (PTX3) belongs to the same family as the C-reactive protein (CRP) and is involved in response to inflammation. Following secretion, PTX3 facilitates pathogen recognition by phagocytes through interaction with several growth factors, extracellular matrix components and activation of the complement cascade. Inflammation is widespread in pre-eclampsia, and thus PTX3 is in abundance in the amniotic epithelium, chorionic mesoderm, trophoblast terminal villi and the perivascular stroma of the placenta through all three trimesters. 4

Neurokinin B

In the late 1990s, a study was conducted to identify the molecules involved in the pathogenesis of pre-eclampsia and there was increased expression of TAC3, the gene which codes for neurokinin B (NKB). TAC3 expression was seen on the outer synctiotrophoblasts49 which allowed direct secretion into maternal blood. There was also expression in the umbilical cord blood which means that NKB could enter the feto-placental circulation and affect the fetus. However its role in the foetus is unknown. NKB is unique to pre-eclampsia, pregnancy and is not associated with any other hypertensive disorders.50

NKB It is a member of the tachykinin family of molecules. Incomplete trophoblast invasion in pre-eclampsia leads to hypoxia and oxidative stress which can be seen as triggers for the release of NKB as a signal to increase placental blood flow. NKB was traditionally classified as a neurotransmitter, however in pre-eclampsia, its levels are shown to be 2.6 times50 higher than in the brain. Therefore, its role in the placenta is endocrine rather than neuronal. Although there is NKB present in the normal placenta, it is ‘switched off' as it has not undergone full procession from its precursor protein. In the pre-eclamptic placenta, NKB is fully processed and therefore it is ‘switched on'.50

NKB has three receptors: NK1, NK2 and NK3, with greatest affinity for NK3 and least affinity for NK1. NK1 has been shown to be associated with vasodilatation and the activation NK3 receptors on the maternal venous circulation are responsible for vasoconstriction and hypertension in pre-eclampsia.50

Page et al showed that a high dose of NKB causes a transient increase in mean arterial blood pressure, and Yang et al. went on to show that the response to NKB is dose related. Low doses cause vasodilatation and a reduction in resting systemic blood pressure through direct modulation of vascular tone. On the other hand, high dose NKB increases resting blood pressure through central and peripheral pathways by increasing the response to angiotensin II.50


In a normotensive pregnant woman, there is an increase in production of insulin by the pancreatic β cells. There is an initial increase in insulin sensitivity; however there is progressive resistance in the second and third trimesters. Insulin resistance is markedly increased in pre-eclamptic pregnancies. Insulin inhibits sex hormone binding globulin (SHBG) which binds free eostrogen and testosterone. Thus, there is an inverse relationship between which will cause an increase in circulating oestrogen and testosterone during pre-eclampsia as a result of the decreased SHBG. The reduced SHBG, estrogen and testosterone can be used as serum markers of pre-eclampsia.2

Insulin increases sympathetic output, muscle blood flow and vascular smooth muscle growth. A test was carried out by Parretti et al. on a group of slim (BMI <25) white pregnant women to rule out any risk factors associated with ethnicity, obesity and metabolic syndrome. They found a direct relationship between insulin resistance and pre-ecalmpsia, however they were unable to establish whether it was a risk factor or part of the pathophysiology of pre-eclampsia.37

Increased insulin resistance is also linked to a decrease in adiponectin, an adiocyte derived cytokine involved in carbohydrate and fat metabolism. It also has anti-inflammatory effects on vascular smooth muscle cells36 and is shown to be protective against diabetes type 2.38 In preeclampsia, serum levels have been shown to be associated with levels of sEng.39 Adiponectin levels are low in the first trimester of pregnancy, however levels are notably different between early-onset and late-onset symptoms which proposes that adiponectin has a different pathogenic role in each case. It has been suggested that it improves insulin sensitivity, which seems paradoxical as the increased insulin resistance causes the reduced adiponectin.


These tables summaries my findings:

Risk factors


Affect on risk of pre-eclampsia

Age >40


Personal history of pre-eclampsia

Increases by Seven fold

Family history of pre-eclampsia


Multiple pregnancy





Insulin dependent diabetes


Chronic hypertension

Increases by 40 fold

Renal disease

Almost triples

BMI >35


Assisted reproduction techniques



Level in pre-eclampsia

Products of oxidative stress


Microparticles from membranes


Activated neutrophils


Plasma lipids


Vascular endothelial growth factor (VEGF)


Placental growth factor


Soluble VEGF receptor 1


Soluble endoglin


P selectin




Placental protein 13




Components of renin-angiotensin system


Pentraxin 3


Neurokinin B


Insulin sensitivity


Insulin resistance


The clinical expression of pre-eclampsia can be explained through the mechanism of over 300 molecules. VEGF and PlGF promote the growth of new blood vessels, however in pre-eclampsia, they are inhibited by the increase in the soluble form of the VEGF receptor 1 (sVEGFR-1).7 Hence, there is reduced angiogenensis and reduced placental perfusion. Renal glomerular cells are highly sensitive to VEGF and its decrease in pre-eclampsia causes renal dysfunction and proteinurea.42 The soluble form of the placental derived TGF-β receptor, sEng, is raised in pre-eclampsia and causes endothelial dysfunction by reducing the proangiogenic and vasodilatatory effects of TGF-β. P selectin and pentraxin 3 are involved in inflammatory rections and there is an increase in these molecules in pre-eclampsia. Placental protein 13 (PP13) is a galectin protein which is involved in proliferation and cell differentiation. It increases through all three trimesters in a healthy pregnancy, however levels are extremely low in pre-eclampsia which causes reduced vascular proliferation and hence reduced blood supply to the placenta. There are also angiotensin receptor 1 autoantibodies (AT1-AA) present in pre-eclampsia. They increase the levelss of sFlt-1 and impair angiogenesis, they stimulate PAI-1 secretion, cause shallow trophoblast invasion and they increase ROS production. Therefore, the spiral arteries suffer from endothelial dysfunction and the woman suffered from pre-eclampsia. There increased expression of TAC3 - the gene encoding for neurokinin B (NKB). NKB has a dose related effect on the arteries and Page et al. have shown that high levels of NKB, as seen in pre-eclampsia, cause severe hypertension in the woman. Pre-eclampsia is also associated with insulin resistance. To answer my title question - ‘The causes of pre-eclampsia: is it a multifactorial disease or is there one main cause' - I can conclude that there is no one main cause of pre-eclampsia. It is a multi-system disease caused by a variety of risk factors and through the action of a range of molecules.

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