A. Definition

1. Systolic Blood Pressure (BP) Elevated >30mm Hg
2. Diastolic BP Elevated >15mm
3. or BP >140/90 on two occasions >6 hours apart

B. Syndromes

1. Pregnancy Induced Hypertension (HTN)
   1. Mild (non-proteinuric)
   2. Severe
2. Preeclampsia (formerly toxemia of pregnancy)
   1. Mild
   2. Severe (HELLP Syndrome, see below)
3. Eclampsia
   1. Defined as preeclampsia with seizures
   2. Definition requires that patient have no prior history of seizures
4. Chronic HTN
   1. HTN prior to pregnancy
   2. Underlying Disease

C. Blood Pressure During Pregnancy [3]

1. BP normally falls slightly during normal pregnancy
   1. Upper limit of normal in 1st or 2nd trimester DPB ~75-80mm Hg
   2. Upper limit of normal in 3rd trimester is 85-90mm
   3. BP decrease may be due to several factors including high uterine Prostaglandin synthesis
   4. Pregnant patients also have a decreased response to Angiotensin II vasoconstriction
2. Chronic HTN
   1. Now called Coincident HTN with Pregnancy
   2. Presence of persistent HTN regardless of cause prior to 20 weeks last menstrual period
   3. Absence of gestational trophoblastic disease
   4. BP remains elevated > 6months after delivery
   5. Presence of proteinuria early in pregnancy in women with chronic HTN is a 3 fold risk factor for premature (<35 weeks) birth and to have small for gestational age babies [4]
3. Pregnancy Induced HTN (PIH)
   1. ~5-10% in general obstetric population
   2. As high as 25% in population with preexistent HTN
   3. Believed to include increased risk of subsequent HTN when not pregnant
   4. Transient HTN in pregnancy is a benign condition but is only clear in retrospect [1]
   5. Key is repeated assessment of BP during pregnancy and evalation of preeclampsia
4. Risks of Elevated BP
   1. Fetus: abruption, IUGR, midtrimester death
   2. Mother: Acute Renal Failure, Cerebral Hemorrhage, Ischemic cardiac disease
5. Pathophysiology
   1. Intravascular (ECF) volume depletion
   2. Systemic vasoconstriction (? due to decreased uterine PGE2 and/or PGI2 synthesis)
   3. Abnormal response to Angiotensin II mediated vasoconstriction
   4. Arteriolar vasospasm may explain most aspects of PIH, preeclampsia and eclampsia
   5. Renal blood flow decreases in PIH, and serum urate and BUN increase
   6. Hyperaldosteronism common due to intravascular volume depletion
6. Treatment of PIH [6]
   1. Antihypertensive treatment of PIH is beneficial to the mother [6]
   2. Antihypertensive treatment of PIH is of questionable benefit to fetus [6]
   3. Some concern that large drops in maternal BP can lead to fetal growth restriction [8]
   4. Methyldopa, clonidine and ß-blockers are safe and effective, reduce fetal risks
   5. Thus PIH should be treated with safe agents
   6. Reducing BP to less than 170/110 mm Hg may not be necessary
7. Aspirin (ASA)
   1. Low dose (50-80mg qd) ASA is ineffective in preventing PIH
   2. Low dose ASA has conflicting results in preeclampsia prevention [10]
   3. Thus, ASA appears to provide no benefit for PIH or other HTN associated disorders [10]
8. Calcium Supplementation [12]
   1. Patients begin taking 2gm CaCO3 qd at 20 weeks gestation
   2. Overall reduction in 5.4/3.4mmHg BP in meta-analysis
   3. Meta-analysis also demonstrated a 62% reduction in preeclampsia with calcium
   4. However, this was not confirmed in a careful prospective study
   5. Calcium supplementation does not reduce HTN or preeclampsia severity or onset

D. Preeclampsia [13,26]

1. Definition
   1. HTN
   2. Proteinuria (>300mg/24 hours or >1gm/L on urinalysis)
   3. Optional (not required): Edema (non-dependent)
2. Occurrence / Risk Factors
   1. Third trimester or postpartum
   2. Low maternal age
   3. Primigravida (~15% PIH in recent studies)
   4. Multiple Pregnancy (large placental mass)
   5. HTN Antedating pregnancy
   6. Primigravida
   7. Short Stature (maternal)
   8. Maternal Diabetes Mellitus (~25% of patients; large placental mass)
   9. Fetal Hydrops
   10. Thrombophilic Disorders
   11. Elevated urinary placental growth factor (mid gestation) [5]
3. Pathogenesis Overview [26,28]
   1. Trophoblast dysfunction has been suggested [14]
   2. Abnormally shallow invasion of spiral arteries from uterus into placenta is well documented
   3. This leads to placental insufficiency (reduced placental perfusion)
   4. Reduced placental perfusion appears to be necessary, but is clearly not sufficient
   5. Thrombophilia risk factors
   6. Hyperhomocysteinemia associated with elevated risk
   7. Absolute and relative decreases in maternal blood flow
   8. Genetic factors have been implicated on both maternal and fetal side [26]
   9. Maternal history of preeclampsia increases fetal risk 3.3X [31]
   10. Paternal history also contributes to development of preeclampsia 2.1X [31]
   11. Reduced HB-EGF in trophoblast may lead to poor invasion into placenta (see below) [27]
   12. Reduced functional levels of angiogenic factors implicated in preeclampsia risk [11]
4. Maternal Endothelial Dysfunction [30]
   1. Can explain many of the symptoms
   2. Women with history of preeclampsia have reduced flow-mediated arterial dilatation [30]
   3. Serum levels of inhibitor of vasodilator nitric oxide such as asymmetric dimethylarginine are elevated in women who subsequently develop PIH associated syndromes [21]
   4. Sera from patients with preeclampsia induces marked dilation of normal endothelia
   5. Preeclamptic sera increases albumin flux through endothelium
   6. Activation of endothelium is mediated through Protein Kinase C alpha and epsilon
   7. Inhibitors of PKC block albumin flux through endothelium
   8. Ca2+ and soluble ICAM 1 increase after exposure of endothelium to preeclamptic sera
   9. Ascorbate (Vitamin C) improved arterial dilatation in women with history of preeclampsia [30]
5. Role of Prostacyclin [16]
   1. Prostacyclin (PGI2) production is reduced months before onset of pre-eclampsia [16]
   2. Thromboxane A2 (TXA2) synthesis does not appear to be affected in pre-eclampsia [16]
   3. Levels of maternal endothelial plasminogen activator inhibitor 1 (PAI-1) increased
   4. Levels of placental PAI-2 are decreased in preeclampsia [17]
6. Cytotrophoblast fails to induce normal spiral artery invasion of placenta [27]
   1. In addition, trophoblast in pre-eclampsia undergoes premature apoptosis
   2. Heparin-binding epidermal growth factor like growth factor (HB-EGF) may be involved
   3. HB-EGF is found in high levels in trophoblast throughout placenta in first trimester
   4. HB-EGF inhibits apoptosis and stimulates trophoblast invasion
   5. HB-EGF levels are reduced ~5X in pre-eclamptic pregnancies
7. Angiogenesis
   1. Dysfunctional angiogenesis implicated in abnormal pre-eclamptic arterial development
   2. Soluble fms-like tyrosine kinase 1 (sFlt-1) is soluble vascular endothelial growth factor receptor 1 (sVEGFR1)
   3. sFlt-1 and soluble endoglin are anti-angiogenic factors [34]
   4. sFlt-1 binds to and blocks vascular endothelial (VEGF) and placental (PlGF) growth factors
   5. Elevated levels of sFlt-1 have been found in patients with preeclampsia [11]
   6. sFlt-1 and soluble endoglin together induce severe preeclampsia in pregnant rats
   7. Circulating soluble endoglin levels increase markedly 2-3 months prior to preeclampsia
   8. Soluble endoglin levels are significantly higher in term and preterm preeclampsia compared with normal pregnancies [34]
   9. Reduced angiogenic activity may partially explain failure of spiral artery invasion
8. Thrombophilia Risk Factors [14]
   1. Thrombosis and pro-atherogenic factors
   2. Mutations in Protein C, S and/or Antithrombin
   3. Antiphospholipid (anticardiolipin and antiprothrombin) antibodies [29]
   4. Factor V Leiden mutation
   5. Methylenetetrahydrofolate reductase (MTHFR) mutations
   6. Prothrombin (Factor II) gene mutations
   7. These mutations may also predispose to other pregnancy complications
9. Clinical Pathophysiology
   1. Initial placental trigger with systemic response by mother [2]
   2. Intravascular volume depletion with secondary hyperaldosteronism
   3. Systemic vasoconstriction probably related to increased response to angiotensin II
   4. Increased placental debris in maternal circulation; may be due to reduced angiogenesis [13]
   5. Sympathetic nervous system hyperactivity has been documented (HTN)
   6. Extracellular, interstitial fluid increase (Edema)
   7. Decreased renal blood flow with glomerular and tubular damage (Proteinuria)
   8. Renal increased resorption of BUN and Uric Acid (urate is highly sensitive for PIH)
   9. Peripheral vasospasm (possible angiotensin II effect)
   10. Abnormal coagulation including antiprothrombin antibodies may play a role [29]
   11. Cerebral vasospasm may lead to convulsions (Eclampsia)
10. Signs and Symptoms
    1. Headache - usually frontal (may be related to hypertension)
    2. Right upper quadrant or epigastric pain - may be hepatic subcapsular hemorrhage
    3. Oliguria: <400mL/day or <30cc/hr with proteinuria >300mg/24 hours
    4. Visual Disturbances - scintillations, blindness
    5. Hyperreflexia and clonus
    6. Up to 20% maternal mortality in severe preeclampsia
11. Diagnosis
    1. BP monitoring
    2. Physical Examination - attention to non-dependent edema
    3. Weight gain >1kg/week or 3kg/mo requires investigation
    4. Proteinuria (1+ or more on dipstick) should be evaluated with 24 hour urine collection
    5. Serum urate and blood urea nitrogen (BUN), liver function test increases (AST, LDH)
    6. Evaluate for DIC and HELLP Syndromes (Severe Preeclampsia)
    7. Newer tests: antithrombin (AT III), serum Fe, and urinary calcium may be useful
    8. Highly elevated levels of inhibin A, activin A, and pro(a)C are found in pre-eclampsia [14]
    9. Evaluation of prostacyclin (PGI2) levels may be beneficial in evaluation [16]
    10. These tests may be useful for diagnosis and monitoring of therapy
    11. Renal biopsy may be required to distinguish preeclampsia from other renal disease
    12. Consider genetic evaluation for patients with hypertensive pregnancy disorders [14]
    13. Ratio of PAI-1 to PAI-2 increased in preeclampsia and may be useful for screening [17]
    14. Reduced levels of urinary placental growth factor mid-gestation [5]
    15. Ten of 28 women with severe preeclampsia had antiprothrombin antibodies with specificity for prothrombin fragment-1 [29]
12. Complications of Severe Preeclampsia [13]
    1. Abruptio placenta (~2%)
    2. HELLP Syndrome (see below; ~15%)
    3. Pulmonary edema / aspiration (~3%)
    4. Acute renal failure (ARF, ~3%)
    5. Eclampsia (<1%)
    6. Liver failure or hemorrhage (<1%)
    7. Rare: stroke, death, long-term cardiovascular morbidity
    8. Preterm delivery (~35%)
    9. Fetal growth restriction (~15%)
    10. Hypoxia-neurologic injury (<1%)
    11. Prenatal death (1-2%)
13. Disseminated Intravascular Coagulopathy (DIC)
    1. HELLP Syndrome
    2. Abruption (premature separation of fetus-placenta)
    3. Amniotic fluid embolism
    4. Fetal Death in utero
    5. Infection

E. Treatment and Prevention of Preeclampsia

1. Close surveillance with early detection critical improves outcome
2. Mid-gestation reduced urinary placental growth factor levels [1]
3. Bed rest with left side down
4. Sedation may be required with bedrest; consider phenobarbital 30-60mg po qid)
5. Termination of pregnancy: 20-24 weeks is indicated; C-section >26 weeks
6. BP control only for Diastolic BP >95mm
   1. Hydralazine 5-10mg IV q 20-30 min is no longer the preferred agent
   2. Calcium channel blockers are currently the preferred agents
   3. Labetolol - 20-80mg IV bolus every 10 minutes or 0.5-2mg/min infusion IV
   4. Atenolol 50-100mg po qd
   5. Diazoxide - 30mg IV bolus; preeclamptic patients very sensitive
7. Magenesium Sulfate [32]
   1. Stabilizes seizure threhold and reduces BP
   2. Reduces maternal mortality ~45% in women with preeclampsia
   3. Reduces risk of developing full-blown eclampsia
   4. Reduces risk of placental abruption ~33%
8. Contraindicated
   1. Thiazides
   2. ACE Inhibitors and Angiotensin II receptor blockers (ARB) - fetal wastage
   3. Nitroprusside - cyanide toxicity
9. Prevention [,]
   1. Early treatment of HTN in pregnancy likely reduces preeclampsia
   2. Alpha-methyldopa, labetolol are first line; nifedipine is alternative first line [15]
   3. ASA did not prevent development of pre-eclampsia in high-risk patients [10]
   4. Antiplatelets did provided 10% overall pre-eclampsia risk reduction in all comers [7]
   5. Calcium supplementation does not prevent pre-eclampsia in high-risk patients
   6. Combined vitamin C and E supplements did not reduce risk of pre-eclampsia [9,20]
10. Correction of prostacyclin (PGI2) deficiency may be beneficial in pre-eclampsia [16]

F. HELLP Syndrome [18,19]

1. Components of Syndrome
   1. Hemolysis - micrangiopathic, intravascular
   2. Elevated Liver enzymes - transaminase elevations
   3. Low Platelets - consumptive coagulopathy may develop
2. Occurrance
   1. Preeclampsia complicates about 3% of pregnancies in the USA
   2. HELLP syndrome occurs in ~0.1% of all pregnancies in the USA
   3. Two thirds of cases occur at 27-36 weeks
   4. One third of cases occur after delivery
3. Symptoms
   1. Fatigue and malaise
   2. Abdominal pain and nausea
   3. Jaundice
   4. Headache
   5. Bruising
4. Maternal laboratory abnormalities peak 1-2 days post-partum
   1. HTN
   2. Right upper quadrant pain
   3. Hemolysis - elevated lactate dehydrogenase and bilirubin
   4. AST and ALT 2-10X normal
   5. Platelets <100K/µL
   6. Highly elevated glutathione S-transferase alpha (liver damage enzyme)
5. Etiology
   1. Unclear pathogenesis
   2. Platelets deposed (consumed) on damaged endothelial surfaces
   3. Liver endothelial and parenchymal damage
   4. Fragmented schizocytes similar to other microangiopathic hemolytic anemias
   5. HTN may be due to increased endothelin, serotonin, thromboxane from placenta
   6. Some relationship to acute fatty liver of pregnancy
6. Treatment
   1. Delivery is critical to maternal and fetal well-being
   2. Delivery is carried out under the most controlled situation possible
   3. Strict bed rest with left lateral decubitus position has been advocated
   4. For <34 weeks gestation, give magnesium sulfate and glucocorticoids
   5. For <26 weeks gestation, attempt to delay delivery until further maturity
7. Complications of HELLP Syndrome
   1. Disseminated intravascular coagulopathy (DIC)
   2. Abruptio placentae
   3. Renal Failure
   4. Pulmonary Edema
   5. Fetal Thrombocytopenia
   6. Fetal Loss - perinatal mortality of infant ~35%
   7. Increased risk of recurrence in subsequent pregnancies
   8. Maternal death may occur in 10-15% of patients

G. Prevention of PIH [28]

1. The following are sometimes used, but no clear documented benefits
   1. Bed rest
   2. Calcium
   3. Aspirin (ASA) - antiplatelet agents provide modest benefit in preventing pre-eclampsia [7]
2. Calcium [12,28]
   1. No overall benefit in larger studies but may be useful in women with low calcium intake
   2. Intake should be ~2gm per day
   3. No side effects reported (no increased incidence of renal stones, tetany, GI dysmotility)
   4. May be relatively contraindicated in patients with history of renal stones
3. ASA [23]
   1. ASA appears to provide no benefit for PIH [10]
   2. Antiplatelet agents provided 10% risk reduction in pre-eclampsia [7]
   3. Antiplatelet agents reduced risk of delivering at <34 weeks by 10% [7]
   4. Questionable benefit in patients with anti-phospholipid antibodies
4. Treatment with alphamethyldopa, labetolol or nifedipine [15]

H. Eclampsia [33]

1. Definition: Preeclampsia with Convulsions (in patients without active seizure disorder)
2. Classified by timing of initial convulsion (ante-partum, intrapartum, post-partum)
3. Variable post-ictal somnolence
4. Managed best with magnesium sulfate therapy (no effect on fetus)
5. Risk for Death
   1. Cardiogenic pulmonary edema
   2. Intracerebral hemorrhage
   3. Respiratory Failure
   4. Renal Failure
6. Laboratory Evaluation
   1. Complete blood count (CBC) and coagulation parameters (PT/PTT)
   2. Serum Electrolytes with Ca and Mg
   3. Liver and Renal Function Tests
7. Preeclampsia aspects treated as above
   1. C-Section for >26 weeks
   2. Termination of pregnancy 20-24 weeks (unclear 24-26 weeks)
8. Treatment and Prophylaxis for Seizures
   1. Magnesium sulfate (MgSO4) clearly superior to phenytoin for prevention of seizures in hypertensive pregnant women at delivery [24]
   2. Magnesium is considerably superior to nimodipine for prevention of seizures in women with severe pre-eclampsia [22]
   3. 20mL 20% MgSO4 IV immediately (Stat! 4gm total) in patients with seizures
   4. 10mL 50% MgSO4 IM each buttock (10gm total) loading dose ± iv dose above
   5. 10mL of 50% MgSO4 IM q 4 hrs or iv drip
   6. Continue iv drip / injections until: UO<100cc in 4hrs, reflexes disappear, RR<12/min
   7. Measure serum Mg levels: Therapeutic 2.0-3.0; toxic >5.0
   8. Side effects of Mg: repiratory depression, hyporeflexia, cardiovascular, tocolytic
   9. Antidote for toxicity is calcium gluconate
   10. Other Seizure Medications: Phenytoin (dilantin), Phenobarbital, Diazepam
9. However, magnesium reduced risk of cerebral palsy in low birth weight babies [25]
10. Only cure for pre-eclampsia or eclampsia is delivery

Resources

Mean Arterial Pressure (MAP)

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