Updates in Hypertensive Disorders with Pregnancy

Introduction;
Hypertension is the most common medical disorder during pregnancy. The term gestational hypertension- preeclampsia is used to describe a wide spectrum of disorders for patients who may have only mild elevation in blood pressure or severe hypertension with various organ dysfunctions that include acute gestational hypertension, preeclampsia, eclampsia and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome (1). A classic triad of preeclampsia includes hypertension, proteinuria, and edema. However, there is now general agreement that edema should not be considered as part of the diagnosis of preeclampsia, Atypical cases are those that develop at_20 weeks of gestation and_48 hours after delivery and that have some of the signs and symptoms of preeclampsia without the usual hypertension or proteinuria(1). Hypertensive disorders complicating pregnancy are common, they complicate 12-22% of all pregnancies, and form one of the great triad along with hemorrhage and infection that continues to be responsible for large number of maternal deaths, accounting for 17.6% of pregnancy related deaths in the United States, About 70% of hypertensive complications in pregnancy are classified as pregnancy-induced hypertensive disorders, sometimes referred to as gestational hypertension, About 30% of the complications are related to chronic hypertension with or without superimposed preeclampsia,(2).

The incidence of hypertension occurs in well over 6% to 8% of all pregnancies, and hypertensive disorders of pregnancy are the leading causes of maternal and perinatal mortality in developed countries. As many as 20% of primigravidas (women for the first time) may develop hypertension, and it was observed that young teenaged primigravidas are at high risk for pre-eclampsia. (2).
Definitions (6) Hypertension in pregnancy: A blood pressure of 140/90 or more is abnormal. Or if there is a rise of 30 mmHg or more in the systolic blood pressure

or 15 mmHg or more in the diastolic blood pressure.

Gestational hypertension: Hypertension diagnosed after midpregnancy without proteinuria. Blood pressure returns to normal before 12 weeks postpartum. Chronic hypertension with pregnancy: Hypertension antedates pregnancy or detected before 20 weeks gestation or lasts more than 12 weeks postpartum. Pre-eclampsia: It is the development of hypertension and pathological proteinuria after 20 weeks of pregnancy. May occur earlier in vesicular mole or twins. Eclampsia (in Greek= Flash of light): It is the occurrence of tonic-clonic convulsions (without any neurological disease) in a woman with pre-eclampsia. Superimposed pre-eclampsia: It is the new development of pathological proteinuria after 20 weeks gestation in a patient with hypertension only during pregnancy. Or increase in the blood pressure, increased proteinuria or decreased platelet count below 100000/mm3 in women with prior hypertension and proteinuria. Pathological proteinuria:

300mg/24 hours urine. +1 dipstick. > 100mg/dl in 2 random samples 6 hours apart. Heavy proteinuria when it is 2gm/24 hours or +2 in dipstick. (4).

Classification I. The American College of Obstetrics and Gynecology (ACOG) classification : A. Pregnancy induced hypertension (PIH): 1. Hypertension without proteinuria.
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2. Pre-eclampsia: 3. Eclampsia.

a. Mild.

b. Severe.

B. Pregnancy aggravated hypertension: 1. Superimposed pre-eclampsia. 2. Superimposed eclampsia. C. Coincidental hypertension: Hypertension antedates pregnancy or persists postpartum. II. National High Blood Pressure Education Program Classification : A. Gestational hypertension. B. Pre-eclampsia (mild, severe). C. Eclampsia. D. Superimposed preeclampsia upon chronic hypertension. E. Chronic hypertension with pregnancy. Harvard Classification, (2007); o Gestational hypertension (6-7%) Onset of HTN without proteinuria after 20wks of gestation with resolution to baseline by 12wks postpartum o Pre-eclampsia (5-8%) Hypertension plus proteinuria 140/90 on two occasions six hours apart 0.3 gm/dl in 24hrs or 1+ on urine analysis o Chronic hypertension (3-5%) HTN prior to pregnancy Gestational HTN which does not resolve within 12 wks of delivery b o Superimposed preeclampsia (25% of CHTN) Chronic HTN plus new onset proteinuria or other signs or symptoms of preeclampsia.

Recently, there are nonclassic and atypical features of preeclampsiaeclampsia

Gestational hypertension plus 1 of the following items: Symptoms of preeclampsia Hemolysis Hemolysis Thrombocytopenia 100,000/mm3) Elevated liver enzymes (2 times the upper limit of the normal value for aspartate aminotransferase or alanine aminotransferase) Thrombocytopenia Elevated liver enzymes Gestational proteinuria plus 1 of the following items: Symptoms of preeclampsia Early signs and symptoms of preeclampsiaeclampsia at < 20 weeks of gestation Late postpartum preeclampsiaeclampsia > 48 hours after delivery) Sibai. Diagnosis and management of a typical preeclampsiaeclampsia. Am J Obstet Gynecol 2009.

Incidence (4). It is a disease of humans only. It is the most common medical disorder complicating pregnancy 5-15% Pre-eclampsia is the most common hypertensive disorder in pregnancy. More common in primigravidas and elderly multipara. More common in winter. More in black races. Risk factors(5,6,31,39); 1. P/H or F/H of pre-eclampsia or eclampsia 2. Chronic hypertension. 3. Chronic nephritis 4. Obesity. 5. Multiple pregnancy. 6. Polyhydramnios.
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7. Vesicular mole. 8. Diabetes mellitus. Etiology(7) It is a disease of theories so any theory should explain that the disease is more common in: Women exposed to trophoblast for the first time. Women exposed to abundance of trophoblasts. Women with known vascular disease. Genetic predisposition. 1. Increased Pressor Response
During normal pregnancy there is decreased response to pressor agents

especially angiotensin II. (7) In cases of pre-eclampsia or in cases which will subsequently develop preeclampsia there is increased response to pressor agents due to: a. Increased amount of pressor agents. b. Increased angiotensin II binding sites. c. Decreased vasodilator agents. d. Increased intracellular Ca++. 2. Abnormal Placentation
The development of pre-eclampsia depends on the presence of trophoblasts and

complete cure occurs after placental delivery.(8&9). During the first 12 weeks of normal pregnancy the trophoblasts invade the intima and media of decidual blood vessels and the media of these vessels are replaced by fibrinoid material making these vessels non responsive to vasopressors.
A second wave of trophoblastic invasion occurs at 12-16weeks which involve

the myometrial segment of spiral arterioles.(8&9)

 In pre-eclampsia and in cases which will subsequently develop pre-eclampsia

there is inadequate trophoblastic invasion, so the vessels are responding to vasopressor stimuli.(8&9).

3. Prostaglandins(10) In pre-eclampsia there is decreased production of prostacyclin (PGI2:vasodilator) and increased production of thromboxane A2 (TxA2:vasoconstrictor). So, there is decrease in PGI2/TxA2 ratio leading to vasoconstriction and tendency to thrombosis. This may be due to altered endothelial activity or abnormal levels of peroxides. 4. Genetic Predisposition(11&12), It is well known that the risk of pre-eclampsia increased in women whom their mothers or grandmothers had PIH. May be associated with expression of angiotensin II gene which increases the pressor effect. May be due to gene abnormality which causes defective trophoblastic invasion leading to decreased uteroplacental perfusion and hypoxia which is essential for production of pre-eclampsia. 5. Immunological Factor: (13); Occurs in women first exposed to trophoblasts (primigravidas). Pre-eclampsia increases in multipara with 1st pregnancy from a new husband. More common where abundant trophoblasts as in vesicular mole and multiple pregnancy. 6. Endothelins; (14,15) There are potent vasoconstrictors especially endothelin 1 which was found to increase in pre-eclampsia. 7. Nitric Oxide; (16)
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 It is an endothelial product with vasodilator action. Its increase leads to increased uteroplacental perfusion and its decrease leads to hypertension, decreased heart rate and reverses the pregnancy induced refractoriness to the processor agents.

8. Vascular Endothelial Growth Factor (VEGF), (17) It is important in angiogenesis and control microvascular permeability. It is increased in the serum of women in pre-eclampsia and its increase may be a compensatory mechanism to restore uteroplacental blood flow toward normal. 9. Inflammatory Factors (18) Pre-eclampsia is considered an inflammatory disease due to increased number of activated leukocytes in the maternal circulation. Cytokines (Tumor Necrosis Factor and Interlukines) contribute to oxidative stresses resulting in: a. Increased oxygen free radicals causing endothelial damage. b. Increased capillary permeability. c. Production of lipid laden macrophages. d. Activation of microvascular coagulation. 10.Free Radicals Theory (19) In pre-eclampsia the levels of free radicals are higher than normotensive women leading to endothelial damage 11.Vitamin E/Lipid Peroxides Imbalance(19,20) During normal pregnancy the vitamin E/lipid peroxides ratio is increased leading to the predominance of the antioxidant effect of vitamin E. In pre-eclampsia this ratio is reversed leading to increased free radicals causing endothelial damage. 12. Endothelial Cell Activation(21): this causes:

a. Increased production of vasoconstrictors. b. Decreased production of vasodilators. 13.Prorenin (22)

c. Increased procoagulants. d. Decreased anticoagulants. e. DIC. f. Altered PGI2/TxA2 ratio.

Uteroplacental hypoperfusion and hypoxia causes increased production of prorenin and increased boold pressure. In pre-eclampsia there is increased production of prorenin . pathogensis
Maternal Vascular Disease Faulty Placentation Excessive Trophoblast

Genetic Immunologic or Inflammatory Factors

Reduced uteroplacental perfusion Vasoactive Agents: Prostaglandins, Endothelins Noxious Agents: Cytokines Lipid Peroxidases

Endothelial Activation

Vasospasm

Capillary Leak

Activation of Coagulation

Edema

Proteinuria

Thrombocytopenia

Hemoconcentration Hypertension Oliguria Abruption Seizures Pathophysiological Considerations 8

In The Development Of Hypertensive Disorders Due To Pregnancy Liver

Ischemia

Pathophysiology

Pathology I. Cardiovascular Changes: (23) 1. Vasospasm: There is generalized arteriolar vasospasm and increased vascular resistance which causes endothelial damage and dysfunction. 2. Increased pressor response: As early as 10 weeks of normal pregnancy infusion of angiotensin II is not followed by increased blood pressure as angiotensin II increases the production of PGI2 causing VD. This effect is not present in pre-eclampsia or in patients supposed to have pre-eclampsia.
3. Hemodynamic changes (40):

Hemodynamic Changes in Pregnancy;

Change Cardiac output Systemic vascular resistance Blood pressure Glomerular filtration rate Normal Pregnancy Increased Decreased Decreased Increased Preeclampsia No change or decreased Increased Increased Decreased

a. Increased after load and contractility caused by hypertension. b. Increased peripheral resistance leads to decrease cardiac output. c. Cardiac preload is normal or low in severe cases due to extravasation into the extracellular spaces . 4. Blood Volume: Hemoconcentration and increased hematocrite due to increased capillary permeability. 5. Blood Cells: Bizarre shaped RBCs which are easily hemolysed and thrombocytopenia. 6. Coagulation disorders: In severe pre-eclampsia there is activation of the coagulation system.
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7. Fluid and Electrolyte changes: There is tendency to salt and water retention due to the effect of increased deoxycorticosterone (DOC) and increased sensitivity to the antidiuretic hormone (ADH). II. Endocrinological Changes (23) 1. Renin angiotensin system Uteroplacental unit is rich in renin secreting cells which is a protective mechanism in uteroplacental hypoperfusion. In uteroplacental hypoperfusion there is increased renin which results in increased angiotensin II and so compensatory increased production of PGI2 leading to vasodilatation. 2. Increased Deoxycorticosterone: leading to Na retention. 3. Aldosteron is decreased than in normal pregnancy due to decreased renal renin . 4. Increased sensitivity to ADH resulting in edema and oliguria. 5. Placental Hormones: increased placental hormones especially estrogen, progesterone and HCG. III. Renal Pathology (24, 41) 1. Glomerular capillary endotheliosis: glomerular cell swelling, mesangeal cell proliferation and fibrin deposits intra and subendothelially. 2. Acute tubular necrosis (reversible) or acute cortical necrosis (irreversible). IV. Uteroplacental Pathology (25) 1. Decreased placental perfusion. 2. Red infarcts and placental abruption. 3. Absent 2nd wave of trophoblastic invasion.

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V. Liver Pathology (26) Occurs in severe cases. 1. Periportal vasospasm, focal hemorrhage, hematoma in the substance of the liver and subcapsular hematoma. 2. Acute fatty degeneration.
3. HELLP syndrome (Hemolysis, Elevated Liver enzymes and Low Platelet

count) occurs in severe cases (26,27). VI. Retinal Changes (23) 1. Retinal exudates or hemorrhage. 2. Blindness which is reversible. VII. CNS Pathology: (23) In severe cases and Eclampsia. Cerebral edema, hyperaemia, thrombosis and hemorrhage (cortical, subcortical, hematoma, hemorrhage in the basal ganglia or pia arachnoid hemorrhage). VIII. Hemorrhage in any Organ: adrenals, stomach, intestine, (28) IX. Coma: (23) Following eclampsia. Due to cerebral edema or hemorrhage.

Diagnosis;
I- Screening;

A method of screening for pregnancy hypertension by a combination of maternal variables, including mean arterial pressure, uterine artery pulsatility index, pregnancyassociated plasma protein-A, and placental growth factor in early pregnancy 11-13 Wks gestation. This method of screening is far superior to the traditional approach, which
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relies entirely on maternal history, (3,4). The maternal mean arterial pressure (MAP) and uterine artery pulsatility index (PI) are increased, and the maternal serum concentration of the placental factors pregnancyassociated plasma protein-A (PAPP-A) and placental growth factor (PlGF) are reduced.(3,4).
II- Prediction: (29,32) The high detection rate for early pre-eclamsia is important because it is associated with increased risk of peri-natal mortality and morbidity and both short term and long term maternal complications. It includes: High risk factors. Rapid weight gain during the 2nd half of pregnancy (due to occult edema). Any increase above 3/4 kg/week in late pregnancy is abnormal. Tests for Prediction: 1. Roll over test is positive (rise of diastolic blood pressure 20 mmHg or more after turning from left lateral to dorsal position). 2. Increased pressor response. 3. Cold pressor test. 4. Inability to increase water excretion. 5. Uric acid: is elevated. 6. Hypercalciuria. 7. Doppler velocimetry to detect uteroplacental hypoperfusion. III. Clinical Manifestations of Pre-eclampsia:
Signs and symptoms and laboratory test results consistent with preeclampsia

Signs and symptoms;

..................................................................................................

Laboratory tests;

- Right upper quadrant pain - Epigastric pain - Retrosternal chest pain - Nausea and vomiting - Shortness of breath/congestive heart failure - Headaches (not responsive to

..................................................................................................

- Persistent proteinuria 300 mg/24 h) - Platelet count < 100,000/mm3) - Liver enzymes (aspartate aminotransferase or alanine aminotransferase) 2 times the upper limit of normal - Serum creatinine > 1.2 mg/dL)

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analgesics) - Visual changes - Altered mental status -Bleeding from mucosal membranes - Jaundice

- Lactic dehydrogenase 2 times the upper limit of normal

Sibai. Diagnosis and management of a typical preeclampsia-eclampsia. Am J Obstet Gynecol 2009.

A. Signs: it is a disease of signs,3 cardinal signs: 1. Hypertension: usually precedes proteinuria, BP 140/90mmHg is considered abnormal during pregnancy. Any increase of 30 mmHg in systolic BP or 15 mmHg in diastolic BP above the basal level is diagnostic. Proteinuria: detected by a. Boiling test. b. Quantitative assay. c. Dipstick test. 2. Edema: occult or manifest, usually after hypertension and may affect the lower extremities, abdominal wall, vulva or may be generalized anasarca. B. Symptoms (non specific): 1. Headache. 2. Blurring of vision. 3. Nausea and vomiting. 4. Epigastric pain (distension of the liver capsule) 5. Oliguria or anuria

IV. Severe Pre-eclampsia and Eminent Eclampsia: (33, 34) The severity of pre-eclampsia is assessed by the frequency and intensity of the symptoms and signs. The more the severity of PET, the more likely is the need to terminate pregnancy.

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Hypertensive Disorders During Pregnancy: Indications of Severity Abnormality Diastolic blood pressure Proteinuria Headache Visual disturbances Upper abdominal pain Oliguria Convulsion Serum creatinine Thrombocytopenia Liver enzyme elevation Fetal growth restriction Pulmonary edema Mild < 100 mg Hg Trace to 1+ Absent Absent Absent Absent Absent Normal Absent Minimal Absent Absent Severe 110 mm Hg or higher Persistent 2+ or more Present Present Present Present Present (eclampsia) Elevated Present Marked Obvious Present

V. Clinical Manifestations of Eclampsia:

Eclamptic fit passes in the following stages
(24):

1. Premonitory stage (1/2 minute): Eye rolled up with twitches of the face and hands. 2. Tonic stage (1/2 minute): Generalized tonic spasm with episthotonus and the patient is cyanosed from asphyxia due to spasm of respiratory muscles and diaphragm. The tongue may be bitten between the clenched teeth. 3. Clonic stage (1-2 minutes): Convulsions occur, tongue may be bitten, face is congested and cyanosed, conjunctival injection, blood stained froth coming out from the mouth, stertorous breathing, temperature may rise and may be involuntary passage of urine or stool. Gradually convulsions stop, cyanosis pass off and the patient may sink into coma
4. Coma
(38,43):

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 Of variable duration due to respiratory and metabolic acidosis. Sometimes deep coma occurs (cerebral hemorrhage) and it indicates poor prognosis. Labor usually starts shortly after the fit, but sometimes labor does not start and convulsions recur again the so called intercurrent eclampsia and carries a bad prognosis. NB; Intercurrent Eclampsia: is eclampsia in which the eclamptic fits recur in the same pregnancy. Recurrent Eclampsia: is eclampsia that recurs in subsequent pregnancy. Eclamptic fit may occur: Antepartum (65%) with the best prognosis. Intrapartum (20%). Postpartum (15%) with the worst prognosis as it indicates extensive pathology and multisystem damage..
Criteria for the severity of Eclampsia (Eden's criteria)
(33):

1. Coma > 6 hours. 2. Temperature > 39C (pneumonia or pontine hge) 3. Systolic Bp > 200mmhg (risk of cerebral hge) 4. Pulse > 120/min. indicates acute heart failure 5. Anuria or Oliguria. Indicates renal failure. 6. Respiratory rate > 40/min. indicates pneumonia 7. More than 10 fits (status eclampticus). VI. Investigations (36, 46,47): A. Laboratory: 1. Urine: 24 hour urine, proteinuria. 2. Kidney functions: serum creatinine, urea, creatinine clearance and uric acid.
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3. Liver functions: bilirubin, Enzymes (SGPT and SGOT). 4. Blood: complete blood picture, Hematocrite (hemoconcentration), hemolysis and Platelet count (Thrombocytopenia). 5. Coagulation Profile: Bleeding and clotting time B. Other Investigations (47,48): 1. Fundus Examination (Ophthalmoscopy): to detect retinal exudates or hemorrhage 2. CT scan for the brain to detect Cerebral hemorrhage. 3. Ultrasonography to diagnose: a. Gestational age. b. Fetal life. c. Presentation and position. d. Oligohydramnios. e. IUGR. f. IUFD. g. Placenta (retroplacental hematoma). 4. Doppler Velocimetry for the umbilical vessels to detect fetuses at risk. VII. Differential Diagnosis: A. Hypertension With Pregnancy: 1. Pre-eclampsia and eclampsia. 2. Chronic Hypertension. 3. Secondary Hypertension (coarctation of aorta, SLE) 4. Chronic Nephritis. 5. Gestational Hypertension.

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B. Proteinuria With Pregnancy: 1. Pre-eclampsia and Eclampsia. 2. Chronic Hypertension. 3. Chronic Nephritis. 4. Contamination with discharge. 5. Collagen Diseases C. Edema With Pregnancy: 1. Gestational edema. 2. General Causes as: renal, cardiac, nutritional and hepatic. 3. Local causes: Inflammation or DVT. 4. Pre-eclampsia and Eclampsia. 5. Orthostatic. D. Convulsions With Pregnancy:
1. Eclampsia
Differential diagnosis of eclampsia;
Cerebrovascular accidents
....................................................................................... ...........

(1,24);

Metastatic gestational trophoblastic disease

.............................................................................................. .............

Hemorrhage

....................................................................................... ...........

Metabolic diseases

Ruptured aneurysm

.............................................................................................. .............

....................................................................................... ...........

Arterial embolism or thrombosis Cerebral venous thrombosis

....................................................................................... ........... ....................................................................................... ...........

Reversible posterior leukoencephalopathy syndrome

.............................................................................................. .............

Hypoxic ischemic encephalopathy Angiomas

Catastrophic antiphospholipid syndrome

....................................................................................... ........... ....................................................................................... ....................

.............................................................................................. .............

Thrombotic thrombocytopenic purpura Postdural puncture syndrome Cerebral vasculitis

Hypertensive encephalopathy Seizure disorder

.............................................................................................. ............. .............................................................................................. ............. .............................................................................................. .............

....................................................................................... .................... ....................................................................................... ....................

Previously undiagnosed brain tumors

........................................................

Sibai. Diagnosis and management of

a typical preeclampsia-eclampsia. Am J Obstet Gynecol 2009

2. Epilepsy. 3. Hysteria.
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4. Meningitis and Encephalitis. 5. Tetanus. 6. Tetany. 7. Strychnine poisoning. 8. Brain tumors. 9. Ureamic convulsions. E. Coma With Pregnancy: 1. Hypoglycemic or hyperglycemic coma 2. Uremic coma. 3. Hepatic coma. 4. Alcoholic coma. 5. Cerebral coma. F. HELLP Syndrome (26,27,36): 1. Acute fatty liver in pregnancy. 2. Viral or drug induced hepatitis. 3. Thrombocytopenic purpura. 4. Hemolytic uremic syndrome.

Prevention;(35,37,44)
Most of the strategies that have been proposed for the prevention of pre- eclampsia have had disappointing results.27 Antiplatelet therapy with aspirin has been proposed as a strategy for preventing preeclampsia by altering the prostacyclin-thromboxane balance. 1. Low dose aspirin: 30-100mg/day, this will decrease TxA2 (from Platelets) and does not affect endothelial prostacyclin (PGI2 which is vasodilator) 2. Calcium supplementation: Decreased serum calcium and decreased urinary excretion of calcium may have a role in the development of preeclampsia. Ca++ supplementation may increase the production of PGI2 from endothelial cells. 3. Magnesium supplementation.
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4. Antioxidants as vitamin C and E. 5. Salt restriction. 6. Prophylactic diuretics and anti hypertensives are contraindicated.

Treatment (42, 43)

1. Expectant treatment. 2. Control hypertension. 3. Prevention and control of convulsions. 4. Treatment of eclampsia 5. Termination of pregnancy . Expectant Treatment (45,46) 1. 2. 3. 4. i.

Rest: Complete Physical and mental rest. Diet: Increase protein and carbohydrate with low Na diet. Sedation: Benzodiazepins or Phenobarbitone. Observation: Maternal: a. Blood pressure. b. Pulse and Respiratory rate. c. Urine output. d. Proteinuria. e. Any new symptoms. f. Investigations (creatinine, creatinine clearance, blood picture, coagulation profile,.) ii. Fetal: fetal wellbeing as daily fetal movement count, NST, CST, biophysical profile, US and Doppler study of the umbilical vessels

Indications for Hospitalization;(37,42)

1-Systolic blood pressure 140 mm Hg and/or diastolic blood pressure
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 90 mm Hg 2- 1+ proteinuria on dipstick 3-> 30 mg of protein per mmol of creatinine 4- Hyperuricemia 5- Platelet count 100 x 109/L 6- Abnormal liver function tests 7- Ultrasound evidence of oligohydramnios 8- Inadequate fetal growth. Control of Hypertension (37,42): A. Parentral drugs: B. Antihypertensive Therapy for Hypertension Disorders in Pregnancy (37,38)
__________________________________________________________________________________________________________

Agent

Initial Dosage

Side Effects

Severe pregnancy hypertension;

Nicardipine Labetalol 5 mg IV/hr 20 mg IV or 200 mg orally (max dose 300 mg IV) Peripheral edema, dizziness, headache Vomiting, dizziness, scalp tingling

Nonsevere pregnancy hypertension;

Methyldopa Labetalol Nifedipine XL 250 mg orally twice daily 100 mg orally twice daily 30 mg orally daily Diarrhea, nausea, myalgia Vomiting, dizziness, scalp tingling Headache, dizziness, flushing, nausea

1. Hydralazine: It is a peripheral VD and the best antihypertensive drug used during Pre-eclampsia and Eclampsia. Dose: 5-10mg IV or IM as initial dose to be repeated every 20-30 minutes until blood pressure is controlled. 2. Labetalol (Trandate): It is and non selective - adrenergic blocker resulting in VD. Dose: 10-20mg IV and the dose can be doubled every 10 minutes if proper response is not achieved. 3. Diazoxide (Hyperstate): It is used in severe dangerous resistant hypertension as a last resort. Dose: 50-150mg IV bolus dose to be repeated every 1-2 minutes until BP decreases.
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B. Oral drugs: 1. -methyl DOPA (aldomet): It is the best and most commonly used. It is -adrenergic agonist causing depletion of catecholamine stores. Dose: 500mg 3-4 times/day orally. 2. Monohydralazine (Aprisoline): It is a weak antihypertensive when given alone, so it used in combination with - blockers to increase its efficacy and decrease its side effects. 3. - adrenergic blockers: as Atenolol (Tenormin) 50-100mg 4 times daily or labetalol (Trandate) 10-20mg 3 times daily. 4. Prazocin (minipres): It is postsynaptic -adrenergic receptor blocker resulting in VD and reflex tachycardia. It is a weak antihypertensive drug so used in combination with other drugs. 5. Calcium Channel Blocker: as Nifedipine (adalat or Epilat) can be used with success. Prevention and Control of Convulsions: (42)
A. Magnesium Sulfate (MgSO4)
(44):

It is the drug of choice. It causes: CNS depression. Mild VD. Mild diuresis. Inhibits platelet aggregation. Increase PGI2 synthesis. It can be given IV (20%) or IM (50%) or SC (15%), The therapeutic level is 4-7mEq/L.
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 IV regimen: initially 4-6 gm (20%) in 100ml solution are given over 15-20 minutes. Then, 2 gm/hour by IV drip. Therapy is stopped 24 hours after delivery. Serum Mg++ level must be checked every 4-6 hours and adjust infusion to maintain level between 4-7 mEq/L. IM regimen: 10 gms of 50% solution are given deeply IM (5 gms in each buttock). Maintain with 5 gm/6 hours of 50% solution IM till 24 hours after delivery. In renal impairment the maintenance dose of MgSO4 is halved with close monitoring of Mg++ serum level. The total dose of MgSO4 should not exceed 24 gms in 24 hours The dose of MgSO4 is monitored by: 1. Preserved patellar reflex. 2. Respiratory rate >16/min. 3. Urine output >100ml/4hours. 4. Serum Mg++ level. Side effects of MgSO4: 1. At a level of 8-10mEq/L patellar reflex is lost and starts myometrial inhibition. 2. 10-15mEq/L respiratory depression. 3. >15mEq/L cardiac depression. 4. Curare like action. 5. Synergistic effect with Ca++ channel blockers. 6. Uterine inertia. 7. Neonatal hypermagnesemia. 8. Decreased beat to beat variability in FHS. Antidote : 10ml of 10 percent calcium gluconate B. Diazepam (Valium): Initially 20-40mg IV slowly then 10-20mg/6hours.

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 IV infusion regimen is also described, with initial dose of 20mg over 5 minutes, then the dose is adjusted at 10mg/hour to maintain drowsiness. This regimen is mainly for eclamptic patients. Side effects: i.Neonatal low APGAR score. ii.Neonatal hyperbilirubinemia.
C. Phyntoin (Epanutin)
(44):

in severe pre-eclampsia the dose is 300mg/day. In

imminent eclampsia the dose is 15mg/kg.

Treatment of Eclampsia (24)

1. General and first aid measures: a. Isolation in a single, quite, semidark room (eclampsia room). b. An efficient nurse should be present. c. The following equipments must be present i. Oxygen source. ii. Airway. iii. Suction apparatus. iv. Bed with movable head and legs with limb ties. d. Ensure patent airway with tracheal and bronchial suction. e. Put the patients in Trendlenburg position (to avoid aspiration of secretions) . f. Insert a catheter, nothing by mouth and fluid chart. g. Observation: i. Pulse, temperature, BP and respiratory rate. ii. Level of consciousness and duration of coma. iii. Fetal heart sounds. iv. Urine output and albuminuria . v. Number of convulsions h. Full laboratory investigation. i. Nasogastric tube may be inserted
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j. Sedation : i. Morphin 10-20mg IM then maintain by diazepam 10mg IV or IM/8 hours. ii. Lytic cocktail (25mg chlorpromazine + 50mg phenergan + 100mg pethidine) given in 500CC fluid over 4 hours and can be repeated after 6 hours but never give 3rd dose. 2. Control of convulsions and prevention of further attacks: a. MgSO4 (as before). b. Sedation (as above). c. Modified Stroganoff method: the use of Morphine + MgSO4. The original Stroganoff method is MgSO4 6gm initially then 4 gm/4hours + 20mg morphine IM. 3. Control of hypertension (see before).. 4. Other drugs: a. Prophylactic digitalis to guard against heart failure. b. Antibiotic for infection. c. IV glucose 25% as a liver support, increases the urine output and improves hemoconcentration. Termination of Pregnancy(48) Indications: 1.Eclampsia. 2.Retinal hemorrhage: by CS to avoid bearing down. 3.Deteriorated cardiac, renal or liver functions. 4.Severe PET not controlled after 24 hours. 5.Mild PET reaching 38 weeks and not controlled. 6.Cases under expectant treatment reaching maturity. 7.Deterioration of the fetal conditions. 8.Other obstetric indications as CPD, malpresentations, APH,(by CS). Methods:
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As a rule vaginal delivery is safer and better than CS. 1.Artificial rupture of membranes and pitocin drip. 2.Caesarean section. Timing: (38)
Mild cases (46):

38 weeks or more : termination of pregnancy Less than 38 weeks: conservative treatment and then termination of pregnancy at 38-40 weeks and dont allow the patient to pass term Severe cases: 34 weeks or more : prevent convulsions , control hypertension, prepare centre for premature baby and termination of pregnancy. 34 weeks or less : prevent convulsions and control hypertension and stabilize the patient then termination of pregnancy. Management during labor (38,47): With the onset of labor give IV hypotensives and sedation. The patient must be at rest with oxygen source and other equipments for treating fits. Maternal observation. Continuous electronic fetal monitoring. Epidural anesthesia is the best for both CS and vaginal delivery. Avoid straining in the second stage. Shorten the 2nd stage by forceps or ventouse. No ergometrine postpartum. MgSO4 stopped 24-48 hours postpartum. Management during CS (38,47): Best done 4-6 hours after the last fit (allow time for recovery from acidosis). Best anesthesia is epidural (provided that DIC is excluded). Follow up after delivery:
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 Improvement is monitored by: Increased urine output. Decreased edema. Disappearance of protienuria within 1 week Decreased hematocrite value to normal level. BP normalize within 2 weeks MgSO4 should be stopped 24-48 hours postpartum.

Work-up of management of Immenent eclampsia and Eclampsia(47)

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Complications of Severe PET and Eclampsia (27,28,36,43)

A- Maternal complications: 1. Airway obstruction and asphyxia during the fit. a. Vomitus aspiration. b. Laryngeal spasm. c. Bitting of the tongue and subsequent edema and bleeding. 2. Intracranial hemorrhage : severe hypertension. 3. Acute pulmonary edema and heart failure.
Pulmonary Edema
o Cardiogenic Systolic dysfunction Diastolic dysfunction Combined o Non cardiogenic Increased capillary permeability o Narrowed COP-wedge pressure gradient a o Decreased COP b o Delayed mobilization of extravascular fluid c o Iatrogenic fluid overload

4. Bronchopneumonia. 5. Renal failure: acute tubular or cortical necrosis. 6. Rupture of subcapsular hepatic hematoma. 7. Placental abruption. 8. Retinal hemorrhage and reversible blindness. 9. DIC. 10. HELLP syndrome. 11. Residual hypertension (25%). 12. Recurrent PET and eclampsia. 13. Maternal mortality: 2% in severe PET - 10% in eclampsia. Causes of maternal mortality (48):
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1. Asphyxia due to vomitus aspiration. 2. Cerebral hemorrhage. 3. Acute pulmonary edema and heart failure. 4. Bronchopneumonia. 5. Acute renal failure. 6. DIC and HELLP syndrome.
B- Fetal complications

(48):

1. Prematurity and its complications due to premature labor or premature termination of pregnancy in severe cases. 2. IUGR : secondary to placental dysfunction. 3. Oligohydramnios: a. Fetal skeletal anomalies. b. IUGR. c. Cord compression. d. Pulmonary hypoplasia. 4. Placental infractions or abruption. 5. Fetal distress: acute or chronic. 6. Perinatal mortality: a. Mild PET 5%. b. Severe PET 25%. c. Eclampsia 30%. Prognosis: BP usually normalize after placental delivery but hypertension may persist. Postpartum eclampsia carries the worst prognosis. Maternal mortality is about 2% in severe preeclampsia and 10% in eclampsia. Perinatal mortality rate is about 5% in mild cases, 25% in severe cases and 30% in eclampsia.

Recurrence (38):
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 Primigravida with mild disease : no recurrence. Primigravida with severe disease : recurrence rate is 15-50% In multipara with severe preeclampsia or eclampsia there is usually underlying disease and recurrence rate is about 70%. The recurrence of HELLP syndrome is about 5%.

Chronic Nephritis Complicating Pregnancy(41,42,43)

Rare complication (1/1000 pregnancies) Past history of nephritis Albuminuria appears before hypertension Albuminuric retinitis Impaired renal functions Urine examination : 1. Low specific gravity (1010) 2. Granular casts 3. Increased urine volume Minimal rise in blood pressure.

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Conclusion; Pregnancy per se aggravates hypertensive vascular disease and remains elusive, despite decades of intensive research; and these disorders remain among the most important unsolved problems in obstetrics (3).
New understanding of the molecular basis for preeclampsia promises to lead to improved therapies and interventions. In the meantime, the need for effective prevention and treatment strategies for preeclampsia is critical. Appropriate management begins with identification of risk factors for preeclampsia in expectant patients, including preexisting hypertension, diabetes, obesity, and twin gestations. Patients without such factors should be monitored for new-onset proteinuria (> 300 mg/24 hr) and hypertension. Clinical vigilance and treatment may lead to improved outcomes while molecular therapies are in development.

References;
1-Sibai, BM, and Stella CL,; Diagnosis and management of atypical preeclampsia- eclampsia, Am J Obstet Gynecol, 2009;200:481.e1-481. 2- Kenneth F, and Trofatter. JR, hypertensive disorders in pregnancy,Hypertension, 2009; 53: 812-818. "Downloaded from internet". 3- Lokesh Upadhyay, M. Mishra, R. Tripathi, and K. Tripathi , 2009, Hypertensive Disorders of Pregnancy "Downloaded from internet". 4- Roberts JM, Pearson G, Cutler J, et al ,; NHLBI Working Group on Research on Hypertension During Pregnancy. Summary of the NHLBI Working Group on Research on Hypertension During Pregnancy. Hypertension, 2003;41:43745. 5-Catov JM, Ness RB, Kip KE, Olsen J. Risk of early or severe preeclampsia related to pre-existing conditions. Int J Epidemiol 2007;36:4129. 6- Catov JM, Ness RB, Kip KE, Olsen J. Risk of early or severe preeclampsia related to pre-existing conditions. Int J Epidemiol 2007;36:4129. 7- August P; Hypertensive disorders in pregnancy. In: Burrow GN, Duffy TP, Copel JA (Eds). Medical Complications During Pregnancy, 2004; 6th ed, Philadelphia: Elsevier. 8- Irwin JC, Suen LF, Martina NA, Mark SP, Giudice LC. Role of the IGF system in trophoblast invasion and pre-eclampsia. Hum Reprod. 1999; 9- Khong TY, De Wolf F, Robertson WB, Brosens I. Inadequate maternal vascular response to placentation in pregnancies complicated by preeclampsia and by small-for-gestational age infants. BJOG. 1986;93: 1049 1059 10- American College of Obstetricians and Gynecologists Committee on Practice BulletinsObstetrics. ACOG practice bulletin: diagnosis and management of pre-eclampsia and eclampsia: Obstet Gynecol. 2002;99:159 167. 11- Snijders RJ, Noble P, Sebire N, Souka A, Nicolaides KH. UK multicentre project on assessment of risk of trisomy 21 by maternal age and fetal nuchal-translucency thickness at 10 14 weeks of gestation. Fetal Medicine Foundation First Trimester Screening Group. Lancet. 1998;352:343346. 12- Kagan KO, Wright D, Baker A, Sahota D, Nicolaides KH. Screening for trisomy 21 by maternal age, fetal NT, free _ hCG and PAPP-A. Ultrasound Obstet Gynecol. 2008;31:618624. 13- Bindra R, Curcio P, Cicero S, Martin A, Nicolaides KH. Uterine artery Doppler at 1114 weeks of gestation in chromosomally abnormal fetuses. Ultrasound Obstet Gynecol. 2001;18:587589. 14- Maynard SE, Min JY, Merchan J, et al . Excess placental soluble fms-like tyrosine kinase 1, (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest. 2003;111:649658.

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15- Ahmad S, Ahmed A. Elevated placental soluble vascular endothelial growth factor receptor-1 inhibits angiogenesis in preeclampsia. Circ Res. 2004;95:884891. 16- Jong Weon Choi, et al; Nitric Oxide Production Increases during Normal Pregnancy and Decreases in Preeclampsia. Annals of Clinical & Laboratory Science, 2002; 32:257-263. 17- Dimitrios P. et al , Vascular endothelial growth factor gene polymorphisms and pre-eclampsia, Molecular Human Reproduction, 2004; Vol. 10, No. 5, pp. 321-324. 18- Tai-Ho Hung D, et al , A Potential Mediator of the Inflammatory Response in Preeclampsia , American Journal of Pathology. 2004;164:1049-1061. 19-R.Madazli, Lipid peroxidation and antoxidants in preeclampsia, European Journal of Obstetrics & Gynecology and Reproductive Biology; 2009, 85: 2, 205-208. 20- Zehra Serdar et al; Lipid and protein oxidation and antioxidant function in women with mild and severe preeclampsia Gynaecology &Obstetrics, 2004; Vol. 268; Apr, 19-25. 21- Scott W. Walsh, Ph.D. What Causes Endothelial Cell Activation in Preeclamptic Women? . Journal of Pathology. 2006;169:1104-1106. American

22- Amanda Gardner; Study Links Protein to Preeclampsia, Jan. 5. 2005, Journal of the American Medical Association, 23- Patricia K. et al; Impairment of endothelial function in women with a history of preeclampsia: an indicator of cardiovascular risk ; Am J Physiol Heart Circ Physiol 2004; 286: 389-393. 24- Lipstein H, Lee CC, Crupi RS. A current concept of eclampsia. Am J Emerg Med 2003; 21: 223-226.

25- Vinnars MT et al, Severe preeclampsia with and without HELLP differ with regard to placental pathology. Epub 2008 May;51(5):1295-9. 26- Knopp U, Kehler U, Rickmann H, Arnold H, Gilemroth J. Cerebral haemo-dynamic pathologies in HELLP syndrome. Clin Neurol Neurosurg 2003; 105: 256-261 27- Knopp U, Kehler U, Rickmann H, Arnold H, Gilemroth J. Cerebral haemo-dynamic pathologies in HELLP syndrome. Clin Neurol Neurosurg 2003; 105: 256-261. 28- Gyi P. et al, Adrenal hemorrhage associated with antiphospholipid antibody syndrome in preeclampsia 2005; Pennsylvania Hospital, Philadelphia, USA.
29-Poon LC, Kametas NA, Pandeva I, Valencia C, Nicolaides KH. Mean arterial pressure at 11(0) to 13(6) weeks in the prediction of preeclampsia. Hypertension. 2008;51:10271033. 30- Poon LCY, Maiz N, Valencia C, Plasencia W, Nicolaides KH. First trimester maternal serum PAPP-A and preeclampsia. Ultrasound Obstet Gynecol. 2008;33:2333. 31- Duckitt K, and Harrington D. Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies. BMJ. 2005;330: 565572.

32- Poon et al, Early Prediction of Pregnancy Hypertension 817, Downloaded from hyper.ahajournals.org by on May 3, 2009. 33- Melanie Smith, 2006 warning signs of preeclampsia.. Health line Pregnancy Guide,.
34- Laurie Barclay Calcium Supplementation May Reduce the Severity of Preeclampsia , American Journal of Obstetrics & Gynecology, 2006. 35- Belfort MA,Anthony J, Saade GR, Allen JC. A comparison of magnesium sulfate and nimodepine for the prevention of eclampsia. N Engl J Med 2003; 348: 304-311. 36- Martin JN jun., Thigpen BD, Rose CH, Cushman J, Moore A, May WL. Maternal benefit of high-dose intravenous corticosteroid therapy for HELLP syndrome. Am J Obstet Gynecol 2003; 189: 830-834. 37- Spinnato JA 2nd. New therapies in the prevention of preeclampsia. Curr Opin Obstet Gynecol 2006;18:6014.

33

38- American College of Obstetricians and Gynecologists Committee on Practice BulletinsObstetrics. ACOG practice bulletin: diagnosis and management of pre-eclampsia and eclampsia: Obstet Gynecol . 2002;99:159 167. 39- Duckitt K, Harrington D. Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies. BMJ. 2005;330: 565572. 40- Bosio PM, McKenna PJ, Conroy R, OHerlihy C. Maternal central hemodynamics in hypertensive disorders or pregnancy. Obstet Gynecol. 1999;94:978 984. 41- Jeyabalan A, Conrad KP. Renal function during normal pregnancy and preeclampsia. Front Biosci 2007; 42- Elisa Ross, Treatment of Pre-Eclampsia , 2004, Spok Company. 43- Magee LA, Helewa M, et al, Hypertension Guideline Committee, Society of Obstetricians and Gynaecologists of Canada. Treatment of the hypertensive disorders of pregnancy. In: Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy. J Obstet Gynaecol Can 2008 Mar;30(3 Suppl 1):S24-36.
44- Lucas, MJ., et al., 2008, A comparison of magnesium sulfate with phenytoin for the prevention of eclampsia. New England Journal of Medicine, 333(4):201 45- Goldenberg, RL., et al. 2008, Bed rest in pregnancy. Obstetrics and Gynecology, 84(1):131-6.

46- Barton, JR, et al. , 2008, Monitored outpatient management of mild gestational hypertension remote from term. American Journal of Obstetrics and Gynecology, 170(3):765-9. 47- Sibai, BM. , 2008, Diagnosis and management of gestational hypertension and preeclampsia. Obstetrics and Gynecology, 102(1):181-92. 48- Nicholson, JM, et al. , 2008, The impact of the interaction between increasing gestational age and obstetrical risk on birth outcomes: Evidence of a varying optimal time of delivery. Journal of Perinatology, 26(7):392-402.

49- Iroldi J, Weinstein L. Clinical significance of proteinuria in pregnancy. Obstet Gynecol Surv 2007;62:117-24.

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