Pre-eclampsia overview

# Overview
Preeclampsia is one of the leading causes of maternal and perinatal mortality worldwide and is defined as new-onset hypertension  after 20 weeks of gestation or near the term accompanied by proteinuria or other maternal organs involvement. Proteinuria may be negative, then other maternal organ dysfunction should be evaluated. Previous classification of preeclampsia into mild and severe is not used now due to suddenly worsening of the preeclampsia in any stages. Right upper quadrant or epigastric pain may be due to periportal and focal parenchymal liver necrosis, hepatic cell edema, or Glissons capsule distension. There is not always a correlation between liver pathology and laboratory tests. Headache is not a reliable symptom for preeclampsia with severe features. Other neurologic abnormalities should be evaluated. Headache,blurred vision,scotoma,hyperreflexia, temporary blindness may happen in the course of disease. If tonic-clonic seizure happens, it is defined as eclapsia. Eclampsia was first identified by Francois Mauriceau, a French obstetrician, born in 1637, following finding the correlation between convulsion in primigravidas and suppression of lochial flow or intrauterine fetal death. Preeclampsia may be the result of entering placental factors into the maternal circulation leading to endothelial dysfunction and hypertension and proteinuria. Increasing  the level of  an angiogenic factor named fms-like tyrosine kinase 1 in placenta correlated  with endothelial dysfunction. In villous trophoblast of preeclamptic women, apoptosis was considered. Following uteroplacental ischemia, and invasion of spiral arteries by trophoblasts, releasing some angiogenic factors cause other organ involvement. Incomplete penetration in recessive or dominant gene was noticed in pathogenesis of preeclampsia. Common causes of preeclampsia include uteroplacental ischemia and genetic predisposition following The formation of atheromatous plaques and fibrinoid necrosis of the spiral vessel walls, Oxidative stress in trophoblast cells, Apoptosis in trophoblast cells, Systemic inflammatory response, Vasospasm, Platelet aggregation, Thrombin formation, Deposition of the fibrin in multiple organs. In new classification proteinuria is not the main indicator for diagnosis of preeclampsia due to high percentage of false negative results. Preeclampsia may be classified according to the time of event into two groups: Early preeclampsia before 34 weeks of gestation, Late preeclampsia after delivery. Preeclampsia with severe feature includes the following characteristics: systolic blood pressure 160 mmHg, diastolic blood pressure 110 mmHg, in two occasions apart 4 hours,Thrombocytopnea (platelet count  2 times upper limit normal concentrations or persistent epigasteric or right upper quadrant pain, Serum creatinine >1.1 mg/dl or doubling serum creatinine level in the absent of other causes of renal insufficiency. All of the hypertensive disorder during pregnancy  including chronic hypertension, white coat hypertension, mask hypertension, gestational hypertension increase the risk of preeclampsia. The prevalence of preeclampsia is approximately 2000-8000 per 100,000 pregnancies worldwide. Between 1987 and 2004, the incidence of preeclampsia was estimated to be 25,000 per 100,000 pregnancies in the united state. Preeclampsia is more commonly observed among pregnant women aged before 20 and after 40 years old. Preeclampsia usually affects individuals of the Non-Hispanic whites and Non-Hispanic blacks and American Indians/Alaska Natives race. Common risk factors in the development of preeclampsia include:
Nulliparity, Multifetal gestations, Preeclampsia in a previous pregnancy, Chronic hypertension, Pregestational diabetes, Gestational diabetes,Thrombophilia, Systemic lupus erythematosus, Body mass index greater than 30 at the beginning of prenatal care, Antiphospholipid antibody syndrome, Maternal age 35 years or older, Kidney disease, Assisted reproductive technology,Obstructive sleep apnea, African-American decent. There is insufficient evidence to recommend routine screening for preeclampsia. Preeclampsic patients are usually asymptomatic and may deteriorate rapidly without any specific signs and symptoms.Early clinical feature after 20 weeks of gestation include blood pressure  140/90 mmHg, proteinuria, evidence of maternal organ involvement. Common complications of preeclampsia include: Intrauterin growth retardation(IUGR), Uteroplacental insufficiency, Fetal asphyxia or fetal death, Maternal seizures, Maternal death. Long term complication of preeclampsia include: Chronic hypertension, Diabetes mellitus, Ischemic heart disease, Cerebrovascular disease, Kidney disease, Thromboembolism, Hypothyroidism , Impaired memory. Prognosis is generally good after delivery and controlling  maternal hypertension and the 5 year mortality rate of the patients with preeclampsia is approximately 0.4%. The diagnosis of preeclampsia is made when at least two of the following three diagnostic criteria are met: 1.Blood pressure (Systolic blood pressure of 140 mm Hg or more or diastolic blood pressure of 90 mm Hg or more) on two occasions at least 4 hours apart after 20 weeks of gestation in a woman with a previously normal blood pressure, Systolic blood pressure of 160 mm Hg or more or diastolic blood pressure of 110 mm Hg or more, 2.Proteinuria (300 mg or more per 24-hour urine collection or Protein/creatinine ratio of 0.3 mg/dL or more or Dipstick of 2+) , 3. Or in the absence of proteinuria, new-onset hypertension with the new onset of any of the following: Thrombocytopenia: Platelet count1.1 mg/dL or a doubling of the serum creatinine concentration in the absence of other renal disease, Impaired liver function: Elevated blood level of liver transaminases to a twice normal level, Pulmonary edema , Intractable  headache or visual symptoms.The previouse classification of  preeclampsia into mild and severe disease is not used now because Preeclampsia may deteriorate rapidly without any specific signs and symptoms. Preeclampsia may present the first time intrapartum or early postpartum. Every hypertensive pregnant woman should be investigated for the symptoms related to organ damage, even in the absence of proteinuria. Symptoms of preeclampsia  may include the following: Epigasteric pain or right upper quadrant pain, Frontal or oxipital headache, Visual scotoma, Shortness of breath, limbs swelling,  Altered mental status, Photophobia. Patients with preeclampsia usually appear edematous .Physical examination may be remarkable for:Hyperreflexia, vision loss or deficit, altered sensorium, confusion, Rale in lungs field, Limbs edema. Posterior reversible encephalopathy syndrome should be considered in the setting of preeclampsia in patients with  vision loss or deficit, seizure, headache, and altered sensorium or confusion.Laboratory findings consistent with the diagnosis of preeclampsia include: elevated liver enzyme tests, thrombocytopenia, elevated serum creatinine, elevated serum uric acid. An elevated concentration of liver enzymes, low platelets, hemolysis is diagnostic of HELLP syndrome. There are no ultrasound  findings associated with the diagnosis of preeclampsia. However, an ultrasound may be helpful for following up on fetal complications of preeclampsia, which include fetal growth restriction. There are no MRI findings associated with preeclampsia. However, a brian MRI may be helpful in the diagnosis of complications of preeclampsia, which include Posterior reversible encephalopathy . Findings on  brain MRI suggestive of Posterior reversible encephalopathy include vasogenic edema, hyperintensities in the posterior aspects of the brain. The aim of therapy is starting treatment in blood pressure 140/90 mmHg in office or clinic and blood pressure  135/85 mmHg at home and reaching the target systolic blood pressure  110-140 mmHg and diastolic blood pressure less than 85 mmHg regardless the type of hypertension in pregnancy. The mainstay of therapy for hypertension in preeclampsia is oral methyldopa, labetalol, oxprenolol, and nifedipine, and second or third line agents include hydralazine and prazosin. Treatment for preeclampsia patients with  proteinuria and severe hypertension or hypertension  with neurologic signs and symptoms, is magnesium sulfate (MgSO4) for convulsion prophylaxis. Urgent therapy for severe hypertension (blood pressure >160/110) is oral nifedipine or intravenous labetalol or hydralazine or oral labetalol. Delivery is definite therapy for preeclampsia in the 37 weeks of gestation or occurrence any of the following: Repeated episodes of severe hypertension(blood pressure 160/110 mmHg, despite maintenance treatment with 3 classes of antihypertensive agents, progressive thrombocytopenia, progressively abnormal renal or liver enzyme tests, pulmonary edema, abnormal neurological features, stroke, myocardial infarction, HELLP syndrome ,eclampsia, suspected acute placental abruption or vaginal bleeding in the absence of placenta previa, abnormal fetal testing, fetal death, fetus without expectation for survival at the time of maternal diagnosis (lethal anomaly, extreme prematurity), persistent reversed end-diastolic flow in the umbilical artery. Effective measures for the primary prevention of preeclampsia  include administration of low dose aspirin (75-162 mg/day) before the 16th week of pregnancy and calcium supplement(1.2-2.5 g/day), especially in the high risk patients. Secondary prevention strategies following preeclampsia include blood pressure monitoring, repeated assessment of proteinuria if the result is negative, clinical evaluation about clonus, measurement of blood test twice weekly for hemoglobin, platelet count, uric acid, liver enzyme test, renal function test.

# Historical Perspective
Eclampsia was first identified by Francois Mauriceau, a French obstetrician, born in 1637, following finding the correlation between convulsion in primigravidas and suppression of lochial flow or intrauterine fetal death. Preeclampsia may be the result of entering placental factors into the maternal circulation leading to endothelial dysfunction and hypertension and proteinuria. Increasing  the level of  an angiogenic factor named fms-like tyrosine kinase 1 in placenta correlated  with endothelial dysfunction. In villous trophoblast of preeclamptic women, apoptosis was considered. Following uteroplacental ischemia, and invasion spiral arteries by trophoblasts, releasing some angiogenic factors causes other organ involvement. Incomplete penetration in recessive or dominant gene was noticed in pathogenesis of preeclampsia.

# Classification
In new classification proteinuria is not the main indicator for diagnosis of preeclampsia.The percentage of false-negative proteinuria especially on the dipstick is high.Preeclampsia may be classified according to the time of event into two groups: Early preeclampsia before 34 weeks of gestation, Late preeclampsia after delivery. Preeclampsia with severe feature includes the following characteristics:Systolic blood pressure 160 mmHg, diastolic blood pressure 110 mmHg, in two occasions apart 4 hours,Thrombocytopnea (platelet count  2 times upper limit normal concentrations or persistent epigasteric or right upper quadrant pain, Serum creatinine >1.1 mg/dl or doubling serum creatinine level in the absent of other causes of renal insufficiency.

# Pathophysiology
Preeclampsia may be the result of entering placental factors into the maternal circulation leading to endothelial dysfunction and hypertension and proteinuria. Increasing  the level of  an angiogenic factor named fms-like tyrosine kinase 1 in placenta correlated  with endothelial dysfunction. In villous trophoblast of preeclamptic women, apoptosis was considered. Following uteroplacental ischemia, and invasion spiral arteries by trophoblasts, releasing some angiogenic factors causes other organ involvement. Incomplete penetration in recessive or dominant gene was noticed in pathogenesis of preeclampsia.

# Causes
Common cause of preeclampsia include uteroplacental ischemia and genetic predisposition following The formation of atheromatous plaques and fibrinoid necrosis of the spiral vessel walls, Oxidative stress in trophoblast cells, Apoptosis in trophoblast cells, Systemic inflammatory response, Vasospasm, Platelet aggregation, Thrombin formation, Deposition of the fibrin in multiple organs.

# Differentiating preeclampsia from Other Diseases
Differential diagnosis of  hypertensive disorder during pregnancy  including chronic hypertension, white coat hypertension, mask hypertension, gestational hypertension whether increase the risk of preeclampsia.

# Epidemiology and Demographics
The prevalence of preeclampsia is approximately 2000-8000 per 100,000 pregnancies worldwide. Between 1987 and 2004, the incidence of preeclampsia was estimated to be 25,000 per 100,000 pregnancies in the united state. Preeclampsia is more commonly observed among pregnant women aged before 20 and after 40 years old. Preeclampsia usually affects individuals of the Non-Hispanic whites and Non-Hispanic blacks and American Indians/Alaska Natives race.

# Risk Factors
Common risk factors in the development of preeclampsia include:
Nulliparity
, Multifetal gestations
, Preeclampsia in a previous pregnancy
, Chronic hypertension
, Pregestational diabetes
, Gestational diabetes
, Thrombophilia
, Systemic lupus erythematosus
, Body mass index greater than 30 at the beginning of prenatal care
, Antiphospholipid antibody syndrome
, Maternal age 35 years or older
,  Kidney disease
,Assisted reproductive technology
, Obstructive sleep apnea
, African-American decent.

# Screening
There is insufficient evidence to recommend routine screening for preeclampsia.

# Natural History, Complications, and Prognosis
Preeclampsic patients are usually asymptomatic and may deteriorate rapidly without any specific signs and symptoms.Early clinical feature after 20 weeks of gestation include blood pressure  140/90 mmHg, proteinuria, evidence of maternal organ involvement. Common complications of preeclampsia include: Intrauterin growth retardation(IUGR), Uteroplacental insufficiency, Fetal asphyxia or fetal death, Maternal seizures, Maternal death. Long term complication of preeclampsia include: Chronic hypertension, Diabetes mellitus, Ischemic heart disease, Cerebrovascular disease, Kidney disease, Thromboembolism, Hypothyroidism , Impaired memory. Prognosis is generally good after delivery and controlling  maternal hypertension and the 5 year mortality rate of the patients with preeclampsia is approximately 0.4%.

# Diagnosis

## Diagnostic Study of Choice
The diagnosis of preeclampsia is made when at least two of the following three diagnostic criteria are met: 1.Blood pressure (Systolic blood pressure of 140 mm Hg or more or diastolic blood pressure of 90 mm Hg or more) on two occasions at least 4 hours apart after 20 weeks of gestation in a woman with a previously normal blood pressure, Systolic blood pressure of 160 mm Hg or more or diastolic blood pressure of 110 mm Hg or more, 2.Proteinuria (300 mg or more per 24-hour urine collection or Protein/creatinine ratio of 0.3 mg/dL or more or Dipstick of 2+) , 3. Or in the absence of proteinuria, new-onset hypertension with the new onset of any of the following: Thrombocytopenia: Platelet count1.1 mg/dL or a doubling of the serum creatinine concentration in the absence of other renal disease, Impaired liver function: Elevated blood level of liver transaminases to a twice normal level, Pulmonary edema , Intractable  headache or visual symptoms.

## History and Symptoms
The previouse classification of  preeclampsia into mild and severe disease is not used now because Preeclampsia may deteriorate rapidly without any specific signs and symptoms. Preeclampsia may present the first time intrapartum or early postpartum. Every hypertensive pregnant woman should be investigated for the symptoms related to organ damage, even in the absence of proteinuria. Symptoms of preeclampsia  may include the following: Epigasteric pain or right upper quadrant pain, Frontal or oxipital headache, Visual scotoma, Shortness of breath, limbs swelling,  Altered mental status, Photophobia.

## Physical Examination
Patients with preeclampsia usually appear edematous .Physical examination may be remarkable for:Hyperreflexia, vision loss or deficit, altered sensorium , confusion, Rale in lungs field, Limbs edema. Posterior reversible encephalopathy syndrome should be considered in the setting of preeclampsia in patients with  vision loss or deficit, seizure, headache, and altered sensorium or confusion.

## Laboratory Findings
Laboratory findings consistent with the diagnosis of preeclampsia include: elevated liver enzyme tests, thrombocytopenia, elevated serum creatinine, elevated serum uric acid. An elevated concentration of liver enzymes, low platelets, hemolysis is diagnostic of HELLP syndrome.

## Ultrasound
There are no ultrasound  findings associated with the diagnosis of preeclampsia. However, an ultrasound may be helpful for following up on fetal complications of preeclampsia, which include fetal growth restriction.

## MRI
There are no MRI findings associated with preeclampsia. However, a brian MRI may be helpful in the diagnosis of complications of preeclampsia, which include Posterior reversible encephalopathy . Findings on  brain MRI suggestive of Posterior reversible encephalopathy include vasogenic edema, hyperintensities in the posterior aspects of the brain.

# Treatment

## Medical Therapy
The aim of therapy is starting treatment in blood pressure 140/90 mmHg in office or clinic and blood pressure  135/85 mmHg at home and reaching the target systolic blood pressure  110-140 mmHg and diastolic blood pressure less than 85 mmHg regardless the type of hypertension in pregnancy. The mainstay of therapy for hypertension in preeclampsia is oral methyldopa, labetalol, oxprenolol, and nifedipine, and second or third line agents include hydralazine and prazosin. The mainstay  of therapy for preeclampsia, who have proteinuria with severe hypertension or hypertension  with neurologic signs and symptoms, is magnesium sulfate (MgSO4) for convulsion prophylaxis.  Urgent therapy for severe hypertension (blood pressure >160/110) is oral nifedipine or intravenous labetalol or hydralazine or oral labetalol.

## Primary Prevention
Effective measures for the primary prevention of preeclampsia  include administration of low dose aspirin (75-162 mg/day) before the 16th week of pregnancy and calcium supplement(1.2-2.5 g/day), especially in the high risk patients .

## Secondary Prevention
Secondary prevention strategies following preeclampsia include blood pressure monitoring, repeated assessment of proteinuria if the result is negative, clinical evaluation about clonus, measurement of blood test twice weekly for hemoglobin, platelet count, uric acid, liver enzyme test, renal function test.