Hypertensive disorders during pregnancy account for approximately 15% of pregnancy related deaths, and represent the second-leading cause of morbidity and mortality in the United States. (1) Pre-eclampsia is a clinical syndrome with signs of hypertension and proteinuria in the 2nd trimester. In addition, pre-eclampsia is a multisystem disease that effects 3-5% of pregnancies in the western world, and is a major source of maternal morbidity and mortality especially in the developing countries. Pre-eclampsia also causes perinatal deaths, preterm birth, and intrauterine growth restriction. (2, 3) Since the only definitive therapy is delivery of the placenta, in western countries preeclampsia is an important cause of premature delivery. This results in infant morbidity and extensive healthcare expenditure. (4)
Diagnosis, Signs, and symptoms of pre-eclampsia
The classic triad of preeclampsia consists of hypertension, proteinuria, and edema. However, edema is not considered as part of the diagnosis of preeclampsia. According to Stella and Sibai (6) in The Journal of Maternal-Fetal and Neonatal Medicine, ‘edema is neither sufficient nor necessary to confirm the diagnosis of preeclampsia, since edema is a common finding in normal pregnancy and approximately one third of eclamptic women never demonstrate the presence of edema.’ Proteinuria is defined as excretion of protein of more than 300 mg in a 24-hour period. According to American College of Obstetrics and Gynecology, hypertension is defined as systolic blood pressure of at least 140 mmHg and diastolic blood pressure of 90 mmHg on at least two occasions. These measurements taken should be four hours apart from each other. Mild preeclampsia is defined by diastolic blood pressure below 110 mmHg and the systolic blood pressure remaining below 160 mmHg. Severe preeclampsia is define as when the systolic pressure is more than 160 mmHg. It is also considered severe pre-eclampsia if there is gestational hypertension with abnormal proteinuria or if there is hypertension in association with severe proteinuria (at least 5 g in a 24-hour period). In addition, it is considered severe in the presence of multisystem involvement such as pulmonary edema, seizures, oliguria, thrombocytopenia, abnormal liver enzymes (causing epigastric or right upper quadrant pain), and or central nervous system symptoms including altered mental status, headaches, blurred vision, or blindness. (6) The diagnosis of preeclampsia is made by the presence of an elevated blood pressure plus proteinuria (measured by either urine dipstick or protein/creatinine ratio) as a new onset of hypertension and proteinuria after 20 weeks of gestation. This criterion is widely used in healthy nulliparous women. However, research has also shown that in some women, pre-eclampsia may develop in the absence of hypertension and proteinuria making it challenging to diagnose and manage the disease. The signs and symptoms observed in majority of women comprise of nausea/vomiting related to HELLP syndrome, right upper quadrant pain and epigastric pain related to subscapsular hepatic hematoma, dyspnea and chest pain related to cardiac failure, headaches, visual changes, altered mental status, brisk tendon reflexes related to cerebral edema, oliguria related to acute renal failure, painful uterine contractions and vaginal bleeding related to placenta abruption. (6,8)
The hypertension in pre-eclampsia is caused by multiple mechanisms which includes changes in sympathetic tone, renin-angiotensin system and production of endothelial- derived vasoactive mediators. (7) It is important to note that levels of renin, angiotensin, and aldosterone are increased despite an overall decrease in systemic vascular resistance in normal pregnancy. In pre-eclampsia this resistance is blunted, resulting in increased sensitivity to angiotensin II. (4) Hence, patients with pre-eclampsia have an increase sympathetic tone than compared with the normotensive pregnant and hypertensive non-pregnant women. Pre-eclamptic women also have high sensitivity to norepinephrine and are more sensitive to angiotensin II. This sensitivity maybe increased due to AT1-B2 heterodimerization or by an autoantibody against the AT1 receptor, which enables the interaction between angiotensin II and the AT1 receptor. Angiotensin II is an important part of the pathophysiology of pre-eclampsia causing hypertension, oxidative stress thru superoxide anions, and activating platelets. The dysfunctional endothelial cells (discussed later) produce different quantities of vasoactive mediators and control the vascular tone. For example, PGI2 which causes vasodilation is decrease in pre-eclampsia, whereas thromboxane A2 which is a vasoconstrictor produced by the platelets is increased. (7)
The proteinuria is considered an important sign of preeclampsia however its presence is not required to make the clinical diagnosis of pre-eclampsia. When proteinuria is absence, preeclampsia syndrome should still be considered when gestational hypertension is present with cerebral symptoms, right upper quadrant or epigastric pain in addition to nausea/vomiting, fetal growth restriction, or with thrombocytopenia and abnormal liver enzymes shown in laboratory tests. Gestational hypertension is associated with higher maternal and perinatal morbidities in the absence of proteinuria. (6) In preeclampsia there is decrease in glomerular filtration and renal blood flow. This is due to vasospasm and glomerular capillary endothelial edema caused by glomerular endotheliosis causing glomerular to become nonfunctional. The endotheliosis of glomeruli is pathological renal lesion seen in women with preeclampsia.(1) As it will be discussed later, the endotheliosis is caused by alterations in functions of vascular endothelial growth factor(VEGF) that is necessary for fenestrations in endothelial cell. The loss of vascular endothelial growth factor causes the glomerular endotheliosis and proteinuria. (7) The Oliguria which is less than 500 ml/24 h, occurs secondary to hemoconcentration and decreased renal perfusion. Persistent oliguria indicate acute tubular necrosis, the most common type of acute renal failure seen in preeclampsia. (1)
Edema is a common finding in normal pregnancy therefore it is not required for the diagnosis of preeclampsia. However, in preeclampsia women notice edema particular on face, hands, and feet, with weight gain. Baumwell and Karumanchi (7) discuss the possible causes of edema in Pre-eclampsia: Clinical Manifestations and Molecular Mechanisms, it has been suggested that the edema of pre-eclampsia is similar to the ‘overfill’ edema of acute glomerulonephritis, in which the renal disease itself is responsible for sodium and fluid retention. The mechanism of edema in pre-eclampsia is not completely understood, but pre-eclamptic women have an increased sensitivity to angiotensin II. According to the studies, ‘endothelial permeability may contribute, as suggested by the faster disappearance of albumin-bound Evan’s blue dye in pre-eclamptic women compared with controls.'(7)
Thrombocytopenia is the most common hematologic abnormality of severe preeclampsia. This is caused by changes in the coagulation cascade and in the fibrinolytic system that activate the syndrome of disseminated intravascular coagulopathy. The cause of these changes again involves vascular endothelial damage that causes activation of platelets and the coagulation cascade. According to Baumwell and Karumanchi, (7) about 10-20% of women with severe preeclampsia develop thrombotic microangiopathy, resulting in HELLP syndrome (hemolysis, elevated liver enzyme, and low platelets). Hemolysis results from red blood cells passing through the small vessels whose intima is made rough by endothelial damage and fibrin deposition. This process also obstructs the hepatic sinusoids resulting in elevated liver enzymes. Right upper quadrant pain results from stretching of Glisson’s capsule, hepatic rupture can also occur if the pressure increases greatly. (7) Hypercoagulable state in normal pregnancy is actually of benefit because it prevents hemorrhage after delivery. In HELLP syndrome, hypercoagulable state is so extensive due to the endothelial damage that it causes disseminated intravascular coagulation, pulmonary edema, subcapsular hepatic hematoma, acute renal failure, and placental abruption. The endothelial injury causing the HELLP syndrome is due to dysfunctional endothelial cells (discussed later) producing circulating factors such as von Willebrand factor, thrombomodulin, fibronectin, and PAI-1. Platelets are expended more through adherence to diffuse sites of endothelial injury. Activated platelets release more thromboxane A2 causing further endothelial injury leading to HEELP syndrome. (7).
The neurological signs seen in pre-eclampsia are headaches, blurry vision, and transient vision loss. These changes are again due to endothelial dysfunction and impaired autoregulation from acute hypertension. The impaired autoregulation is similar to emergency hypertensive encephalopathy, causing cerebral edema, and visual disturbances. The hypertensive encephalopathy in preeclampsia is distinguished from the presence of endothelial dysfunction seen in pre-eclamptic women. Pre-eclampsia also puts women at high risk of developing eclampsia which is defined by presence of seizures with hypertension and proteinuria. (7)
Preeclampsia in the long run
It is reported that women with preeclampsia develop cardiovascular complications in the long term. They are at risk for developing chronic hypertension, ischemic heart disease, and stroke. The long term effects are influenced and increased by multiple risk factors such as obesity, hyperlipidemia, chronic hypertension, and insulin resistance or as a result of preeclampsia itself, which is not well understood. However, it is clear that women with preeclampsia develop cardiovascular complications. Baumwell and Karumanchi (7) discussed the CHAMPS study, which found a two-fold increase in hospital admissions for revascularization of coronary, cerebral, or peripheral arteries in women with preeclampsia with no history of cardiovascular diseases. In women with risk factors mentioned above, they had a three times higher risk plus a small-for-gestational- age infant. Also an earlier retrospective study showed similar results. (7)
The mechanisms behind cardiovascular disease in women with a history of preeclampsia is not understood, nonetheless endothelial dysfunction has been associated to atherosclerosis, which continues in women with preeclampsia many years after an unaffected pregnancy. It also has been reported that history of pre-eclampsia makes these women more sensitive to angiotensin II. (4) Powe et al (4) also demonstrates that the mediators of endothelial activation, including vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, seem to be higher >15 years after pregnancy in women with history of preeclampsia. (4)
It has also been suggested that preeclampsia may contribute to diabetes in the future. In Preeclampsia and future maternal health, Carty at el (2) reported the relationship between preeclampsia and future diabetes in the mothers. A questionnaire study, reported diabetes in over 3600 women at 21 years after delivery. They found that women with history of preeclampsia had a two-fold increase in the risk of future diabetes compared to those with normal pregnancies. Many other studies also showed similar findings. These studies confirm that surveillance should be increased to monitor the development of diabetes in women with a history of preeclampsia. (2)
Pathogenesis involved in pre-eclampsia
Preeclampsia is a multifaceted vascular disease that affects the central nervous system and liver in the pregnant women. Hepatic infarction, intra-abdominal bleeding, placental abruption, pulmonary edema, ascites, acute renal failure, and hepatic rupture all relate to severe clinical manifestations associated with preeclampsia. And the most dreaded complication of preeclampsia is its progression to eclampsia. The cerebrovascular injury in eclampsia is associated with cerebral edema and characteristic white matter changes of reversible posterior leukoencephalopathy syndrome, which is similar to findings noted in hypertensive encephalopathy. The neurological complications, such as stroke and intracranial hemorrhage, are responsible for the vast amount deaths related to preeclampsia-eclampsia. (4) According to Fenton at el, (5) all of the above outcomes (hepatic infarction, hepatic rupture, intra-abdominal bleeding, pulmonary edema, and acute renal failure) reflected progressive endothelial dysfunction across many targeted organs. This was an important implication because recognition that endothelial dysfunction was one of the mechanisms underlying pre-eclampsia not only led to focus on the aspects of management, it also triggered the need to identify the causative agents that were causing the dysfunction. (5)
The pathogenesis of pre-eclampsia is complex; it involves the environmental, genetic, and immunological factors. (7) The initial chain of reaction of the inciting events is however unidentified. Nevertheless, it has been suggested that pre-eclampsia is a two-step process. The first step is asymptomatic. (4) Pathological studies show that the center of the pathogenesis begins with abnormal placentation. Placenta is required for pre-eclampsia, and not the fetus. Furthermore, placenta removal upon delivery, resolves the pre-eclampsia. Histological examination of placentas from women who have severe pre-eclampsia shows the lesions of acute atherosis with multiple infarcts; sclerotic, narrowed arteries and arterioles; deposition of fibrin and thrombosis and vascular resistance increased, with placental ischemia. The abnormal development of placental vasculature and hypoxic insult is the key factor for the development of the pre-eclampsia. The maternal spiral arteries deliver blood to the placental intervillous space. During normal pregnancy, remodeling of the maternal spiral arteries occur to increase the blood flow to the fetus and placenta, the vessels that were high resistance are remodeled into high-capacitance and low-resistance vessels, and provide oxygen and nutrients for the placenta and fetus. In pre-eclampsia the placenta does not develop normally, the trophoblasts cannot regulate the remodeling of the spiral arteries and fail to differentiate into endothelial cells and are unable to do vasculogenesis. As a result it causes high resistance vessels, which deliver less blood causing placental ischemia. (7)
In the journal article, ‘Pre-Eclampsia: Clinical Manifestations and Molecular Mechanisms’ (7) the authors also identified that several circulatory proteins play role in preeclampsia. Some of the identified proteins are soluble fms-like tyrosine kinase (sFlt1), soluble endoglin (sEng), and placental growth factor (PlGF). The Endothelial dysfunction is caused by the release of the circulating mediator factors from abnormal placentation such as sFlt1 (soluble fms-like tyrosine kinase 1), sEng (soluble endoglin). sF1t1 and sEng are a potent antagonist of both VEGF (a pro angiogenic factor) and placental growth factor (PlGF). In preeclampsia, placenta produces high amounts of sF1t1 and hence low levels of VEGF and PIGF. The dysfunctional endothelial cells produce altered quantities of vasoactive mediators (decrease amounts of VEGF and PIGF), which leads to vasoconstriction causing endothelial dysfunction and the clinical signs and symptoms of preeclampsia. (7) For example, injury of the hepatic endothelium leading to hemolysis, elevated liver enzymes, and low platelet count (HELLP syndrome), cerebral endothelium damage leading to neurological disorders including eclampsia, initiation of coagulation system, and proteinuria (8). This imbalance between pro-angiogenic and anti-angiogenic proteins play a key role in the pathogenesis of the preeclampsia (7), and is known as second stage of pre-eclampsia (maternal symptoms).
Management of preeclampsia
In spite of many recent advances in the field, the cause of preeclampsia, its treatment, and prevention still remains unclear. Longo et al, (1) reported that the treatment and management of the hypertensive disorders of pregnancy have not changed significantly in the past 50 years. Presently, the therapy is to control the symptoms, for example, controlling maternal blood pressure with drugs like methyldopa, beta blockers, calcium channel blockers or alpha blockers to prolong pregnancy and thus gain better fetal maturity while alleviating the maternal risks of severe hypertension. This approach has significantly improved maternal and child health outcomes, however, it does not actually treat the disease. Physicians only manage the overt clinical signs of the disease ‘the hypertension’ to protect the mother until delivery is feasible. The hypertension in this disease progresses and resolves only after delivery of the placenta. It is vital to make careful diagnosis, classification, and further investigation of the causes of hypertensive disorders in pregnancy to achieve the optimum management of affected women and their fetuses. (1, 5)
Overall, the treatment and management varies depending on the severity and gestational age. Women suspected of pre-eclampsia should be immediately hospitalized and further evaluated. Delivery of the fetus is definitive cure for the preeclampsia. It is indicated when preeclampsia is diagnosed at or after 38 weeks of pregnancy, regardless of the severity of the disease. Women with mild preeclampsia in a preterm pregnancy are required hospital bed rest until delivery with close monitoring of mother and fetus for signs and symptoms of severe preeclampsia and eclampsia. (1)
Perinatal outcome of pre-eclampsia in parous women
According to the article Perinatal outcome of preeclampsia in parous women by Jian-Ying and Xia, (9) women with prior history of more than two or recurrent preeclampsia had more adverse outcome than a women without history of preeclampsia or preeclampsia in first pregnancy. Preeclampsia is hypertension more than 140/90 mmHg after 20 weeks of gestation. It complicates about 2.5-3.0% of pregnancies and it is accountable for maternal morbidity and mortality. According to this article, many previous studies “have demonstrated that previous pre-eclampsia is a risk factor for recurrent pre-eclampsia. Women with a history of pre-eclampsia, especially pre-term pre-eclampsia, have increased risks of pregnancy complications associated with abnormal placentation in the second pregnancy, even in the absence of pre-eclampsia.” (9) This infers that women with history of previous preeclampsia are at increased risk of developing preeclampsia in the future pregnancies and are at increased risk of adverse pregnancy outcome in the future pregnancies. The study designed by Jian-Ying and Xia was a retrospective cohort study to understand preeclampsia in parous women and to investigate the relationship between previous preeclampsia and future pregnancies. (9) The data for this retrospective study was collected from January 2006 to December 2010 from all parous women who experienced preeclampsia at Fujian Maternity and Child Health Hospital. The study was divided into 2 groups: parous women with recurrent preeclampsia and other group included parous women with preeclampsia without a history of preeclampsia in first pregnancy. The data collected from all participants in the study included: maternal age, gestational weeks, blood pressure, BMI, perinatal care, mode of delivery, laboratory values of uric acid, urine protein in 24 hours, albumin and dimers, maternal outcome, and fetal outcome. The criteria used in this study for preeclampsia was blood pressure more than 140/90 mmHg in 2 separate occasion at least 4 hours apart and proteinuria more than 300mg/24hour or +1 on urine dipstick after 20 weeks of gestation. The standard used for severe preeclampsia was blood pressure more than 160/110 mmHg, proteinuria more than 300mg/24hour or + 2 on urine dipstick with low platelets count(less than 100,000/L) and serum creatinine more than 1.2mg/dl. The diagnostic criterion for early onset preeclampsia was onset of preeclampsia after 20 weeks of gestation but before 34 weeks of gestation. Late onset preeclampsia is defined as onset of preeclampsia after 34 weeks of onset. Lastly, the criterion for small for gestational age were birth weight less than 10th percentile. According to this study, of 381 parous pregnant women, 69 had the history of pre-eclampsia in the previous pregnancies whereas 312 of the parous women did not have the prior history of pre-eclampsia in the past pregnancies. This study showed that in the group of parous women with history of prior or recurrent preeclampsia, 44.9% of the women experienced severe preeclampsia. 36.9 % of women experienced severe eclampsia from the other group that included women with no history of prior preeclampsia in first pregnancy. According to the study, early onset of pre-eclampsia was observed in 47.8% in the group of recurrent pre-eclampsia/history of previous pre-eclampsia and 13.1% in first pre-eclampsia group with no prior history of preeclampsia. This retrospective study showed that the rate of pre-eclampsia and premature caesarian was higher in recurrent group than in first pre-eclampsia parous group without prior history of pre-eclampsia. The study also showed that the renal injury was higher in recurrent pre-eclampsia group. According to the study, good news was that no maternal deaths were observed in both groups. The study showed that the rate of preterm delivery, neonatal weight and length, and small for gestational age were higher in recurrent pre-eclampsia group than first pre-eclampsia parous group. According to the article, women with history of previous pre-eclampsia had imbalance of vascular growth factor and anti-vascular endothelial growth factor which promotes preterm delivery. Also, the article discusses that the parous women with history of previous pre-eclampsia had complicated organ damage that is life threatening for the mother. This study showed no statistically significant difference between the two 2 groups in observing rate of placenta abruption, oligohydraminos, gestational diabetes, fetal distress and liver dysfunction. (9) The study failed to show significant statistical difference between 2 groups maybe due to low number of participant of preeclampsia in parous group and lack of data regarding previous pregnancies. (9) The study concludes that recurrent pre-eclampsia has worst neonatal outcomes. Lastly, this retrospective study accomplished that the parous women with recurrent preeclampsia experienced worse perinatal outcome compare to the parous women without prior history of pre-eclampsia in previous pregnancies. (9)
Pre-eclampsia is a multi-systemic disorder with a variety of clinical presentation and remains the leading cause of maternal and fetal morbidity and mortality. Some patients have underlying conditions related to endothelial dysfunction and inflammation, whereas others are healthy and have no known risk factors until pre-eclampsia develops during pregnancy. Widespread ongoing research has shown the molecular pathogenesis that may be involved in the etiology of preeclampsia and the preceding maternal symptomatic outcome. However, complete understanding of the mechanism involved in the diseases still remains unknown. The treatment options still remain limited. The mainstays of therapy are supportive care and delivery.
Further ongoing efforts are continued to better understand the pathophysiology of the disease as a manifestation of clinical signs and the development of targeted therapies. (7)
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