Ovarian Hyperstimulation Syndrome (OHSS)

- It is a complication of some forms of fertility medication. Most cases are mild, but small proportions are severe.

Causative Medications:

- Associated with the injection of a hormone called human chorionic gonadotropin (hCG) which is used for inducing final oocyte maturation and/or triggering oocyte release.

- The risk is further increased by multiple doses of hCG after ovulation and if the procedure results in pregnancy.

- Using a gonadotropin-releasing hormone (GnRH) agonist instead of hCG for inducing final oocyte maturation and/or release results in an elimination of the risk of OHSS, but a slight decrease of the delivery rate of approximately 6%.

Epidemiology:

- Sporadic OHSS is very rare and may have a genetic component.

- Clomifene citrate therapy can occasionally lead to OHSS, but the vast majority of cases develop after the use of gonadotropin therapy (with the administration of FSH), (Menopur, Pergonal, Repronex) and administration of hCG to induce final oocyte maturation and/or trigger oocyte release, often in conjunction with in vitro fertilization (IVF).

- The frequency varies and depends on patient factors, management, and methods of surveillance. About 5% of treated patients may encounter moderate to severe OHSS.

- Mortality is low, but several fatal cases have been reported.

Risk Factors:

- Risk factors include young age, the development of many ovarian follicles under stimulation, extremely elevated serum estradiol concentrations, the use of hCG for final oocyte maturation and/or release, the continued use of hCG for luteal support, and the occurrence of a pregnancy (resulting in hCG production).

Pathophysiology:

- OHSS has been characterized by the presence of multiple luteinized cysts within the ovaries leading to ovarian enlargement and secondary complications.

- The central feature of clinically significant OHSS is the development of vascular hyperpermeability and the resulting shift of fluids into the third space.

- As hCG causes the ovary to undergo extensive luteinization, large amounts of estrogens, progesterone, and local cytokines are released. It is almost certain that vascular endothelial growth factor (VEGF) is a key substance that induces vascular hyperpermeability, making local capillaries "leaky", leading to a shift of fluids from the intravascular system to the abdominal and pleural cavity.

- Supraphysiologic production of VEGF from many follicles under the prolonged effect of hCG appears to be the specific key process underlying OHSS. Thus, while the patient accumulates fluid in the third space, primarily in the form of ascites, she actually becomes hypovolemic and is at risk for respiratory, circulatory, and renal problems. Patients who are pregnant sustain the ovarian luteinization process through the production of hCG.

- Avoiding OHSS typically requires interrupting the pathological sequence, such as avoiding the use of hCG. One alternative is to use a GnRH agonist instead of hCG.

Classification:

Mild OHSS:

- The ovaries are enlarged (5–12 cm), slight weight gain, mild abdominal distension, abdominal pain, nausea, diarrhea, and there may be an accumulation of ascites.

Moderate OHSS:

- Excessive weight gain (> 2 pounds/day or > 1 kg/day), increased abdominal girth, vomiting, darker urine and oliguria, excessive thirst, and dry skin and/or hair (in addition to mild symptoms).

Severe OHSS:

- Marked abdominal distention, lower abdominal pains, darker urine or anuria, pleural effusion, respiratory distress, calf and chest pains. There may be hemoconcentration, and thrombosis (in addition to mild and moderate symptoms).

- Symptoms generally resolve in 1 to 2 weeks but will be more severe and persist longer if pregnancy occurs. This is due to hCG from the pregnancy acting on the corpus luteum in the ovaries in sustaining the pregnancy before the placenta has fully developed. Typically, even in severe OHSS with a developing pregnancy, the duration does not exceed the first trimester.

- Early OHSS develops before pregnancy testing and late OHSS is seen in early pregnancy.

Criteria for Severe OHSS:

- Enlarged ovary, ascites.
- Hematocrit > 45%, WBC > 15,000/microliter.

- Oliguria, creatinine 1.0-1.5 mg/dL, creatinine clearance > 50 ml/min.

- Liver dysfunction, anasarca (extreme generalized edema).

Critical OHSS:

- Enlarged ovary, tense ascites with hydrothorax and pericardial effusion.

- Hematocrit > 55%, WBC > 25,000/microliter.

- Oligoanuria, creatinine > 1.6 mg/dL, creatinine clearance < 50 mL/min.

- Renal failure, thromboembolic phenomena (DVT, PE), ARDS.

Complications:

- Ovarian torsion, ovarian rupture, thrombophlebitis, and renal insufficiency.

Prevention:

- Physicians can reduce the risk of OHSS by monitoring FSH therapy, and by withholding hCG medication.

- Regarding dopamine agonists as prophylaxis, a systematic review and meta-analysis concluded that prophylactic treatment with Cabergoline (Dostinex) reduces the incidence, but not the severity of OHSS, without compromising pregnancy outcomes.

- OHSS may also be prevented by coasting, which is ovarian hyperstimulation in IVF without hCG administration for final maturation of follicles.

Treatment:

Mild OHSS:

- Can be treated conservatively with monitoring of abdominal girth, weight, and discomfort on an outpatient basis until either conception or menstruation occurs. Conception can cause mild OHSS to worsen in severity.

Moderate OHSS:

- Is treated with bed rest, fluids (IV hydration), and close monitoring of labs such as electrolytes (hyponatremia, hyperkalemia, acidosis), blood counts, and coagulation profile (PT, aPTT, INR). Ultrasound may be used to monitor the size of ovarian follicles. Depending on the situation, a physician may closely monitor a patient's fluid intake and output on an outpatient basis, looking for an increased discrepancy in fluid balance (over 1-liter discrepancy is cause for concern). Resolution of the syndrome is measured by decreasing the size of the follicular cysts on 2 consecutive ultrasounds.

Severe OHSS:

- Aspiration of accumulated fluid (ascites) from the abdominal (paracentesis) / pleural cavity may be necessary, intercostal tube, as well as opioids for the pain.

- If the OHSS develops within an IVF protocol, it can be prudent to postpone the transfer of the pre-embryos since the establishment of pregnancy can lengthen the recovery time or contribute to a more severe course. 

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Peripartum Cardiomyopathy (PPCM)

Anesthetic Management of Peripartum Cardiomyopathy (PPCM)

➧ It is a form of heart failure affecting females in their last months of pregnancy or early puerperium.

➧ The role of the anesthesiologist is important in the peri-operative and ICU.

Diagnostic Criteria for PPCM:

➧ Development of heart failure within the last month of pregnancy or 6 months postpartum.

➧ Absence of any identifiable cause for heart failure.

➧ Absence of any heart disease before the last month of pregnancy.

➧ Echo- Criteria of LV dysfunction:

-Ejection fraction < 45%.

-Left ventricular fractional shortening < 30%.

-Left ventricular end-diastolic dimension > 2.7 cm/m² BSA.

Risk factors:

-Black race, Family history.

-Advanced maternal age.

-Multiparity, Multiple gestations.

-Obesity, Malnutrition.

-Gestational HTN, Pre-eclampsia, C.S.

-Poor antenatal care, Breastfeeding.

-Alcohol, Cocaine, and Tobacco abuse.

Incidence:

-1 in 4,000 live births.

-This wide variation may be explained by the influence of genetic and environmental factors, as well as different reporting patterns and diagnostic criteria used.

Etiology:

1) Myocarditis

-It is not known whether it is an association or a cause.

-Only diagnosed by histological examination of endometrial biopsy.

-Also, the vasopressor therapy in PPCM may lead to Histological changes resembling myocarditis.

2) Viral Infection

-During pregnancy, there is a degree of depressed immunity that may lead to viral infection. Viral infection has been implicated as a cause of myocarditis that would lead to cardiomyopathy.

-On the other hand, it has been argued that viral cardiomyopathy should not be included as a cause of PPCM. But rather a separate entity.

3) Autoimmune Theory

-Studies hypothesized, that fetal cells may escape to the systemic circulation triggering an immune response.

-Higher rates of PPCM with twin pregnancies and its familial predisposition support this theory.

4) Inflammatory Cytokines

-In PPCM patients, higher concentrations of inflammatory cytokines like TNF α, CRP, and IL-6 were found. CRP levels correlated inversely with left ventricular ejection fraction (LVEF).

5) Selenium Deficiency

-Significantly low selenium concentrations in PPCM patients were found, still, this might be a mere incidental association rather than a cause.

6) Exaggerated Hemodynamic Response

-In pregnancy, there are physiologic changes in the CVS. It has been postulated that PPCM may be an exacerbation of this normal phenomenon.

7) Prolonged Tocolytic Therapy

-Usually, tocolysis causes tachycardia and vasodilation, so it may actually unmask existing heart disease rather than play an etiologic role.

Diagnosis:

-The symptoms & signs are the same as heart failure.

-You have to exclude other causes of heart failure as valvular and IHD.

Symptoms:

-Dyspnea on exertion, cough, orthopnea, and paroxysmal nocturnal dyspnea, resembling left-sided heart failure.

-Non-specific symptoms include palpitations, fatigue, malaise, and abdominal pain.

-Embolic manifestations may be present, as mural cardiac thrombi commonly occur. The patient may complain of chest pain, hemoptysis, and hemiplegia, rarely myocardial infarction may be the presentation due to coronary embolism.

Signs:

-Blood pressure may be normal/elevated/low.

-Tachycardia, Gallop rhythm.

-Engorged neck veins, Pedal edema

-Clinically, the heart may be normal or there may be mitral and/or tricuspid regurgitation with pulmonary crepitations.

Investigations:

➧ ECG: No specific findings.

➧ Chest x-ray: May show: Cardiomegaly, Pulmonary venous congestion.

➧ Echocardiography: It is the most important diagnostic tool, and assesses the severity and the prognosis of PPCM.

Echo findings are:

-Decreased LVEF and LVFS, Increased LVEDD.

-Dilatation of all cardiac chambers with subsequent functional mitral, tricuspid, pulmonary and aortic regurgitation.

➧ Dobutamine stress Echo: is a better prognostic tool than the ordinary Echo.

➧ TEE and Cardiac MRI: are better tools for detecting intramural thrombi than the ordinary Echo.

Complications:

1-Thromboembolism

-Thrombi often form in patients with LVEF < 35% and are associated with a mortality rate of 50%.

2-Arrhythmias

-All kinds of arrhythmias have been reported up to VT and heart arrest.

3-Organ failure

-Acute liver failure and hepatic coma due to passive liver congestion secondary to cardiac failure. Also, multiorgan failure may occur.

4-Obstetric & Perinatal complications

-There is an increased incidence of Abortion, Premature deliveries, IUGR, and Intrauterine fetal deaths.

Management:

A) Non-pharmacological measures:

-As with any heart failure, salt and water restriction (2-4 g/d., 2 L/d.).

-Once the severe symptoms are improved, modest exercise should be encouraged.

B) Pharmacological measures

-As with any heart failure: (Digoxin, Diuretics, VD, and Anticoagulation) are the mainstay.

-But we have to consider the safety of these drugs in pregnancy and lactation:

1-Digoxin

-It is a class C drug but presumed safe in low doses.

-In a pregnant female, the serum level should be monitored.

-Some studies claimed that digoxin for 6 m. decreases the risk of recurrence of PPCM.

2-Diuretics

-They are safe during pregnancy and lactation.

-Aim to reduce preload.

-Usually, loop diuretics are used and thiazides are used in milder cases. Spironolactone is very beneficial in heart failure but is better avoided during pregnancy.

-Should be used with caution not to induce dehydration and uterine hypoperfusion. Also, metabolic alkalosis may develop.

3-Vasodilators

-They reduce the preload and afterload in heart failure, and so increase the CO.

-Hydralazine and Nitrates are the VD of choice during pregnancy.

-ACEI and ARB are the mainstays in heart failure but they are class D, and contraindicated in pregnancy due to teratogenicity. So, they are considered after labor, but breastfeeding has to be discontinued.

4-Calcium Channel Modulators

-Calcium channel blocker: Although has –inotropic, but has been shown to improve the survival in cardiomyopathy patients. it also reduces the level of inflammatory cytokines so they would play an important in PPCM.

-Levosimendan: is especially valuable and used with success in PPCM. but again, breastfeeding should be avoided during its use.

5-Beta Blockers

-Like CCB, BB now has an important role in heart failure and they are not contraindicated in pregnancy, though associated with low birth weight.

-Both BB and ACEI have an additional role in immunosuppression and prevent remodeling and reduce ventricular dimensions.

6-Antiarrhythmic agents

-No antiarrhythmic agent is completely safe in pregnancy.

-Quinidine and Procainamide have a high safety profile, but treatment should always start in a hospital because of the high incidence of torsades de pointes.

-Amiodarone may cause: Hypothyroidism, Growth retardation, and Perinatal death, So it should be reserved for life-threatening arrhythmias only.

7-Anticoagulation therapy

-Anticoagulation therapy targets patients with LVEF < 35%, bedridden, Atrial fibrillation, Mural thrombi, Obese, or with a history of thromboembolism.

-The therapy may persist for as long as 6 w. in the Puerperium.

-Heparin is used in the antepartum and Heparin or Warfarin is used in the postpartum period as warfarin is contraindicated in the antepartum period due to its teratogenicity.

Obstetric management:

-Induction of delivery should be considered if pt. condition deteriorates despite maximal medical management.

-If the pt. is compensated, normal vaginal delivery is preferred.

-If the patient is severely decompensated or there are obstetric indications, C.S. should be done.

-In both cases, the pt. should be admitted to ICU for early detection of complications.

Anesthetic management:

A) Anesthesia for Vaginal Delivery:

-Controlled epidural a. under invasive monitoring is a safe and effective method.

-Sympathectomy induced by epidural leads to afterload and preload reduction that improves myocardial function in PPCM patients.

B) Anesthesia for Cesarean Section:

Both General anesthesia (GA) and Regional a. (RA) have been used.

1-Regional Anesthesia

-Single-shot spinal a. is not preferred, because of its rapid hemodynamic changes and hypotension.

-Epidural a. is used because of its better hemodynamic stability.

-Continuous spinal a., with its lower failure rates, faster onset, good muscle relaxation, less drug requirement, postoperative analgesia facilities, and better maintenance of hemodynamics has also been successfully applied.

-In severely compromised pt.: Local infiltration with Bilateral ilioinguinal blocks has been used.

2-General Anesthesia

-GA may be needed in emergency situations or when RA is contraindicated, particularly in the anticoagulated patient.

-Advantages: Airway control and ventilation, and it facilitates the use of TEE.

-Disadvantage: It can cause maternal and fetal cardiorespiratory depression, and the stress of rapid sequence induction on the decompensated heart could be dangerous. There is also an increased risk of LVF and pulmonary edema. GA does not provide thromboprophylaxis like RA.

-opioid-based anesthesia may be advantageous in compromised cardiac conditions, but carries a high risk of fatal respiratory depression.

-Monitoring: In mild cases, noninvasive monitoring can be used. in severely decompensated cases, the use of invasive monitoring is a must. This includes the use of an arterial line and may be a pulmonary artery catheter.

C) Postoperative management:

-All PPCM patients should be managed in an ICU as they are prone to develop LVF and pulmonary edema during this period. Also, to monitor the possible complications.

-Postoperative pain can be managed by RA or parenteral opioid-based techniques.

Prognosis:

➧ Poor prognosis criteria, the worst prognosis is found in patients with:

-Higher age and parity, Multiple gestations.

-Black race.

-Later onset of symptoms (> 2 w.) after delivery.

-Coexisting medical illness.

-Delay of initiation of medical treatment.

-Intracardiac thrombi, Conduction defects, Persistence of ventricular dysfunction > 6 m.

Risk of Recurrence in subsequent pregnancy:

-The highest risk of recurrence remains in patients with persistent cardiac dysfunction and the lowest risk is in those whose cardiac functions have been normalized, as evidenced by the dobutamine stress test.

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Management of Pre-eclampsia

➧ The main therapy for pre-eclampsia is to deliver the baby as soon as he/she is most prudent, to enhance maternal and fetal well-being.

1-Magnesium Sulphate (MgSO₂):

➧ Magnesium sulfate has anti-seizure effects as well as being a vasodilator. 

➧ It decreases the pulsatility index in uterine, umbilical, and fetal arteries in women with pre-eclampsia.

➧ It normalizes placental interleukin-6 secretion in a model of pre-eclampsia, which supports the fact that some of its benefits may drive from anti-inflammatory actions. 

➧ The use of MgSO₂ in the management of women with severe pre-eclampsia can reduce the development of eclampsia. However, in women with mild pre-eclampsia, the routine use of MgSO₂ for seizure prophylaxis is not recommended. 

➧ The two most widely used regimens of magnesium sulfate administration are the IV regimen and the IM regimen. 

In the IV regimen: A loading dose of 4 g (usually in 20% solution) is given over 5 min. which is followed by an IV infusion of 1 g/h. for 24 h. after the last seizure.

In the IM regimen: An IV loading dose of 4 g is given over 5 min. followed immediately by 5 g (usually in 50% solution) as a deep IM injection into the upper outer quadrant of each buttock. Maintenance therapy is in the form of a further 5 g IM every 4 h., to be continued for 24 h. after the last fit. If convulsions recur, both regimens advocate a further 2-4 g (depending on the woman’s weight, 2 g if < 70 kg) to be given IV over 5 min.

➧ Parenterally administered magnesium sulfate is cleared almost totally by renal excretion, and magnesium intoxication is avoided by ensuring that urine output is adequate, the patellar or biceps reflex is present, and there is no respiratory depression. 

➧ Eclamptic convulsions are almost always prevented by plasma magnesium levels maintained at 4-7 mEq/L (4.8-8.4 mg/dL or 2-3.5 mmol/L). Patellar reflexes disappear when the plasma magnesium level reaches 10 mEq/L. This sign serves to warn of impending magnesium toxicity. When plasma levels rise above 10 mEq/L, respiratory depression develops, and at 12 mEq/L or more, respiratory paralysis and arrest follow.

2-Antihypertensives:

➧ Due to the risk of hemorrhagic stroke in the presence of systolic hypertension, most guidelines recommend lowering non-severe blood pressure to a systolic level of 140-150 mmHg and a diastolic of 90-100 mmHg. 

➧ Oral safe agents include methyldopa, labetalol, calcium channel blockers (nifedipine or isradipine), and some β-adrenoceptor blockers (metoprolol, pindolol, propranolol) and low-dose diazoxide. 

➧ β-adrenoceptor blockers may cause fetal bradycardia and decrease uteroplacental blood flow.

➧ Atenolol is not recommended due to fetal growth restriction.

➧ Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers are contraindicated.

➧ Methyldopa is the drug of choice, with well-documented safety after the 1st trimester. It is oral dose is 0.5-3 g/d. in 2 divided doses. 

➧ Labetalol oral dose is 200-1200 mg/d. in 2-3 divided doses.

➧ Nifedipine may inhibit labor and has synergistic interaction with MgSO₄. It is oral dose is 30-120 mg/d. of slow-release preparation.

➧ Medical management of blood pressure should be achieved before obstetric or anesthetic interventions if possible. Control of blood pressure with IV hydralazine, labetalol, or infusions of nitroglycerin or nitroprusside should be commenced with arterial and central venous monitoring in severe cases.

Hydralazine:

➧ It is the drug of choice with long experience in safety and efficacy. Its dose is 5 mg IV or IM, then 5-10 mg every 20-40 min.; or a constant infusion of 0.5-10 mg/h. 

➧ It is also typically employed in more refractory cases.

➧ The use of hydralazine is often accompanied by maternal tachycardia and cautious administration of up to 500 ml crystalloid is recommended before or at the same time as the initial dose of IV hydralazine to reduce the chance of a precipitous fall in blood pressure.

Labetalol:

➧ It produces less tachycardia and arrhythmia than other vasodilators. 

➧ Its dose is 20 mg IV, then 20-80 mg every 20-30 min. up to a maximum of 300 mg; or a constant infusion of 1-2 mg/min.

Glyceryl trinitrate (GTN):

➧ It is the pharmacological agent of choice in women with pre-eclampsia and acute pulmonary edema. 

➧ It is administered as an infusion of 5 µg/min., increasing every 3-5 min. to a maximum dose of 100 µg/min.

Sodium nitroprusside (SNP):

➧ Sodium nitroprusside is rarely used in pregnancy and has known maternal adverse effects of hypotension and paradoxical bradycardia in women with severe pre-eclampsia. 

➧ Fetal cyanide toxicity is a complication of prolonged treatment. SNP should be used with extreme caution in situations of life-threatening hypertension, immediately before delivery in circumstances where clinicians are familiar with its use.

➧ It is administered as an IV infusion at 0.25–5.0 µg/kg/min.

3-Aspirin:

➧ Since inflammation appears to play a significant role in the pathogenesis of pre-eclampsia, benefits from aspirin in the prevention of pre-eclampsia and its vascular complications may derive not just from an anti-inflammatory action but from its effect of restoring the balance between thromboxane and prostacyclin in the vasculature. 

➧ Before using aspirin to prevent pre-eclampsia, consideration must be given to the toxicity in the gastrointestinal tract (GIT) and its effects on renal function.

4-Intravenous fluids:

➧ The use of either crystalloid or colloid solutions has been associated with transient improvements in maternal cardiovascular system parameters. 

➧ Fluid management guided by CVP in severe cases has been demonstrated to improve urine output, maintain mean arterial blood pressure, and decrease diastolic blood pressure. 

➧ If oliguria persists after normalization of CVP (usually 2-3 cm H₂O) or the physiologic state is complicated by pulmonary edema or cardiovascular decompensation, a pulmonary artery catheter (PAC) may be helpful.

➧ A cardiology consultation and an assessment of cardiopulmonary function with a transthoracic echocardiogram may assist with the diagnosis and management.

➧ The use of IV fluids to increase plasma volume or treat oliguria in a woman with normal renal function and stable serum creatinine levels is not recommended. 

➧ Acute pulmonary edema is associated with positive fluid balances of > 5500 mL, which is a frequent cause of admission to intensive care and is a leading cause of death in women with pre-eclampsia.

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Complications of Pre-eclampsia

➧ The course of pre-eclampsia can be complicated by mild to severe coagulopathy even in the presence of a normal platelet count.

➧ Severe maternal complications include antepartum hemorrhage due to placental abruption, eclampsia, cerebrovascular accidents, organ failure, and disseminated intravascular coagulation (DIC). 

➧ Deaths are due to intracranial hemorrhage, cerebral infarction, acute pulmonary edema, respiratory failure, and hepatic failure or rupture. 

➧ Eclampsia is the occurrence of seizures in a woman with pre-eclampsia that cannot be attributed to other causes. The seizures are grand mal and may appear before, during, or after labor. Seizures that develop more than 48 h. postpartum may be encountered up to 10 days postpartum. 

➧ Maternal endothelial dysfunction can last for years after the episode of pre-eclampsia. A history of pre-eclampsia is associated with a doubling of the risk for cardiac, cerebrovascular, and peripheral vascular disease compared to women without such a risk factor. Furthermore, such women have an increased risk for renal diseases, such as Focal segmental glomerulosclerosis (FSGS) and microalbuminuria, hypertension, and ischemic heart disease, in later life. 

➧ Pre-eclampsia is the leading cause of fetal growth restriction, intrauterine fetal demise, and preterm birth. 

➧ The children born after pregnancies complicated by pre-eclampsia have also been shown to be at high risk for complications like diabetes mellitus, cardiovascular disease, and hypertension. The pathogenesis of this increased risk has been contributed to fetal malnutrition, epigenetic modification, and postnatal growth acceleration. 

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Pathophysiological changes in Pre-eclampsia

1-Cardiovascular changes:

➧ Hypertension in pre-eclampsia is due to marked vasoconstriction because both cardiac output and arterial compliance are reduced.

➧ There is a reversal of the normal circadian rhythm, with the highest blood pressure now at night, and a loss of the normal pregnancy-associated refractoriness to pressor agents; the sensitivity to infused angiotensin II increases weeks before the overt disease.

➧ Increases in insulin resistance and sympathetic nervous system tone also occur and have been implicated in the vasoconstriction characteristic of pre-eclampsia.

➧ The heart may reveal endocardial necrosis similar to that caused by hypoperfusion in hypovolemic shock.

2-Renal changes:

➧ Renal hemodynamics increase markedly in normal gestation, and renal plasma flow (RPF) and GFR decrease in pre-eclampsia (~25%); thus, values may be still above or at those of a non-pregnant state.

➧ The proteinuria of pre-eclampsia is associated with a pathognomonic renal lesion known as glomerular endotheliosis, in which the endothelial cells of the glomerulus swell and endothelial fenestrations are lost.

➧ Podocyturia has been recently associated with pre-eclampsia during clinical disease.

➧ The decrement in RPF is attributable to vasoconstriction, whereas the fall in GFR relates both to the decrement of RPF and the development of glomerular endotheliosis. In rare cases, acute renal failure may develop.

3-Cerebral changes:

➧ There is increased cerebral blood flow in pre-eclamptic women. Cerebral edema and intracerebral parenchymal hemorrhage are common autopsy findings in women who died from eclampsia. However, cerebral edema in eclampsia does not correlate with the severity of hypertension, suggesting that edema is secondary to endothelial dysfunction rather than a direct result of blood pressure elevation.

➧ Findings from head computed tomography (CT) scans and magnetic resonance imaging (MRI) are similar to those seen in hypertensive encephalopathy, with vasogenic cerebral edema and infarctions in the subcortical white matter and adjacent gray matter, predominantly in the parietal and occipital lobes. This syndrome is known as a posterior reversible leuko-encephalopathy syndrome (PRES).

4-Hepatic changes:

➧ Pre-eclampsia also affects the liver. Manifestations include elevated aspartate aminotransferase and lactic dehydrogenase levels, the increments are usually small, except when the HELLP syndrome supervenes.

➧ The gross hepatic changes in pre-eclampsia are petechiae ranging from occasional to confluent areas of infarction, as well as subcapsular hematomas, some having ruptured and caused death.

➧ The characteristic microscopic lesion is periportal, manifesting as hemorrhage into the hepatic cellular columns and at times concurrent infarction.

5-Coagulation changes:

➧ Pre-eclampsia is associated with activation of the coagulation system, with thrombocytopenia (usually mild) as the most commonly detected abnormality.

➧ There is increased platelet activation and size, plus decrements in their lifespan.

➧ The hypercoagulability of a normal pregnancy is accentuated (e.g. reduced antithrombin III, protein S, and protein C) even when platelet counts appear normal.

➧ Occasionally, the coagulopathy can be severe, as in the HELLP syndrome.

6-Eye changes:

➧ The severity of retinal changes depends upon the degree of hypertension. Retinal changes are likely to occur when SBP is above 150 mmHg and DBP is more than 100 mmHg.

➧ Visual disturbances occur including scotoma, diplopia, diminished vision, and photopsia.

➧ The three most common visual complications are hypertensive retinopathy, exudative retinal detachment, and cortical blindness.

➧ Possible explanations for these complications include coexisting or preexisting systemic vascular disease, changes in the hormonal milieu, endothelial damage, abnormal autoregulation, hypoperfusion ischemia, or hyperperfusion edema.

7-Metabolic changes:

➧ These include dyslipidemia with elevated triglycerides, free fatty acids, and low-density lipoprotein (LDL) cholesterol, and reduced high-density lipoprotein (HDL) cholesterol, with an increased prevalence of low dense LDL.

➧ Insulin resistance and uric acid, other components of the metabolic syndrome, are also increased in pre-eclampsia.

8-Utero-Placental changes:

➧ Shallow and abnormal placentation is a hallmark of pre-eclampsia, highlighted by a failure of the normal trophoblastic invasion of the spiral arteries, these vessels fail to remodel and dilate.

➧ This aberration underlies theories that restriction of placental blood flow leads to a relatively hypoxic uteroplacental environment, with subsequent events mediated through hypoxemia-induced genes resulting in the release of factors (e.g. antiangiogenic proteins) that enter the mother’s circulation and initiate the maternal syndrome.

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Classification and Pathogenesis of  Pre-eclampsia

Classification of Pre-eclampsia:

1. Mild Pre-eclampsia:

Is defined as systolic blood pressure (SBP) of at least 140 mmHg and/or diastolic blood pressure (DBP) of at least 90 mmHg on at least two occasions at least 6 hours apart after the 20th week of gestation in women known to be normotensive before pregnancy and before 20 weeks of gestation plus proteinuria (≥ 300 mg/24 h.). If 24 h. urine collection is not available, then proteinuria is defined as a concentration of at least 30 mg/dL (at least 1+ on dipstick) in at least two random urine samples collected at least 6 hours apart. 

➧ Serum urate levels are often elevated in pre-eclampsia. Hyperuricemia is associated with perinatal complications, and although elevated levels have not predicted adverse maternal outcomes, urate is frequently measured in clinical practice. 

2. Severe Pre-eclampsia:

Is defined as sustained elevations in SBP to at least 160 mmHg and/or in DBP to at least 110 mmHg for at least 6 hours in association with abnormal proteinuria or if there is hypertension in association with severe proteinuria (≥5 g/24 h.). In addition, pre-eclampsia is considered severe in the presence of multiorgan involvement such as pulmonary edema, oliguria (< 500 mL/24 h.), thrombocytopenia (platelet count < 100000 / mm³), abnormal liver enzymes in association with persistent epigastric or right upper quadrant pain, or persistent severe central nervous system (CNS) symptoms (altered mental status, headaches, blurred vision or blindness). 

➧ A severe variant of pre-eclampsia also features hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome). This condition occurs in about 1/1000 pregnancies. Predisposing factors are positive family history, hypertension, diabetes, preexisting renal disease, multiple pregnancies, and poor obstetric history. Pre-eclampsia with hepatic dysfunction, without hemolysis, may occur in severe pre-eclampsia.

Pathogenesis of Pre-eclampsia:

➧ The etiology of preeclampsia remains unknown; however, defective remodeling of spiral arteries during trophoblast invasion is a recognized predisposing factor for pre-eclampsia. Abnormal trophoblast differentiation and incomplete invasion by the placenta of uterine blood vessels leads to the formation of a placenta in which uterine spiral arteries fail to undergo the normal thinning out of muscular walls that permits enhanced perfusion of the placenta. Thus, perfusion of the intervillous space is impaired, leading to placental hypoxia. 

➧ Pre-eclampsia is characterized by placental hypoxia and/or ischemia, excessive oxidative stress, in association with endothelial dysfunction. The release of soluble factors from the ischemic placenta into maternal plasma plays a central role in the ensuing endothelial dysfunction, the most prominent feature of this disease. 

➧ Endothelial dysfunction in pre-eclampsia results from an antiangiogenic state mediated by high circulating levels of soluble Fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin in concert with low levels of proangiogenic factors like placental growth factor (PlGF), vascular endothelial growth factor (VEGF). The placenta makes sFlt1 in large amounts, but circulating mononuclear cells are an extra source of sFlt1 in pre-eclampsia. 

➧ High-circulating levels of sFlt-1 predate the onset and the severity of pre-eclampsia. Thus sFlt1 acts as a potent inhibitor of VEGF and PIGF by binding these molecules in the circulation and other target tissues, such as the kidneys. Thus excessive sFlt-1 plays a central role in the induction of the pre-eclampsia phenotype as sFLt-1 decreases VEGF binding to its receptor which reduces phosphorylation of endothelial nitric oxide synthase (eNOS) by VEGF leading to reduced eNOS. 

Other Pathophysiologic Mechanisms:

Include immunologic intolerance between fetoplacental and maternal tissues, placental and endothelial dysfunction, immune maladaptation to paternal antigens, exaggerated systemic inflammatory response, maladaptation to the cardiovascular or inflammatory changes of pregnancy, dietary deficiencies, and genetic abnormalities. 

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