Obstetrics and Gynecology
- Stroke and pregnancy
- 1. What every clinician should know
- Clinical features and incidence
- 2. Diagnosis and differential diagnosis
- 3. Management
- 4. Complications
5. Prognosis and outcome
6. What is the evidence for specific management and treatment recommendations
Stroke and pregnancy
1. What every clinician should know
Clinical features and incidence
Stroke may be categorized as ischemic or hemorrhagic. Most strokes are ischemic in the non-obstetrical population. The clinical manifestations will depend on the vascular area of the brain involved.
Ischemic strokes may arise from local arterial thrombosis (e.g., atherosclerotic plaques that rupture, leading to thrombosis in situ) or may be secondary to embolic phenomena coming from clots in other parts of the body, such as the left atrium in patients with atrial fibrillation, carotid atherosclerotic plaques that rupture, or paradoxical emboli from a pelvic deep venous thrombosis where a clot goes from the right heart to the left heart through a patent foramen ovale or an existing congenital heart defect. Ischemic strokes may also involve thrombosis of the cerebral veins and sinuses. The latter is a rare condition, but, when found, is typically in the post-partum period.
Hemorrhagic strokes include intracerebral hemorrhages (ICH) and subarachnoid hemorrhages (SAH). ICH are commonly associated with hypertensive emergencies, and most are located in the basal ganglia. SAH may be due to rupture of aneurysms or arteriovenous malformations (AVM) with subsequent accumulation of blood in the subarachnoid space. In the non-obstetric population, most non-traumatic SAH are secondary to aneurysmal rupture. In younger populations, such as pregnant women, AVM rupture plays an important role in the etiology of SAH.
Physiologic changes of pregnancy increase the risk for both ischemic and hemorrhagic strokes. The increase in blood volume/cardiac output coupled with a decrease in the collagen and elastin content of blood vessel walls predispose pregnant patients to hemorrhagic strokes. Similarly, the hypercoagulable state of pregnancy increases the risk of ischemic strokes, with the highest risk in the post-partum period.
Certain obstetrical conditions may lead to strokes. Preeclampsia may be associated with hypertensive-related ICH and even ischemic strokes (secondary to excessive cerebral vasoconstriction as a result of extreme auto-regulation). Ischemic strokes may also occur postpartum as part of postpartum angiopathy syndrome, a condition associated with diffuse cerebral vasospasm.
2. Diagnosis and differential diagnosis
The clinician should suspect an ongoing stroke in any patient with new onset of neurological complaints/deficits such as coma, confusion, severe headache, seizures, and motor or sensorial focalizations.
ICH may manifest with a wide variety of symptoms depending on the extent of the bleed. History of poorly controlled hypertension or severe preeclampsia is an important risk factor for ICH. Patients may have profound coma with inability to protect the airway or may only complain of severe headache. In patients with an elevated intracranial pressure (normal is < 20 mmHg) secondary to mass effect from edema and/or mass effect from hematoma, the classical Cushing's triad may develop (hypertension, bradycardia, and abnormal respiratory pattern).
This triad is the result of the body's compensatory mechanism to maintain cerebral perfusion pressure (CPP is the mean arterial blood pressure minus intracranial pressure) through liberation of cathecolamines, leading to hypertension with concomitant bradycardia mediated through the baroreceptor response. Ideally, CPP should be > 60 mmHg at all times.
The typical clinical presentation of an SAH is the complaint of the "worst headache of my life." SAH also are commonly accompanied by photophobia and nuchal pain/rigidity. Similar to ICH, the clinical presentation of SAH will depend on the extent and location of the hemorrhage. Most aneurysms are located in the posterior cerebral communicating artery, followed by the anterior cerebral communicating artery and the middle cerebral artery. Massive bleeds will present with coma or death.
The key point is to suspect the possibility of this condition in the appropriate patient. In any patient with new onset focalizations, seizures, unexplained coma, and hypertensive emergencies with persistent neurologic complaints, it is necessary to image the central nervous system with a non-contrast computed tomography (CT). This is the optimal initial imaging modality because if contrast is administered and the patient had an SAH, the contrast material will obscure the identification of aneurysms/AVMs in the subsequent diagnostic tests (mainly angiography).
ICH will be diagnosed with the first non-contrast enhanced CT. Blood usually appears to be bright on the scan. If the first scan reveals blood in the subarachnoid space, then identification of the source of bleeding is of paramount importance to guide therapeutic modalities. The next step is to perform a diagnostic angiography. In many hospitals, the use of magnetic resonance angiography (MRA) is increasingly used to identify the source of SAH (aneurysms or AVMs). Small aneurysms (< 1 mm) may not be readily detected by MRA, requiring classical angiography for the diagnosis.
Remember that the initial CT scan may fail to identify an SAH in 10% of cases. Similarly, the initial angiography may fail to identify the source of the bleeding in 10 - 30% of cases. Usually these patients will be managed with conservative therapy, with follow up imaging in a week.
Similarly to hemorrhagic strokes, the clinical diagnosis of ischemic strokes is suspected based on the findings of acute onset of a focal neurologic deficit without an alternative cause. Always rule out conditions such as hypoglycemia, electrolyte disorders, metabolic encephalopathy from the liver, or kidney disease.
The initial imaging modality should be, similar to the work up in the case of a hemorrhagic stroke, a non-contrast enhanced CT. If the CT is normal, the clinical findings are consistent with ischemic stroke, and other potential causes for the symptoms have been ruled out, then an ischemic stroke is likely and the patient should be considered for thrombolytic therapy (early neurology consult is of paramount importance in these cases). Brain ischemia may be identified with magnetic resonance imaging (MRI), even though it is not required for a definitive diagnosis when choosing to administer thrombolytics.
Ischemia of the brain leads to cytotoxic edema secondary to dysfunction of the sodium-potassium ATPase pump, resulting in sodium accumulation inside the neurons with concomitant intra-cellular edema. This type of edema is in contrast with vasogenic edema, which is secondary to increased hydrostatic pressure inside blood vessels with resultant fluid leakage into the third space (e.g., posterior reversible encephalopathy syndrome or hypertensive encephalopathy). MRI using fluid attenuated inversion recovery (FLAIR), diffusion weighted imaging (DWI), and apparent diffusion coefficients (ADC) is both sensitive and specific in differentiating vasogenic from cytotoxic edema.
Patients in the post-partum period complaining of severe headaches and/or neurologic focalizations frequently need to have thrombosis of the cerebral veins and sinuses ruled out. The optimal diagnostic test for this condition is magnetic resonance venography (MRV). Any sinus may be involved, but most thrombosis will be located in the transverse cerebral sinuses.
If the pregnant patient requires neuroimaging to establish the diagnosis, studies should not be withheld due to concerns regarding radiation exposure to the fetus. When possible, MRI should be used, as it does not involve ionizing radiation. However, CT scans should be used as indicated if MRI is not available. During imaging, the fetus must be properly shielded to minimize radiation exposure.
Although CT and MRI without contrast can almost always distinguish between hemorrhagic and ischemic strokes, if the source of a bleeding episode must be indentified (e.g., an aneurysm or an AVM in a patient with SAH), the use of contrast media for vascular imaging is necessary. Both iodinated and gadolinium-based contrast media cross the placenta and enter the fetal circulation. Afterwards, these agents are excreted renally into the amniotic fluid and then swallowed by the fetus.
Limited data exists on the potential teratogenicity of both contrast media. The use of iodinated contrast media for CT studies and paramagnetic contrast media (gadolinium) for MRI should be limited during pregnancy, but not withheld if the clinical situation requires its use per the American College of Obstetricians and Gynecologists and the American College of Radiology.
Only small amounts of contrast media (iodinated or gadolinium) reach maternal milk. If a woman who is breast feeding receives intravenous contrast, lactation should be discontinued for the next 24 hours.
Once the diagnosis of stroke has been confirmed, efforts should be made to ensure the best possible neurologic outcome and avoid secondary brain injury(from hyperthermia, hyperglycemia, seizures, hyponatremia, and malnutrition).
If an ischemic stroke is diagnosed, the first therapeutic dilemma will be whether thrombolytic therapy (recombinant tissue plasminogen activator (rTPA) and Alteplase) should be administered. rTPA is the most effective therapy available for patients with ischemic stroke. If, after an evaluation by the obstetrician and the neurologist, it is believed that the patient will benefit from the use of thrombolysis, it may be used during pregnancy. The effect on the fetus appears to be minimal as the large molecular weight of rTPA limits placental transfer. Candidates for rTPA should have a significant neurologic deficit during examination, and this deficit should not be rapidly improving, otherwise the patient may not need the thrombolytic.
The time frame between the onset of symptoms and the administration of rTPA is very important. Typically, rTPA has been indicated for patients presenting within 3 hours from the onset of symptoms. New data has extended this time frame to 4.5 hours. Contraindications to the use of rTPA include:
Initial CT scan with evidence of hemorrhagic stroke or a large ischemic stroke, which increases the possibility of hemorrhagic transformations with thrombolysis.
Any history of a previous hemorrhagic stroke.
Brain tumors, cerebral aneurysms, or AVMs.
Uncontrolled hypertension (> 185/110).
Seizures at stroke onset.
Platelet count < 100,000 mm³, current therapy with heparin with prolonged aPTT, or with warfarin and INR above 1.7.
Major surgery or serious trauma in the last 2 weeks.
Gastrointestinal or genito-urinary bleeding in the last 3 weeks.
Stroke or head injury in the last 3 months.
It is important to check blood glucose levels prior to administering rTPA to ensure that the symptoms are not secondary to either hypoglycemia or hyperglycemia.
If the patient presents with severe hypertension and is a candidate for thrombolytic therapy, an arterial line should be placed and parenteral antihypertensive therapy started with either labetalol or nicardipine to maintain blood pressure below 185/110. rTPA is given in a dose of 0.9 mg/kg (maximum 90 mg) IV in 1 hour, with 10% of the dose given in the first minute and the rest in 60 minutes. During administration, the blood pressure should be kept < 180/105.
After the infusion, the patient should remain in the ICU, and no antiplatelet agents or heparin should be given for 24 hours. After 24 hours, DVT prophylaxis may be started if indicated, while low dose heparins and aspirin may be started at 325 mg the first day, then 100 mg/day thereafter. If the patient is not a candidate for rTPA, then treatment is mainly based on antiplatelet therapy (aspirin 325 mg the first dose, then 100 mg a day) and DVT prophylaxis should be administered if required.
In patients not receiving rTPA, blood pressure management is important. Very high blood pressure leads to higher hydrostatic intravascular pressure with more cerebral edema and a higher risk of conversion into hemorrhagic stroke. On the other hand, low blood pressure may decrease cerebral perfusion pressure, leading to worsening ischemia. Current guidelines recommend antihypertensive therapy if blood pressure is > 220/120.
When treated, the aim should be to reduce blood pressures by 15%. Remember that the reason for the hypertension commonly is a compensatory mechanism to maintain cerebral blood flow in the setting of high intracranial pressure secondary to brain edema that forms after the ischemic insult. Again, the recommended agents are labetalol and nicardipine.
Most of the literature does not recommend full anticoagulation in the setting of an acute ischemic stroke (even if cardio-embolic etiology). Full anticoagulation in a "fresh" ischemic stroke increases hemorrhagic transformations of the stroke. After the acute phase, secondary prophylaxis with either clopidogrel or a combination of aspirin-dipyridamole are superior to aspirin alone.
If the initial work up is consistent with a thrombus in the cerebral veins or sinuses, which is frequently seen in the post-partum period, the management is different. These are ischemic strokes, but 40 - 50% will have hemorrhagic transformations at the time of the diagnosis. Therapy involves full therapeutic anticoagulation with heparin or low molecular weight heparin. Anticoagulation should be continued for a period of 6 months, and warfarin may be used if the patient is not pregnant.
The management of patients with intracerebral hemorrhages (ICH) is mainly supportive. Most of these are secondary to hypertensive emergencies. Current guidelines recommend treating hypertension in the setting of ICH when blood pressure is > 180/110 (MAP > 130). Recent data suggests that lowering blood pressure in the setting of ICH to systolic blood pressures around 140 mmHg may be safe and may limit hematoma expansion. The clinical significance of this is unknown.
A rational approach may be to maintain systolic blood pressures between 140 - 180. Normalization of blood pressure is not recommended, as this may lead to cerebral hypoperfusion. In patients where the ICH is secondary to the use of anticoagulants, the cornerstone of therapy will be to reverse the anticoagulation, either with fresh frozen plasma, prothrombin concentrate complexes, or activated recombinant factor VII.
The role of surgery in ICH is controversial and beyond the scope of this review. Infratentorial hemorrhages (cerebellar hemorrhages) should have an early neurosurgery consult to evaluate for emergent evacuation, since there is limited space for these bleeds to expand. Evacuation is frequently required if there is evidence of brain stem compression, hydrocephalus, or clinical deterioration. Small, deep cerebellar hemorrhages may be treated medically with close surveillance. Routine surgical evacuation of supratentorial hemorrhages is not recommended. Trials evaluating the role of surgical evacuation in supratentorial hemorrhages are ongoing.
Patients with an SAH secondary to rupture of an aneurysm will require a surgical intervention. The aneurysm may be either clipped, which involves a craniotomy, or may be coiled by interventional radiology. Comparative data between both techniques is limited. Some data suggests that coiling is associated with better survival but carries a higher risk of rebleeding, requiring further therapy. Choosing between coiling or clipping of the aneurysm depends on local expertise and anatomical location of the aneurysm.
SAH also may be secondary to rupture of AVMs. The management of a ruptured AVM is very controversial and is guided by neurosurgical principles (location, size, depth of venous drainage). Options include surgical resection, catheter embolization, and stereotactic radiosurgery.
If a pregnant patient is found to have either an aneurysm or an AVM that has not been treated, a cesarean section is recommended to avoid Valsalva efforts during labor. If the aneurysm or AVM has already been secured (surgically or endoscopically), route of delivery should be guided by obstetrical principles.
In all stroke patients, the airway should be secured if needed. Attention to oxygenation and ventilation is pivotal. The partial pressure of carbon dioxide (PaCO2) should be maintained between 35 - 40 mmHg (close to 30 mmHg during pregnancy), and hypercapnia avoided as it leads to cerebral vasodilation with subsequent cerebral edema. Oxygenation should be maintained, as hypoxia also leads to cerebral vasodilation.
Regardless of the type of stroke, all patients with central nervous system catastrophes should have strict temperature and glucose control. Blood glucose should be maintained between 140 - 180 mg/dL. Temperature elevations should be treated and kept below 37.5 °C. Sodium control is of paramount importance. Patients with strokes should not receive hypotonic solutions, as hyponatremia will worsen cerebral edema.
Whenever a patient who has suffered a stroke presents with unexplained coma, consider performing an electroencephalogram to rule out non-convulsive status epilepticus.
Algorithm of the basic steps in the initial diagnosis and management of a patient with suspected stroke.
The most catastrophic complication of ischemic stroke therapy involves bleeding secondary to the use of rTPA. Intracerebral bleeding occurs in 6% of cases. If bleeding occurs during thrombolytic therapy, the infusion should be stopped immediately and administration of platelets and cryoprecipitate (6 - 10 units of each) should follow.
Rarely seizures will occur in patients with ischemic strokes. Prophylactic anti-seizure medications are not recommended in arterial ischemic strokes. In cases of cerebral venous/sinus thrombosis, seizures may occur in up to 40% of patients. The use of prophylactic anti-seizure medications may be considered in this case.
In cases of ICH, one common complication is hematoma expansion. Hematomas commonly expand during the first 24 hours after bleeding onset. Prevention of hematoma expansion involves reversing any anticoagulants the patient might be taking (e.g., warfarin) and blood pressure control.
As discussed previously, current guidelines recommend treating hypertension in the setting of ICH when the blood pressure is > 180/110 (MAP of 130). Recent literature suggests that if hypertension is treated to maintain the systolic blood pressure < 140 mmHg, hematoma expansion is limited. However, no changes in outcome have been described with this intervention. The use of recombinant activated factor VII to prevent hematoma expansion in ICH is not recommended.
Seizures complicating ICH are rare and depend on the brain area affected. If the bleeding is in the basal ganglia or the posterior fossa, the incidence of seizures is extremely low. If the ICH affects the cerebral cortex, seizures may occur more frequently. Controversy exists as to whether antiseizure prophylaxis should be administered to all patients with ICH. The American Stroke Association does not recommend universal seizure prophylaxis in the setting of ICH.
SAH is a multisystemic disease with many potential complications. The four most common complications are vasospasm, hydrocephalus, rebleeding, and cerebral salt wasting syndrome.
Cerebral vasospasm occurs mostly in non-traumatic aneurysmal SAH. It is less common with SAH secondary to AVM ruptures or traumatic SAH. Many mechanisms are involved, including a scavenger-like activity of free hemoglobin from the hemorrhage on nitric oxide, leading to local vasospasm that may lead to ischemic strokes. All patients with aneurysmal SAH should be placed on nimodipine 60 mg PO every 4 hours for 21 days to prevent potential vasospasm. Vasospasm may be responsible for neurologic deterioration when brain imaging rules out rebleeding and hydrocephalus. Cerebral angiography will confirm the diagnosis.
Treatment of symptomatic vasospasm has traditionally included triple-H therapy, induction of hypervolemia and hemodilution by administering fluids and induced hypertension by using vasopressors like norepinephrine, phenylephrine or dopamine. Data on the benefits of triple-H therapy are extremely limited. Hemodilution may decrease arterial oxygen content by decreasing hemoglobin levels and compromise oxygen delivery to the brain. Recent data suggests that induced hypertension alone may be the most beneficial strategy. Once the aneurysm is secured, induced hypertension commonly involves maintaining MAP > 120 mmHg with systolic blood pressure > 180-200 mmHg.
If hydrocephalus develops, patients will need a ventriculostomy placed to drain cerebrospinal fluid. Rebleeding may happen before the aneurysm or AVM is secured. In these situations, blood pressure control is of paramount importance, and the systolic blood pressure should be maintained below 140 - 160 mmHg. Labetalol or nicardipine may be used.
Up to 30% of patients with a SAH may develop hyponatremia. As discussed previously, patients with neuro-intensive diseases should not be hyponatremic, as this will lead to worsened cerebral edema. A minority of these cases are due to inadequate or excessive secretion of anti-diuretic hormones, causing excessive water resorption in the distal nephron. Most cases are secondary to cerebral salt wasting syndrome.
The pathophysiology of this syndrome is unclear. SAH is associated with a systemic inflammatory response and a massive secretion of cathecolamines, likely to raise blood pressure and maintain cerebral perfusion pressure in the setting of elevated intracranial pressure. The cathecolamine release leads to pulmonary and systemic vasoconstriction with increased afterload to both right and left ventricles. The increase in "pressure load" in both ventricles stimulates secretion of B-type natriuretic peptide (BNP) from both ventricles. BNP is a natriuretic leading to renal sodium wasting. The treatment typically involves administration of normal saline. Rarely will 3% saline need to be administered.
Approximately 30% of patients with SAH develop cardio-pulmonary complications. The cathecolamine release associated with SAH may lead to subendocardial vasoconstriction with myocardial necrosis and mild troponin leakage that, in most cases, is not related to coronary artery disease. Arrhythmias may be observed. Pulmonary edema (neurogenic pulmonary edema) may happen secondary to cathecolamine-induced constriction of the pulmonary veins, with increasing hydrostatic pressure in the lung capillaries, coupled with lung endothelial injury induced by the massive inflammatory response associated with SAH. Treatment of all these cardiac/pulmonary complications is mainly supportive, with mechanical ventilation and anti-arrhythmics as needed. Very rarely will the elevation of troponins require a cardiac catheterization.
Seizures are a rare complication. It is common clinical practice is to administer antiseizure prophylaxis to all patients who suffer a SAH, but this practice has been associated with lower cognitive development in survivors. Investigators have recently suggested that prophylaxis for only 3 days may suffice.
5. Prognosis and outcome
The prognosis of patients with strokes depends on the location and extent of the injury and the ability to prevent secondary brain injuries (e.g., seizures, hyponatremia, rebleeding, and progressive cerebral ischemia). Maternal mortality is higher for hemorrhagic strokes than for ischemic strokes.
Patients with a previous ischemic stroke (arterial or venous) will likely require a work up for thrombophilias (both congenital and acquired). If positive, anticoagulation should be instituted and, depending on the condition, may be required for long periods of time, including future pregnancies, and possibly for life.
In women with a previous hemorrhagic stroke (SAH, ICH) the recurrence rate will depend on the initial event. If the patient had an ICH associated with severe hypertension secondary to preeclampsia, strict blood pressure control and prenatal care with a maternal fetal medicine specialist may prevent recurrences in future pregnancies. If an SAH was secondary to an isolated aneurysm or AVM, and the lesion has already been treated, the likelihood of recurrence is low.
6. What is the evidence for specific management and treatment recommendations
Feske, SK. "Stroke in pregnancy". Seminars in Neurology. vol. 27. 2007. pp. 442-52.(This is a good overall review of stroke in pregnancy.)
Stam, J. "Thrombosis of the Cerebral Veins and Sinuses". N Engl J Med. vol. 352. 2005. pp. 1791-8.(Detailed review on the topic.)
Lukovits, TG, Goddeau, RP. "Critical care of patients with acute ischemic and hemorrhagic stroke: update on recent evidence and international guidelines". Chest. vol. 139. 2011. pp. 694-700.(Excellent reference, updated with current guidelines.)
Albers, GW, Amarenco, P, Easton, JD. "Antithrombotic and thrombolytic therapy for ischemic stroke: American College of Chest Physicians evidence-based clinical practice guidelines". Chest. vol. 133. 2008. pp. 630S-669S.(Provides details of evidence-based management of ischemic stroke.)
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