Preeclampsia is a multifactorial disorder and an unpredictable syndrome, encircled with many theoretical speculations on its aetiology; it is unique to humans, and is clinically recognised as a hypertensive disorder in pregnancy. Placental ischemia plays a central role in pathology of preeclampsia. This is thought to be due to implantation defects by invasive trophoblast cells. The maternal immune system is also compromised during preeclampsia. An increased oxidative state is observed in most preeclamptic placentas that could result in endothelial dysfunction. The renin angiotensin system expresses lower levels of its components in preeclampsia compared to normal pregnancy, causing possible disorders in blood pressure regulation. In addition it has been observed that preeclamptic women are more prone to development of cardiovascular disease and diabetes in later life, the risk amplifies in those with superimposed preeclampsia. It has also been speculated that foetal programming of cardiovascular disease that occurs during gestation in preeclamptic women increases the chances of CVD in later life for the foetus. Genetic risk factors have been considered, however not very comprehensively. There is yet no definitive treatment for preeclampsia as it is the clinical end point of several physiological disorders, which each require their own approach; therefore prevention of preeclampsia is highly dependent on early detection of hypertension and proteinuria.
Introduction
Pregnancy is a period of essential physiological changes, where many adaptations are required in women’s physiological systems, in order to enable them to be a reliable medium for creating, nourishing and protecting a new life. Respiratory, metabolic, renal, hematologic and cardiovascular changes are prime examples of these modifications. In an event where any of these systems fail to comply with the newly required adaptations, serious complications may arise, which may potentially endanger the mutual wellbeing of the mother and the foetus both.
One of the chief causes of poor outcome in pregnancy is the common complication of raised blood pressure. Hypertensive disorders account for 10% of all complicated pregnancies, with preeclampsia being the most dominating with a 6-8% share (Drost et al., 2010).
Preeclampsia is unique to human’s pregnancy, recognised with hypertension as a key symptom, accompanied with widespread endothelial damage and dysfunction, proteinuria, oedema and platelet aggregation. It is often linked to impaired placentation which compromises placental perfusion, rendering it insufficient. This insufficiency in placental perfusion has often proven to negatively affect foetal growth and wellbeing during gestation and later in life.
The wide spectrum of symptoms that are related to preeclampsia can hint to the magnitude in complexity of this disorder. As a result of growing research and literature in this field it has been suggested that this condition is most probably the result of a group of disorders that converge to form the symptoms that are observed in the clinical diagnosis of preeclampsia.
Amongst the many suggested defective mechanisms that induce the onset of preeclampsia, there are number of mechanisms that have exhibited a more dominant role in pathology of this condition. Endothelial dysfunction, improper invasion of trophoblast cells during gestation, generation of free radicals and consequent oxidative damage to the placenta with defects in the renin angiotensin system have all shown to give rise to cardiovascular complications for both the foetus and the mother.
It has been suggested that preeclampsia continues to affect maternal and foetal health even after pregnancy, many cohort studies have shown that those who have suffered from preeclampsia have a higher chance of developing cardiovascular disease later in life. Despite all the breakthroughs in understanding the principals and mechanisms of preeclampsia, it yet remains to be challenged as a leading cause in maternal and foetal morbidity and mortality.
Trophoblast Invasion in Preeclampsia
It is believed that a lack of successful Trophoblast invasion may play a major role in preeclampsia (Rodeck & Whittle, 2009). Trophoblasts are cells on the exterior of a blastocyst (Lindheimer, Roberts & Cunningham, 2009). These cells eventually develop into part of the placenta and assist with providing important nutrients to the developing embryo. These cells arise during the initial stage of pregnancy. In fact, they are the first cells, which differentiate after fertilization of the egg. The placental villi have a core that is covered by two layers of Trophoblasts. One layer of mononuclear cytotrophoblasts is fused and forms a multi-nucleated layer of syncytiotrophoblast cells, which cover the entire placenta (Lindheimer et al., 2009).
Trophoblasts and Preeclampsia
The invasion of Trophoblasts in humans is an essential part of hemochorial placentation (Bothamley & Boyle, 2009). This is true with many primate species, but especially so with humans in whom the invasion is deeper than any other species examined. It is rare for preeclampsia to be manifested in other species. Therefore, it has been theorized that the deep trophoblastic invasion in humans may be responsible or associated with the condition of preeclampsia (Bothamley & Boyle, 2009).
In a human pregnancy, there are a number of vascular alterations to the spiral arteries (Bothamley & Boyle, 2009). These arteries pass the mother’s blood to the placenta. The change in these arteries is essential and is restricted in the condition of preeclampsia. It is thought that there may be a problem with the Trophoblast invasion which triggers preeclampsia (Bothamley & Boyle, 2009).
Biopsies of the placental bed have been done in order to investigate the possibility that there is a problem with the spiral arteries which results in the condition of preeclampsia (Bothamley & Boyle, 2009). The placentas of the normal pregnancies had unusual structures, which were only identified as spiral arteries after tracing them back to the radial arteries of the myometrium. It was found that the physiological changes in normal pregnancies were not pathological and a fibrinoid matrix had replaced the smooth muscle wall. This matrix had a number of embedded cells, which are likely to have been formed by the invasion of Trophoblasts (Bothamley & Boyle, 2009).
Biopsies have also been done on the placental bed of women suffering from preeclampsia (Lindheimer et al., 2009). In these placentas, there were arterial structures, which could be easily recognized and found in the inner part of the myometrium. It is believed that the lack of physiological changes in these arteries may be caused by insufficient Trophoblast invasion. The preeclamptic placentas only showed evidence of proper Trophoblast invasion in the decidual portion in the spiral arteries. These observations helped researchers understand how maternal blood was properly passed to the placenta (Lindheimer et al., 2009).
Figure1 | (a) Placental bed biopsy of preeclamptic women showing the physiological change of the spiral artery near the decidual junction. This is characterised by the overtaking of fibrinoid (darkly stained with embedded trophoblastic cells (T)) over the smooth muscle layer. (b) Same vessel showing darkly stained Trophoblast (T), using cytokeratin immunostaining. (c) Actin immunostaining, outlining the replacement of the original vascular smooth muscle by fibrinoid. Thickening of the intima (*). (d) Spiral artery undergone limited physiological change. Sign of intimal thickening (*) at the site of Trophoblast invasion (Lyall and Belfort., 2007).
Improper Trophoblast invasion is believed to be a major factor in the majority of preeclampsia cases (Rodeck & Whittle, 2009). The physiological changes which occur in the blood vessels of the placenta as a consequence of this invasion are essential to maintaining suitable maternal blood flow to the placenta. In a normal pregnancy, there is a loss of vascular components, which are musculo-elastic. This causes the arteries to dilate and allows the maternal blood to flow more freely to the placenta. In preeclampsia the lack of Trophoblast invasion results in arteries which are unchanged. These arteries continue to have a significant musculature. They do not dilate and remain narrow. Blood flow to the placenta is reduced. This reduced blood flow is responsible for the condition known as preeclampsia (Rodeck & Whittle, 2009)
Oxidative stress
Throughout recent years oxidative stress has been under extensive study as a major cause of endothelial dysfunction in preeclampsia. Oxidative stress is defined as a disequilibrium between the generation of reactive oxygen species (ROS) and the rate of their consumption by antioxidants (Hung, 2007).
As a result of growing experiments and reports, it has been suggested that oxidative stress may play a key role in onset and development of preeclampsia and is not simply an accompanying condition of this maternal syndrome. This Hypothesis is further supported by growing evidence in hindering effects of oxidative stress on proteins, DNAs and lipids; accompanied with a significant reduction in total antioxidant capacity of both maternal and placental blood, as well as depletion of individual antioxidants which form the first line of defence against an oxidative insult. (Raijmakers et al, 2005). Oxidative stress is a typical example of a pathological process where endothelial cell dysfunction occurs due to combination of various factors.
Aerobic organisms all form and degrade reactive oxygen species and are distinguished into two different categories, consisting of oxygen free radicals and non-radical ROS. Oxygen free radicals are chemical species that contain one or more unpaired electrons which are able to survive on their own and include singlet oxygen the hydroxyl radical, the superoxide anion and nitric oxide. On the other hand, non-radial ROS such as hydrogen peroxide and peroxynitrate anion are molecules that are deficient of unpaired electrons (Hubel, 1999).
Enzymatic processes in cells are the main generators of reactive oxygen species. These processes may occur via the action of oxidases or by electron escaping from mitochondrial electron transport chain. ROS are involved in endothelial cell and mitochondrial dysfunction, modifications to membrane integrity and permeability and modifications to normal enzyme activity via protein denaturation. In addition to these effects, ROS may also be involved in changes to sarcoplasmic reticulum calcium transport, potentially cause inflammatory responses by acting as chemotactic agents and amend signal transduction, cause disruptions to DNA, RNA, protein synthesis and regulation of cell cycle (Hubel, 1999).
An increased Oxidative state has been associated with preeclampsia (Walsh et al., 2000). Direct evidence of increased oxidative stress in the preeclamptic placenta can be established by the elevation of placental and plasma concentrations of 8-epiprostoglandin-F2a (a factor that increases platelet adhesion and diminishes nitric oxide’s anti-adhesive and anti-aggregatory effects) that were found to be up to two fold higher in the uterine lining of women with preeclampsia in contrast to normal pregnant women (Walsh et al., 2000). 8-epiprostoglandin-F2a is produced as a consequence of free radical induced peroxidation of arachadionic acid and acts as a potent vasoconstrictor, platelet activator and mitogen (Roberts and Morrow, 1995).
Figure2 | Suggested link between placental oxidative stress and maternal vascular dysfunction. It is suggested that free radical generation via xanthine oxidase/NAD(P)H oxidase in the placenta activates maternal neutrophils, this activation with maternal endothelial activation results in formation of a malicious circle of events in which it may result in sustained NAD(P)H oxidase activity and release of superoxides (Adapted from Raijmakers et al., 2004).
Rise in generation of superoxides have also been detected in preeclamptic placentae (Sikkema et al., 2001) with isolated Trophoblast cells capable of generating significantly greater concentration of superoxide (Wang and Walsh 2001). The generation of superoxide in the preeclamptic placentae may be the result of xanthine oxidase (and oxidising enzyme) activity due to hypoxia/re-oxygenation of the placenta (Kirshner and Fantini, 1994).
Increased Superoxide may be linked to findings that the number of mitochondria in preeclamptic placentae is significantly increased, with 47% more mitochondrial protein and a 56% increase in citrate synthase activity associated with the condition (Wang and Walsh, 1998). In addition to increased mitochondrial number, preeclamptic placentae mitochondria have been found to establish an abnormal appearance (Jones and Fox, 1980). Such variations in mitochondrial number and morphology may result in the increased leakage of electron from the electron transport chain and subsequent production of superoxides which in turn will promote oxidative stress in the placenta and endothelial cell dysfunction (Wang and Walsh, 1998).
Free radical damage appears to play a major role in preeclampsia. The placenta is the likely source of origin, but oxidative stress is compounded by the later contribution of superoxides, generated maternally. Large clinical trials are currently underway to determine whether antioxidants offer any medical benefit.
Changes in membrane integrity and its associated functions have been recently linked to lipid peroxidation, this is referred to as a central feature of oxidative stress; this link is assessed by various methods including quantification of peroxidation’s end products (Llurba et al., 2004). Lipid hydroperoxides are the first main products of lipid peroxidation. In a study of 53 preeclamptic and 30 healthy women it was established that plasma lipid hydroperoxide levels are considerably higher in preeclamptic women compared to healthy controls (Llurba et al., 2004). The plasma levels of this product were higher in more serious cases of the disease.
Figure 3 | (A) Lipid hydroperoxide levels in normal and preeclamptic women. (B) Lipid hydroperoxide levels in mild and severe preeclampsia, compared to healthy pregnant controls (Llurba et al., 2004).
Elevated levels of circulating lipid peroxides in conjunction with declining antioxidant activity in preeclamptic patients further supports the hypothesis that endothelial dysfunction in preeclampsia is conceivably linked to free radical generation (Llurba et al., 2004).
The Vascular Endothelium
The Vascular Endothelium is a continual single layer of cells that encompass the blood vessels of the entire vascular system. Since all normal blood vessels have continuous blood flow, the endothelium comes under constant exposure to mechanical forces such as shear stresses produced by the pulse pressure of the vascular system and fluctuations in blood flow. The endothelium is actively involved in control of blood flow, vessel permeability to solutes and water, hemostasis and thrombosis (Born and Schwartz., 1997).
Figure 4 | The autonomic nervous system, the endothelium and intrinsic vascular smooth muscle reflexes influence the vascular tone (Lyall and Belfort., 2007).
Most of the endothelium activities such as the control of blood flow and vessels permeability relies on the preservation and actions of an operative layer of cells, the endothelial cells. This prompts the endothelial cells to be flexible in adapting to new physiological conditions and respond efficiently to physical stresses such as a change in oxygen tension. This adaptation and flexibility is made possible by active amendments in cellular shape and maintenance of the internal structure, in a bid to oppose externally induced pressure variations on the cells. Endothelial cells like muscle cells contain all the contractile apparatus such as actin and myosin II, it is this feature that enables them to transform their shape by changes in their cytoskeleton in reaction to physical forces.
Stimulation of endothelial receptors results in activation of pathways within the endothelium that results in a change in underlying vascular smooth muscle tone in a relaxing or constrictive manner. Endothelium-derived vasoactive factors are substances secreted by endothelial cells which influence the arterial diameter and consequently affect the vascular resistance (Halliday A, et al., 1998). Some endothelium derived factors cause vasoconstriction such as endothelin-1 and others cause relaxation of the vessels such as nitric oxide and prostacyclin.
Endothelial Cell Dysfunction
The vascular integrity of the endothelium is maintained by healthy endothelial cells which in addition to their vital role in prevention of platelet adhesion, also impact the tone of the vascular smooth muscle beneath. As all cells are prone to damage, endothelial cells are no exception and may also be damaged, this results in increased capillary permeability, platelet coagulation and vasoconstriction (Flavahan and Vanhoutte, 1995). The conditions described upon endothelial cell damage are all found in preeclapmsia, this could be a significant observation which leads to the assumption that in part preeclapmsia is an endothelial disorder (Roberts et al., 1989).
Endothelial cell damage can be identified before the onset of preeclampsia’s physiological symptoms. This is identified by an increase in circulating markers of endothelial dysfunction such as Von Willebrand factor and fibronectin. Within these markers the levels of fibronectin and antigens linked to Factor 8 are specially high in women whose pregnancies are later complicated with preeclapmsia (Roberts and Redman, 1993).
In a normal functioning endothelial cell, endothelial nitric oxide (eNOs) plays an important role in determining vascular diameter by acting as a vasodilator in a typical vessel. It is also known to actively play a part in inhibition of platelet aggregation and adhesion. In other words Endothelial NO plays a fundamental role in maintaining vascular homeostasis (Wang et al., 2004). Nitric oxide is synthesized from L-arginine and oxygen in the endothelial cell. Its release is stimulated by shear stresses and neurotransmitters such as acetylcholine. Once NO is released from the endothelium it targets the underlying vascular smooth muscle and induces the production of cyclic guanosine monophosphate (GMP). GMP prompts the smooth muscle cells to relax. It is the cooperation of these relaxing factors such as NO with other vasoconstrictive factors that bring about the balanced control of vascular tone. Hence an effectively operational endothelial cell is crucial to a normal vascular tone and important in gestational vascular adaptations required during pregnancy
Preeclampsia’s main pathophysiological feature is known to be a dysfunction in the vascular endothelium, hence it is expected that this will bring on impairments to the endothelial nitric oxide activity and other endothelial regulatory factors. The pathophysiological changes in preeclampsia are unanimously indicative of a maternal circulation under high vasoconstriction, which may be the indication of low levels of vasodilators released by the endothelium as a result of this impairment (Wang et al., 2004).
In a study it was revealed that endothelial cells in women with preeclampsia exhibit an altered endothelial junction and show elevated endothelial permeability with a declined eNOs activity (Wang et al., 2004). This increase in permeability is suggested to be influenced by a chemokine called Interleukin 8 (IL-8). IL-8 is produced by both macrophages and is also synthesised in endothelial cells and is stored in vesicles called the Weibel-Palade bodies (Wolf et al., 1998). In an experiment conducted by scientists at Louisiana state university in 2004 it was demonstrated that IL-8 could be recognised as a contributory agent in the increased endothelial permeability observed in preeclampsia. Wang et al., 2004).
Figure 5 | The ratio change of endothelial permeability in normal (Nor-ECs) and preeclamptic (PE-ECs) pregnancies. Normal endothelial cells show a greater response to IL-8 at higher concentrations (25pg/mL) than those of preeclamptic endothelial cells (Wang et al., 2004).
Endothelial cells from normal and preeclamptic pregnancies where tested by being treated with IL-8 in order to observe the premiability response of the endothelial cells to this stimulation. It was discovered that endothelial monolayer cells in women with preeclampsia were significantly more permeable compared to cells from normal pregnancies. Granted that individual values obtained from the IL-8 experiment clearly showed that permeability is increased in endothelial cells, however as seen in figure 2 above, as well as the endothelial cells being affected by changes in concentrations of IL-8 “ the ratio change of increased prermeability is less in endothelial cells from preeclampsia in response to IL-8 at a higher concentration”. This may be part of the unpredictable endothelial functions that are observed in preeclamptic women (Wang et al., 2004).
Renin-Angiotensin system (RAS)
The Renin-Angiotensin System is a signalling cascade, playing a regulatory role in controlling blood pressure and maintains a balanced electrolyte concentration. RAS is typically described by referring to mechanisms that happen in the kidney. These include the release of renin by cells, “macula densa” of the kidneys mediated by prostaglandins.
Renin is transformed into a 10 amino acid long peptide in the liver called angiotensin-1(ANG I) (Irani and Xia, 2008).This mechanism continues by transforming ANG I a non-biologically active molecule of the cascade to a more reactive peptide, this is achieved by cleaving it using the angiotensin converting enzyme (ACE), mainly found in the lung endothelium. This results in production of angiotensin-2 (ANG II), a highly vasoconstrictive and biologically active hormone (Irani and Xia, 2008).
There are two main types of angiotensin receptors (AT), AT1 and AT2. The effects of ANG II are specifically evident when it comes into contact with these receptors where they mediate its actions, causing vasoconstriction and heightened sympathetic activities accompanied with increased aldosterone secretion.
Role of Renin-Angiotensin system in Preeclampsia
During a normal pregnancy the RAS undergoes variations in response to this condition. These changes can be seen in a form of elevated levels of renin due to extra renal released locally by the maternal decidua and ovaries (Irani and Xia, 2008). In addition the liver is up regulated to synthesise more angiotensinogen; this surge in synthesis is due to the growing placenta’s circulating oestrogen. Increased angiotensinogen levels result in increased aldosterone in the serum and more ANG II as a consequence of the conversion mechanism that follow angiotensinogen. However the increased ANG II levels in pregnant women with no complications are less effective than normal women.
In 1961 Assali et al. carried out a rather exceptional study where they found that pregnant women whose pregnancies are not complicated require a double dose of intravenous ANG II, in order to show the same vasomotor effects that ANG II shows with a single dose in normal non pregnant women. It was speculated that this was due to de-sensitising effects of progesterone and prostacyclins on ANG II. So as their levels rise during pregnancy ANG II sensitivity decrease likewise (Irani and Xia, 2008).
Additionally the way that AT1 receptors behave in normal pregnancies may be a reason for the decreased sensitivity of angiotensin II. Since in the course of pregnancy there is an increase in reactive oxygen species, the monomeric AT1 receptors are inactivated, the rise in ROS renders them ineffective to interactions with ANG II (Irani and Xia, 2008). By analysing these findings we can gain a better appreciation as of why there is a reduction in sensitivity to ANG II in normal pregnant women. These observations help to gain a better understanding and greater means of comparison when looking at complicated pregnancies, in this case those affected with preeclampsia.
Table 1 | Serum RAS levels in normotensive and preeclamptic pregnancies versus non-pregnant women. In normal pregnancies a general increase in levels of circulating RAS components is observable, whereas preeclamptic women do not show a change as similar. Legend: ++, greatly increased over non-pregnant; +, slightly increased over non-pregnant; =, same as non-pregnant; –, decreased compared to non-pregnant (Merrill et al., 2002).
In preeclampsia the RAS exhibits alterations in some of its features in comparison to an uncomplicated pregnancy. Normotensive pregnancies are all accompanied with a rise in circulating components of RAS; despite the exception of angiotensin converting enzyme, where its levels do not change significantly (Irani and Xia, 2008). However in 2002 Merrill et al. showed that the changes observed in normotensive pregnancies are different to preeclamptic women. As observed in Table 1, it was demonstrated that circulating levels of renin, aldosterone and ANG-I are considerably lower in preeclamptic women compared to those with uncomplicated pregnancies. ANG-(1-7), a vasodilatory member of the renin angiotensin system; drops significantly in preeclamptic women where ACE levels almost stayed the same (Merrill et al., 2002).
ANG-(1-7) is a peptide produced by several tissues all through the body, such as kidney and the ovary. The significant drop in ANG-(1-7) levels in preeclamptic women compared to those in normal pregnancy state sparks an interest in identifying its potential role in preeclampsia . ANG-(1-7) can be produced directly from ANG I without the need of ACE. It can also be formed by the actions of several enzymes on ANG II by removing an amino acid from its C-terminal. In an experiment carried out on rats proximal tubules by Handa RK, it was demonstrated and suggested that ANG-(1-7) does not only interact with typical AT1 and AT2 receptors, but it may also act through its own specific receptor.
Uteroplacental RAS
The uteroplacental unit is essentially important in pregnancy as the signalling cascade is influenced by the foetal and maternal tissue both. Therefore in addition to the circulating RAS, there are also modulations in the uteroplacental RAS; this difference is observed in a form of up regulated expression of AT1 receptors in the maternal decidua of preeclamptic women, there is no resemblance between uteroplacental RAS and the circulating RAS changes in preeclampsia (Herse et al., 2007).
In the same experiment carried out by Herse et al. it was observed that preeclamptic decidua did not show heightened levels of renin in contrast to normal placentas. These findings contradicted to prior observations carried out by Shah et al. who believe that the maternal decidua is a secondary site for activation of RAS, where the locally produced ANGII enters the maternal circulation but regardless of its small quantity it is thought to be enough to down regulate the production of ANGII in the kidneys (Irani and Xia, 2008).
Figure 6 | A, RT-PCR verification of AT1 receptor results from decidua of preeclamptic women showing the increased number of AT1 receptors in preeclampsia (Herse et al., 2007).
Chymase production of ANG II and ET-1-(1-31)
Chymase is a serine protease released by mast cells and smooth muscle cells; this enzyme is an ACE independent ANG II producing enzyme that generates ANG II in large and is able to inactivate the vasodilator bradykinin. In preeclamptic women, the levels of Chymase in the Trophoblast cells within the placenta are considerably higher in comparison to normotensive women (Irani and Xia, 2008). In an experiment carried out on transgenic mice it was discovered that Chymase derived from human vessels, results in all symptoms observed in preeclamptic women, including increased blood pressure, thickening of tunica media and vasoconstriction (Ju et al., 2001).
Figure 7 | Medial thickening in the mesenteric artery of 10 to 12 week old mice. (A) A pentachrome staining showing the medial thickening of the mesenteric artery in the mice with over expressed Chymase (strain b) in comparison to three control mice (a, c, d). This thickening results in narrowing of the vessels lumen which may consequently result in increased blood pressure. (B) Quantification of media to lumen ratio showed a 93% increase in the mesenteric artery from mice with Chymase over expression compared with control mice. Adapted from (Ju et al., 2001).
ET-1-(1-31) is a 31 amino acid long member of the endothelin family. There is evidence that Chymase is involved in production of this endothelin through a biosynthetic pathway by cleaving the big endothelin-1 (ET-1). ET-1-(1-31) role is best described as a potent vasoconstrictor, predominantly found in the umbilical artery, where it could have significant effects on foetal vasculature and may restrict intrauterine growth. Therefore it could be a potential factor contributing to the hypertension observed in preeclampsia (Irani and Xia., 2008).
Preeclampsia and future Cardiovascular Disease (CVD)
Over the past few years, as a result of further research on female gender specific risk factors for CVD, it has been proposed that complicated pregnancies can be regarded as significant risk factors in CVD. Preeclampsia and CVD have many common risk factors such as hypertension, endothelial dysfunction, insulin resistance, obesity and hyperglycaemia. These common risk factors suggest a possible mutual basis to these two conditions and it has been proposed that the metabolic syndrome may be a mechanism mutual to both preeclampsia and CVD (Lindheimer et al., 2009).
Figure 8 | Common pathophysiology between cardiovascular disease (CVD) and preeclampsia (PE) (Baker and Kingdom., 2004).
Women who have had multiple births are two times more likely to suffer from ischaemic heart disease than those with a single pregnancy; meanwhile normotensive women and those with uncomplicated pregnancies are at a lower risk of developing CVD further on in life in comparison to women with complicated pregnancies (Rodie et al., 2004).
Hypertensive disorders in pregnancy such as preeclampsia have been linked to increased risk of CVD in women later in life (Lindheimer et al., 2009). Risk of developing diseases such as chronic ischeamic heart disease, angina pectoris and thromboembolism, is significantly higher in women with a history of preeclampsia compared to those women whose pregnancies were not complicated with hypertension (Rodie et al., 2004).
By exploring the potential relationship between CVD, normal hypertension and preeclampsia, it has been shown that mortalities from ischaemic heart diseases were mainly constituted of women who have had preeclampsia, compared to women with hypertension only (Jonsdottir et al., 1995). Therefore this study suggests that hypertension alone is not the main factor resulting in increased post-partum CVD risk, whereas the metabolic agitations linked with preeclampsia may be the prime factors for this increase in CVD risk for women with a history of preeclampsia.
Superimposed Preeclampsia
A number of studies show an increase in prenatal mortality in women who had been diagnosed with hypertension before the 20th week of gestation, which did not suffer from superimposed preeclampsia. Superimposed preeclampsia is the development of preeclampsia in patients who have already affected by a chronic hypertensive vascular or renal disease prior to pregnancy. The hypertension must antedate the pregnancy, and a rise of 30 mmHg or 15 mmHg in systolic or diastolic blood pressure respectively is required to diagnose the patient with superimposed preeclampsia.
However, nearly all studies carried out on women who have had chronic hypertension and superimposed preeclampsia, collectively and unanimously have associated this situation with elevated cases of perinatal morbidity and mortality in all reports. In a study, 10074 Caucasian and 2880 African American women were divided into four groups constituted of those with and without chronic hypertension in addition to another two groups consisting of those with and without superimposed preeclampsia (Lindheimer et al., 2009). Expectedly the perinatal mortality rates were 2-3 times higher amongst women with chronic hypertension, but more interestingly was the 6-10 fold rise in rates of prenatal death among the group with both chronic hypertension and superimposed preeclampsia. Therefore the combination of existing maternal disease and preeclampsia results in an aggravated situation, risking foetal health and maternal wellbeing.
In addition to the relationship between chronic hypertension and preeclampsia and the result that it has on foetal mortality rates, another disorder also closely follows the trend. Women who’ve had suffered from diabetes before their pregnancy were more prone to experience a perinatal death if their pregnancy was also complicated with preeclampsia, compared to diabetic pregnant women who were not preeclamptic (Garner et al., 1990). Garner et al. recorded that the perinatal mortality rates for normotensive diabetic patients were considerably lower than preeclamptic diabetic patients. In a group study of 1000 preeclamptic diabetic women, 60 were subject to perinatal death; whereas in the other test group including pregnant women with diabetes alone, a substantially lower rate of 3/1000 perinatal deaths were recorded.
Therefore it is clear that women suffering from pre-gestational diabetes and hypertension are more likely to be affected by complicated perinatal outcomes. However if these conditions are convoyed with superimposed preeclampsia, the perinatal consequences deteriorate even further, increasing the possibility of perinatal mortality. In addition, biochemical risk markers associated with CAD, including uric acid, have been used to predict neonatal morbidity and mortality amongst preeclamptic women, whom high levels of such markers are observed in, which are high early in their pregnancy (Lindheimer et al., 2009).
Metabolic syndrome, preeclampsia and CVD
The multisystemic and complex complications that preeclampsia brings about for the patient is thought to be multifactorial. As the search for possible aetiologies of this disorder continues, the possible contribution of the metabolic syndrome (syndrome X) has been of some interest in this field. Metabolic syndrome is a collective term referring to a gathering of metabolic disorders linked to diabetes mellitus type II, obesity, hypertension and atherosclerosis.
These characteristics are often observed in women with a history of preeclampsia whose health have been compromised after the disorder (Lindheimer et al., 2009). Typical factors that contribute in the pathogenesis of preeclampsia such as microvascular dysfunction, endothelial dysfunction and metabolic disorders are similar to the chain of events that result in development of atherosclerosis; as a result of this relation it is thought that remote cardiovascular disease and preeclampsia may both be derivatives of the metabolic syndrome (Lindheimer et al., 2009).
It has been shown in several studies that the postpartum state is by no means the ending point for all the metabolic and vascular complications that preeclampsia has caused. On the contrary majority of follow up studies reported an increase in systolic and diastolic blood pressure, higher lipid contents, raised total cholesterol levels with greater expressions of vasoconstrictive elements in the plasma (Sikkema et al., 2001).
Table 2 | Postpartum characteristics according to pregnancy outcome; increased BMI, SBP and DBP are apparent in postpartum characteristics of women with a history of preeclampsia. Family history of CVD is defined as coronary artery disease, myocardial infarction, or cerebrovascular disease in any first- degree relative (Thadhani et al., 2004).
As a result there are rising evidences that suggest being predisposed to the metabolic syndrome at the pre-gestational period, increases the likelihood of developing preeclampsia during pregnancy and more susceptible to developing hypertension, obesity, type 2 diabetes mellitus and all other CVD risk factors that ultimately give rise to cardiovascular diseases (Lindheimer et al., 2009).
Preeclampsia and Foetal Origins of Cardiovascular Disease
Although the lifestyle choices, diet and amount of exercise that an individual chooses to pursue throughout life has a significant effects on one’s health, there is an additional factor that is often undermined while looking at possible causes of diseases. The “foetal origin” hypothesis suggests that the environment, in which a foetus develops during the gestational period and the adaptations that it develops during that time, interferes with the foetus’s possible susceptibility or grounds for development of future diseases (Hocher, 2007).
Adult hypertension, insulin resistance and dyslipidaemia are factors leading to increasing number of cardiovascular diseases and non-insulin dependent diabetes which are thought to have originated from adaptations that the foetus develops as a result of inadequate nutrition. This insufficiency in nutrition may have occurred due to maternal under nutrition or insufficient placental perfusion. Insufficient placental perfusion may occur as a result of changes in the spiral arteries, which is an essential adaptation in normal pregnancy however restricted in the condition of preeclampsia. These arteries are the chief transporters of maternal blood to the placenta; hence their malfunctioning results in inadequate blood supply to the placenta and consequently affect the foetal growth.
A classical risk factor that displays the occurrence of foetal programming during pregnancy is a low birth weight that is due to unbalanced foetal growth (Hocher, 2007). Poor nutrition in early life has been repeatedly linked to low birth weight and development of cardiovascular disease in later life; however it has been suggested that other factors such as administration of low dose steroids during pregnancy seem to adversely affect foetal birth weight which consequently results in foetal programming for future CVD in later life (Hocher, 2007).
However, recent animal studies have suggested that the foetal programming that occurs during pregnancy may not exclusively have an impact on the birth weight, and other factors may also be affected. Putting pregnant rats on a high protein diet and observing their offspring’s birth characteristics demonstrated this. It was concluded from this study that a high protein diet in a normal pregnant rat resulted in foetal programming of blood pressure, food efficiency as well as body weight (Hocher, 2007).
Thus it is believed that inadequate nutrition during gestational period as a result of insufficient placental perfusion due to improper adaptation of spiral arteries in preeclampsia results in foetal growth restrictions, which have been associated with increased risks of CVD development in later life. Although genetic factors have also been shown to interfere with foetal programming of CVD, it yet remains to be an area of growing interest until a conclusive proposition is established (Hocher, 2007)
Management of Preeclampsia
Diagnosis
An important part of managing preeclampsia is a proper diagnosis (Baker & Kingdom, 2004). This has been attempted using a number of different maternal blood and urine tests. Unfortunately, the majority of these instruments have not proven reliable. These diagnostic instruments have been graded on a scale of A to D with A being the most accurate. Table 1 below shows the accuracy of many of these instruments:
Table 3 | Maternal tests for preeclampsia, (Baker and Kingdom., 2004)
According to Baker & Kingdom (2004) the only grade A diagnostic instrument for preeclampsia which can be obtained from the maternal fluids is urinary dipstick testing that indicates proteinuria. This can be considered a diagnostic instrument with high levels of accuracy. Doppler velocimetry of the umbilical artery is relatively accurate and can be considered as a grade B method of diagnosis. Another diagnostic instrument that is relatively accurate and can be considered to be grade B is the measurement of serum uric acid (Baker & Kingdom, 2004).
Prediction with Blood Pressure Measures
The many adverse health consequences of preeclampsia, and its difficulty for accurate diagnosis, have led researchers to look for possible methods of predicting these pathological problems. One method, which has been attempted in a number of studies, is to determine possible problems with preeclampsia by measuring the diastolic and systolic blood pressure as well as mean arterial pressure. A meta-analysis (Cnossen et al., 2008) analyzing 34 studies of more than 60,000 women was conducted. This amounted to more than 3300 cases of preeclampsia. This analysis indicated that when blood pressure is used during the first or 2nd trimester the mean arterial pressure is the best predictor of preeclampsia (Cnossen et al., 2008). It is more useful than diastolic or systolic blood pressure. It is also a better predictor than an increase in blood pressure. These results can be seen in figure 2 below:
Figure 9 | sensitivities of systolic, diastolic, and mean arterial blood pressure, (Cnossen et al. 2008)
Expectant Therapy
A number of methods have been developed to reduce the negative effects of preeclampsia (Baker & Kingdom, 2004). One approach has become known as expectant therapy. In this type of treatment the delivery is delayed until there is a reason for shortening the length of pregnancy. Aggressive management of preeclampsia limits the gestation period to less than 34 weeks. With expectant therapy this may not be necessary and a longer gestation time can sometimes be achieved. Women on both types of therapies routinely receive antihypertensive medications and corticosteroids (Baker & Kingdom, 2004).
A study was done of 133 women suffering from preeclampsia. All were being managed with corticosteroids and antihypertensive medications. The expectant therapy increased the average length of gestation by 2 weeks. This significantly reduced neonatal morbidity (Baker & Kingdom, 2004). The results of the expectant versus aggressive management are shown below:
Table 4 | Expectant versus aggressive management of preeclampsia, (Baker & Kingdom., 2004).
Antihypertensive Medications
The use of antihypertensive medications for patients suffering from preeclampsia has significantly increased during the past 25 years (Baker & Kingdom, 2004). This has been associated with a decrease in deaths of mothers due to hypertensive disorders and cerebral complications. Unfortunately, intracranial haemorrhaging is still the most common cause of death in women suffering from preeclampsia. Many have seen this as reflecting a failure of proper antihypertensive treatment. There is not consistent agreement on the best antihypertensive medication to use or the appropriate threshold at which treatment must be deemed necessary. It is agreed that the goal of antihypertensive treatment for preeclampsia is to prevent damage to organs (Baker & Kingdom, 2004).
A number of antihypertensive medications are now routinely used with women suffering from preeclampsia (Baker & Kingdom, 2004). Hydralazine is commonly used and works by relaxing the smooth muscles of the arteries. Other medications, which are frequently used, consist of Labetalol, Nifedipine, and a variety of calcium channel blockers (Baker & Kingdom, 2004).
Conclusion
Preeclampsia is a syndrome, and no single marker can be used to reflect all its important pathophysiological changes. The variability amongst different clinical presentations is a clear identification of the complex underlying pathology of this condition and it further supports the idea of preeclampsia being a non-organ specific disorder, but a collection of maternal responses to a pathologically complicated pregnancy.
The data obtained from the conducted studies clearly indicate the significance of defective cytotrophoblastic invasion and the subsequent spiral arteries modifications in preeclampsia, and the unfavourable outcomes that it has on foetal growth and maternal circulation.
Placental dysfunction is the main pathophysiological characteristic of preeclampsia that is known to result in poor placental perfusion, which triggers a tissue hypoxia state, in which an oxidative damage may be imminent in the tissue. Towards late pregnancy the oxidative damage usually intensifies giving rise to endothelial dysfunction and a maternal hyper immune response which is understood to give rise to the clinical symptoms of preeclampsia.
The renin angiotensin system (RAS) is known to actively regulate blood pressure and body fluid levels, however irregularities of the RAS in preeclampsia expressed by lower than normal levels of renin, aldosterone and ANG-I have shown to give rise to hypertension. In addition, chymase’s production of ANG-II and ET-1-(1-31) a potent vasoconstrictor found predominantly in the umbilical artery has been found to cause severe hypertension. These changes are also true for the uteroplacental RAS which is regulated by the foetus and mother’s both, hence affecting the foetus too.
Preeclampsia is proven to have long term effects on both the maternal and foetal health later in life. These long term effects are usually linked to cardiovascular disease and diabetes. As the result of many cohort studies, it was determined that women with a history of preeclampsia had a higher chance of developing CVD and diabetes, however those who suffered from superimposed preeclampsia are even at a higher risk of CVD. Foetal programming of CVD has shown to have links with preeclampsia as well as genetic factors. It is believed that the foetuses programming of future CVD occurs in gestation as a response to the stress it is going under, such as insufficient placental perfusion and malnutrition.
Regardless of preeclampsia’s severity and spread, there is yet to be a conclusive theory addressing a single causative factor for this multi-organ disorder. There is the expected possibility that this disorder is the clinical end point of various contributory factors (Tranquilli and Landi, 2010), and the prospects of finding a single cause for this condition is unlikely.
References
- Baker, P. N., & Kingdom, J. C. (2004). Preeclampsia, current perspectives on management. London: Parthenon Publishing.
- Born GVR, Schwartz CJ. (1997) Vascular Endothelium: Physiology, Pathology, and Therapeutic Opportunities, New Horizon Series. Stuttgart, Germany: Schattauer Verlagsgesellschaft mbH 3.
- Bothamley, J., & Boyle, M. (2009). Medical conditions affecting pregnancy and childbirth. Oxford: Radcliffe.
- Cnossen, J. S., Vollebregtn, K. C., Vrieze, N. D., Riet, G. T., Mol, B. W., & Franx, A. , et al. (2008). Accuracy of the mean arterial pressure and blood pressure measurements in predicting preeclapmsia:systematic review and meta-analysis. BMJ, 336, 1-7.
- Drost, J. T., Maas, A. H. E. M., Van Eyck, J. & Van Der Schouw, Y. T. (2010). Preeclampsia as a female-specific risk factor for chronic hypertension. Maturitas, 67, 321-326.
- Flavahan, N. A. and Vanhoutte, P. M. (1995). Endothelial cell signalling and endothelial cell dysfunction. Am. J. Hypertens., 8, 28S–41S.
- Florian Herse, Ralf Dechend, Nina K. Harsem, Gerd Wallukat, Jürgen Janke,Fatimunnisa Qadri, Lydia Hering, Dominik N. Muller, Friedrich C. Luft and Anne C. (2007). Dysregulation of the Circulating and Tissue-Based Renin-Angiotensin System in Preeclampsia. AHA. (1), 2-7.
- Garner P, D’Alton M, Dudley D, Huard P, Hardie M (1990). Preeclampsia in diabetic pregnancies. Am J Obstet Gynecol.; 163:505–508.
- Halliday A, Hunt BJ, Poston L, Schachter M (1998). From Physiology to Pathophysiology. Cambridge, UK: Cambridge University Press
- Herse F, Dechend R, Harsem NK, Wallukat G, Janke J, Qadri F, et al (2007). Dysregulation of the circulating and tissue-based RAS in preeclampsia. Hypertension; 49(3): 604–11.
- Hocher, Berthold, (2007). Foetal programming of cardiovascular diseases in later life – mechanisms beyond maternal undernutrition. J Physiol , 579.2, 287–288
- Hubel CA. (1999) Oxidative Stress in pathogenesis of preeclampsia. Society for Experimental Biology and Medicine (New York, N. Y.) 22: 222-235
- Hung, J.-H. (2007). Oxidative Stress and Antioxidants in Preeclampsia. Journal of the Chinese Medical Association, 70, 430-432.
- Irani, R. A. & Xia, Y. (2008). The Functional Role of the Renin-Angiotensin System in Pregnancy and Preeclampsia. Placenta, 29, 763-771.
- Jonsdottir LS, Arngrimsson R, Geirsson RT, Sigvaldason H, Sigfusson N (1995). Death rates from ischemic heart disease in women with a history of hypertension in pregnancy. Acta Obstet Gynecol Scand 74(10): 772–6.
- Ju H, Gros R, You X, Tsang S, Husain M, Rabinovitch M (2001). Conditional and targeted overexpression of vascular chymase causes hypertension in transgenic mice. Proc Natl Acad Sci U S A; 98(13):7469–74.
- Kirschner RE, Fantini GA (1994) Role of iron and oxygen-derived free radicals in ischemia-reperfusion injury Journal of American Coll Surgery 179: 103-117
- Lindheimer, M. D., Roberts, J. M., & Cunningham, F. G. (2009). Chesley’s hypertensive disorders in pregnancy. (3rd ed.). London: Academic Press.
- Llubra, E., Gratacos, E., Martin-Gallan, P., Cabero, L. & Dominiguez, C. (2004). A comprehensive study of oxidative stress and antioxidant status in preeclampsia and normal pregnancy. Free Radical Biology and Medicine, 37, 557-570.
- Merrill DC, Karoly M, Chen K, Ferrario CM, Brosnihan KB (2002). Angiotensin-(1–7) in normal and preeclamptic pregnancy. Endocrine; 18(3): 239–45.
- Raijmakers, Dechend, Poston, Maarten T.M., Ralf, Lucilla, (2004). Oxidative Stress and Preeclampsia. Rationale for Antioxidant Clinical Trials. Hypertension, 98320.01, 2-5
- Ravi Thadhani Ashi Daftary, Alia S. M. Shakir, Ellen W. Seely, James M. Roberts, (2004). Angiogenesis and Insulin Resistance Preeclampsia and Future Cardiovascular Disease: Potential Role of Altered. endocrinology & metabolism, 89, 6239-6243
- Roberts LJ, Morrow JD (1995) The isoprostanes: Novel markers of lipid peroxidation and potential mediators of oxidant injury. Advances in Prostaglandin Thromboxane and Leukocyte Research 23: 219-224
- Roberts, J. M. and Redman, C. W. G. (1993). Preeclapmsia: more than pregnancy-induced hypertension. Lancet, 341, 1447–51.
- Roberts, J. M., Taylor, R. N., Musci, T. J., et al. (1989). Preeclampsia: an endothelial cell disorder. Am. J. Obstet. Gynecol., 161, 1200–4.
- Rodeck, C. H., & Whittle, M. J. (2009). Foetal medicine: basic science and clinical practice. (2nd ed.). Amsterdam: Elsevier.
- Sikkema JM, Valk HW, de Huisjes AH, et al (2001) Insulin resistance in women with a history of early onset and late onset preeclampsia. J Soc Gynecol Investig 8:580.
- Tranquilli, A. L. & Landi, B. (2010). The origin of preeclapmsia: From decidual “hyperoxia” to late hypoxia. Medical Hypotheses, 75, 38-46.
- Vanessa A. Rodie, Dilys J. Freeman, Naveed Sattar, Ian A. Greer, (2004) Preeclapmsia and cardiovascular disease: metabolic syndrome of pregnancy? Atherosclerosis, Volume 175, Issue 2, Pages 189-202.
- Walsh SW, Vaughan JE, Wang Y, Robers LJ II (2000) Placental isoprostane is significantly increased in preeclampsia. FASEB Journal 14:1289-1296
- Wang Y, Walsh SW (1998) Placental mitochondria as a source of oxidative stress in preeclampsia. Placenta 19: 581-586
- Wang, Y., Gu, Y., Zhang, Y. & Lewis, D. F. (2004). Evidence of endothelial dysfunction in preeclampsia: decreased endothelial nitric oxide synthase in preeclampsia. American Journal of Obstetrics and Gynecology, 190, 817-824.
- Wolff B, Burns AR, Middleton J, Rot A (1998). “Endothelial cell “memory” of inflammatory stimulation: human venular endothelial cells store interleukin 8 in Weibel-Palade bodies”. Exp. Med.188 (9): 1757–62.
