Pregnancy-related stroke occurs in 30/100,000 pregnancies and is increasing in frequency.^1,2,3 Prevalence of ischemic stroke is approximately 12/100,000 pregnancies, similar to prevalence of hemorrhagic stroke.³ The highest risk is in the peripartum and postpartum period.^2,4 Elgendy et al queried the National Inpatient Sample in the United States and found that acute stroke (ischemic and hemorrhagic) occurred in 0.045% of pregnancy-related hospitalizations (1/2222 hospitalizations) and was associated with in-hospital mortality rate nearly 385 times higher than patients who did not experience a stroke.⁵

For ischemic stroke, hypertension, preeclampsia, diabetes, hyperlipidemia, atrial fibrillation, and obesity are among the modifiable risk factors that are on the rise in young women of child-bearing age, while tobacco use is down trending. Migraine with aura is also associated with higher risk of stroke in women, and risk is thought to correlate with higher circulating estrogen levels.⁶ Other mechanisms include arterial thrombosis secondary to hypercoagulable state, lupus, paradoxical venous thromboembolism, amniotic fluid embolism, trophoblastic embolism through a patent foramen ovale or extracardiac shunt, cervical artery dissection, vasculitis, venous infarction secondary to cerebral venous sinus thrombosis (CVT), and “reversible” cerebral vasoconstriction syndrome (RCVS). Typical presenting symptoms include aphasia, double vision, facial weakness, slurred speech, limb weakness, incoordination, sensory loss, or gait disturbance, and rarely, unexplained loss of consciousness due to basilar artery occlusion.

Initial management of stroke involves stabilization and consideration of acute therapies. Treating clinicians should ascertain, to the best of their ability, the time the patient was last known to be neurologically normal, pertinent medical history, and whether the patient is taking antithrombotic or anticoagulant medications. Historical or clinical features suggesting a stroke mimic (such as migraine with aura, seizure with postictal neurological deficits, or extreme hypoglycemia or hyperglycemia) should be taken into consideration. The initial decision-making should focus on stabilization and consideration of acute treatment. Hypoxia and significant glucose aberrations should be treated immediately; a rapid neurologic examination should be obtained.

A computed tomography (CT) of the head without contrast should be performed as quickly as possible to exclude the possibility of hemorrhage and
evaluate for signs of established infarct or other process. If there is concern for a large vessel arterial occlusion due to symptom severity, presence of cortical signs, or sudden loss of consciousness, emergent vascular imaging should also be performed, preferably concurrently. A CT angiogram (CTA) of the head and neck will typically be the most readily available study and provide the most accurate information about the presence of a large vessel occlusion; however, if there is a significant contraindication to using iodinated contrast (eg, significant kidney disease or known contrast allergy), magnetic resonance angiogram (MRA) of the head and neck can be used as an alternative. If the head CT shows no evidence of hemorrhage or other alternative explanation for the patient’s symptoms, treating physicians may consider use of alteplase for some patients (see below). Prior to alteplase administration, blood pressure must be no greater than 185/110 mm Hg and must be kept under 180/105 mm Hg in the postadministration monitoring period. IV antihypertensives, including labetalol, hydralazine, nicardipine, and clevidipine may be required to get and/or keep blood pressure within the necessary range both during and after the infusion to reduce risk of intracranial hemorrhage.

If the CTA or MRA demonstrates a large vessel arterial occlusion, the patient should be referred immediately to a stroke center with neurointerventional radiology services capable of performing mechanical thrombectomy and providing neurocritical care expertise.

With acute stroke treatment, time to treatment is critically important to reduce risk of disability from irreversible tissue death, and every effort must be made to expedite time to treatment. Once acute treatment decisions have been made, additional diagnostic workup will typically include electrocardiogram (ECG), telemetry monitoring (with particular attention to presence of atrial fibrillation, atrial cardiopathy, wall motion abnormalities, and valvular disease), and transthoracic echocardiogram. Additional studies may be indicated, particularly if the patient’s medical history is not well established or if there is concern for illness such as lupus, antiphospholipid syndrome, connective tissue disease, or occult infection.

The only U.S. Food and Drug Administration (FDA)-approved medication for treatment of acute ischemic stroke in the United States as of this publication date is alteplase, a recombinant human tissue plasminogen activator (tPA), which has been shown to significantly reduce stroke-related disability. The American Heart Association (AHA) states that alteplase “may be considered in pregnancy when the anticipated benefits of treating moderate or severe stroke outweigh the anticipated increased risks of uterine bleeding” depending on the overall risk/benefit analysis as determined by the treating clinicians.⁴

For stroke occurring postpartum, risk of hemorrhagic complications with alteplase would need to be carefully considered before administration of the drug. Exclusions would include, among others, recent neuraxial anesthesia (including epidural medication delivery), cesarean delivery, or other surgery. Additionally, mechanical thrombectomy has been successfully performed in a number of obstetric patients^7,8 and should be considered for any pregnant women presenting with a disabling stroke attributable to a large vessel occlusion.

Although neither alteplase nor thrombectomy have been prospectively studied in pregnant or postpartum patients, observational and registry data suggest that these therapies are associated with similar rates of vascular reperfusion and favorable outcomes compared to women who are not pregnant or peripartum.^9,10 Leffert et al⁹ created a cohort of pregnant and postpartum patients treated with reperfusion therapy (alteplase and/or mechanical thrombectomy) using the United States-based Get With The Guidelines stroke database. The 40 patients who received reperfusion therapy had similar risk-adjusted short-term outcomes (in-hospital death, independent ambulation on discharge, and discharge to home), despite a nonsignificant trend toward increased symptomatic intracranial hemorrhage and higher baseline stroke severity.

The AHA guidelines on management of acute ischemic stroke outline recommendations on this topic in more detail,¹¹ as well as management considerations pertinent to use of alteplase.

Stroke prevention in patients with prior history or deemed high risk for stroke will need close anticipatory guidance to help reduce their stroke risk factors. Counseling addressing management of hypertension, diabetes/insulin resistance, tobacco and substance use avoidance, and other modifiable risk factors is critical, preferably prior to conception when possible. Medication prophylaxis may consist
of an antiplatelet agent, such as aspirin, or an anticoagulant (typically in the form of low-molecular-weight heparin), depending on the individual’s underlying condition(s). Typically, individuals with prior history of stroke should be under care of a neurologist with experience in stroke management before and during pregnancy, and those with underlying hematologic or rheumatologic conditions predisposing to stroke, such as antiphospholipid syndrome or lupus, should be under care of a hematologist and/or rheumatologist as indicated. A comprehensive reference outlining management of cardiovascular disease in pregnancy, including cerebrovascular disease, was published by Mehta et al³ and is available free to the general public online.

Intracerebral hemorrhage (ICH) occurs in approximately 12/100,000 pregnancies³ and carries profound morbidity and mortality. Meeks et al¹² tracked over 3 million pregnant women in three US states during pregnancy and for 24 weeks postpartum and found that risk of ICH was highest in the third trimester and remained increased during the first 12 weeks after delivery. Pregnancy-related ICH was associated with increased maternal and fetal death.¹² In a systematic review of pregnant or postpartum patients by Ascanio et al, the 43 identified patients with spontaneous ICH had a mortality rate of 48.8%, and fetal outcomes were evenly distributed between preterm or term delivery and fetal or neonatal death.¹³

Typical risk factors for ICH in pregnancy include hypertension (including gestational), preeclampsia and eclampsia, coagulopathy, age >35 years, black race, and tobacco use.³ Presentation in pregnancy is commonly related to uncontrolled hypertension and resultant loss of integrity in the intracranial arterial wall, though vascular malformations such as arteriovenous malformations and dural arteriovenous fistulas, cerebral vein thrombosis, and metastatic lesions with propensity to hemorrhage (eg, choriocarcinoma or renal cell carcinoma) are among other possible causes.

Onset of ICH may be accompanied by a severe, abrupt-onset headache, nausea, or vomiting; profound abrupt-onset hemiparesis may occur and can progress quickly to coma.¹⁴ Symptoms may be indistinguishable from those of ischemic stroke, though rapid progression to altered mental status and coma is more common due to rapid enlargement of hematoma, compression of brain structures, and elevation of intracranial pressure.

Initial management of suspected ICH during pregnancy or the postpartum state is typically the same as that provided to a nonpregnant patient, with exception that close consultation with an obstetrics consultant is needed to help guide management and fetal monitoring. A detailed guideline recommendation on management of spontaneous ICH has been written by Hemphill et al and published by the American Heart Association¹⁵ (Table 36.1).

Initial evaluation should include airway and hemodynamic stabilization, blood pressure measurement and initiation of rapid control, a quick neurological assessment, CT imaging to assess for hemorrhage presence, type, and size, and blood work, including a complete blood count and coagulation studies. History should be obtained about the patient’s prior medical history, and with attention to hemorrhage risk factors, and current use of any antiplatelet or antithrombotic agents, as with latter, reversal therapies may be indicated.

Once blood pressure control has been initiated, typically with intravenous agent(s), additional imaging with CT angiogram may be needed to evaluate for underlying vascular malformation, aneurysm, and to assess for large vessel vasculopathy (such as might be seen in RCVS; see below). The patient should be monitored closely, preferably in a setting in which neurocritical care consultation is available. Once clinically stabilized, magnetic resonance imaging (MRI) of the brain is typically obtained to further evaluate for structural pathology, including mass lesions, ischemic stroke, and vasogenic edema (as would be seen in posterior reversible encephalopathy syndrome [PRES]; see below).

For women with a prior history of ICH, subarachnoid hemorrhage (SAH), or the other abovementioned conditions associated with hemorrhage, anticipatory guidance before or during pregnancy may reduce risk of hemorrhagic complications. Though brain arteriovenous malformations (AVMs) were previously assumed to be associated with increased risk of hemorrhage during pregnancy, recent studies have either found no clear association or conflicting results, while others have found three times greater risk of ICH in women with AVM during pregnancy and puerperium.¹⁶ Similarly, the frequency of aneurysm rupture is not clearly greater than that in the general population. Robba et al reviewed this topic and conducted a meta-analysis of seven retrospective studies and internal case series with 52 patients and found that the majority experienced rupture in the third trimester. Association was found with hypertension, alcohol and tobacco use, obesity, and advanced maternal age.¹⁷ Intervention with clipping was done in all seven internal cases reviewed, all with favorable outcomes for mother and fetus.

In general, for women who have a known vascular malformation or cerebral aneurysm, consultation with a physician specializing in neurovascular disease is suggested, as an individual patient’s risk of hemorrhage may be significantly influenced by morphology of cerebrovascular lesion or other comorbid conditions.

Prevention and management of hypertension before and during pregnancy, combined with avoidance of tobacco and sympathomimetic substances, are the most critical modifiable risk factors for preventing pregnancy-related ICH. For patients with a prior history of refractory hypertension, prior ischemic or hemorrhagic stroke, underlying vasculopathy (moyamoya disease or syndrome, sickle cell disease, etc), or known vascular malformation, consultation and comanagement with a neurovascular neurologist and/or neurosurgeon is recommended.

A review of ICH management in pregnancy and postpartum period was recently published by Toossi and Moheet.¹⁸

Aneurysmal SAH is often heralded by a headache often described as “the worst headache of life” and may be accompanied by photophobia, neck stiffness, nausea, and vomiting. There is sometimes a history of less severe headache and/or syncope in the preceding days or weeks, referred to as a “sentinel bleed.” Symptoms may resemble those of bacterial or viral meningitis, but the abrupt onset of headache, and (typically) absence of fever and leukocytosis should raise suspicion for the former. SAH may occur independently or in conjunction with parenchymal ICH and occurs at a similar rate in pregnant women as in the general population. Bateman and colleagues found a prevalence of 5.8/100,000 deliveries using the Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project in the United States.¹⁹

Risk factors for intracranial aneurysm include family history, smoking, drug and alcohol use, sickle cell disease, moyamoya syndrome, sinus venous thrombosis, and connective tissue diseases such as Ehlers-Danlos or Marfan syndrome, among others. In the Bateman et al study, African Americans, Hispanics, and women of advanced maternal age were found to be at higher risk of
aneurysmal SAH.¹⁹ Pregnancy is thought to potentiate aneurysm formation, growth, and rupture, and the incidence of aneurysmal SAH is increased in pregnant patients.^20,21 The third trimester and postpartum period are thought to carry the greatest risk of rupture due to sudden and persistent elevation in intracranial pressure during parturition.²²

SAH increases maternal and fetal morbidity and mortality considerably, and therefore, preventative strategies through lifestyle intervention, hypertension management, and preventative aneurysm management (particularly for aneurysms >10 mm) are important. Nussbaum and colleagues recently reviewed this topic in detail and provide clinical recommendations,²³ including consideration of treatment for unruptured aneurysms that are symptomatic, enlarging, or >10 mm.

RCVS, sometimes referred to as “postpartum angiopathy” in the postpartum period, is a condition thought to be mediated by alteration in blood-brain barrier integrity due to endothelial dysfunction, resulting in an abrupt change in cerebrovascular arterial tone leading to vasoconstriction in one or more of the medium or large cerebral arteries, most commonly the middle cerebral arteries. Use of sympathomimetic substances, such as selective serotonin reuptake inhibitors (SSRIs), ephedrine derivatives, cannabis, and cocaine, have been associated with RCVS.

Clinical presentation of RCVS is often marked by sudden onset of thunderclap headache with or without fluctuating neurologic symptoms. Diagnosis is based on clinical suspicion and imaging of the cerebral vasculature, commonly using MRA, CTA, or conventional angiogram. Of note, the appearance of RCVS can be indistinguishable from that of vasculitis (primary angiitis of the CNS, infectious vasculitis, or systemic vasculitis affecting the CNS), so clinical presentation and absence of other typical clinical features associated with helps to distinguish RCVS.

If RCVS is suspected, based on clinical presentation and/or imaging, evaluation for underlying modifiable triggers (eg, use of SSRIs, triptan, or other sympathomimetic drug) should be undertaken, and patient may benefit from use of calcium channel blockers.

As mentioned, RCVS can be associated with SAH, ICH, ischemic stroke, and seizures and thus can have variable clinical and radiographic presentation. RCVS can occur concurrently with PRES (see below), and both can be associated with nonaneurysmal SAH, typically at the convexities. Although by definition the vasospasm associated with RCVS should resolve on imaging within several months, the term “reversible” does not always imply that it is entirely benign due to potential association with PRES and occasional complication by nonaneurysmal SAH, ICH, or ischemic stroke.

PRES, a radiographic and clinical syndrome characterized by vasogenic edema in the white matter tracts of the brain or brainstem, is also associated with loss of autoregulatory control of the arterial cerebral vasculature. It is most commonly associated with hypertension and preeclampsia or eclampsia in the setting of pregnancy.

Typical presentation includes abrupt or gradual onset of headache, vision changes (including unilateral or bilateral cortical vision loss), other focal neurological deficits, and seizures. Blood pressure is typically, but not always, elevated, and PRES may occur in the context of preeclampsia or eclampsia. Treatment is typically targeted at lowering blood pressure and treating preeclampsia or eclampsia if concurrently present.

Cerebral vein thrombosis (CVT) can occur in the setting of pregnancy or the postpartum period, with a recent meta-analysis suggesting association specifically with the puerperium.²⁴ Preexisting inherited thrombophilia, malignancy, smoking, dehydration, and infection are among factors that may increase risk. CVT is typically associated with a more gradual-onset headache, though presence of hemorrhage may result in sudden worsening of the pain and additional accompanying symptoms.