The physiologic changes of pregnancy result in increased risk of many cerebrovascular disorders. Additionally, the consideration of the developing fetus results in alterations in diagnostic testing and therapies to treat such conditions. It is important for neurologists and critical care clinicians to familiarize themselves with the care and approach of the pregnant patient for two lives and not just one. If the mother is clinically deteriorating despite aggressive medical management of the underlying neurological condition, consideration of early delivery should be discussed with neonatology, anesthesiology, and obstetrical clinicians. For women who are less than 32 weeks gestation and delivery is being considered, it is recommended to provide glucocorticoids prior to delivery to help with fetal lung maturity.
Thrombotic Events: Ischemic Stroke and Cerebral Sinus Thrombosis
Pregnancy is associated with a significant increase in clotting factors. Pregnant women have between a 20% to 1000% increase in their factors VII, VIII, IX, X, XII, a 400% increase in their von Willebrand factor, and a two- to three-fold increase in the fibrinogen level. These factors are maximally increased at time of delivery, indicating that the third trimester and especially the postpartum period, is arguably the time of maximum vulnerability for these patients. Thus, the risk of a thrombotic event such as pulmonary embolism, deep venous thrombosis, cerebral sinus thrombosis, and ischemic stroke are much higher as compared to nonpregnant patients.
Signs and Symptoms
Pregnant patients who have suffered an ischemic stroke will present with similar symptomatology as their nonpregnant counterparts with focal neurologic deficits based on the areas of ischemia.
Cerebral sinus thrombosis will also present in the traditional fashion. These patients have clinical manifestations that include encephalopathy (seizures and mental status changes), focal deficits, and/or headache. Headache is usually the earliest and most frequent symptom and in some patients may be the only symptom.
Diagnostic Testing Consideration
Magnetic resonance imaging (MRI) is considered safe during pregnancy, as it poses no radiation risk to the fetus. Gadolinium crosses the placenta and has a longer half-life to the fetus as compared to iodinated contrast. Animal data using gadolinium has suggested teratogenicity when used in high doses. Because of these data, it is generally not recommended to use gadolinium during pregnancy. A computed tomography (CT) scan of the head, using a fetus shield during the scan, exposes the fetus to only <10 mrad of radiation. This is considered a safe level, as it is not until levels of 5,000 mrad are reached that there becomes a concern for fetal anomalies, growth restriction, intellectual disability, and future pediatric oncogenic risks. Iodinated contrast materials, when given intravenously, will cross the placenta and can theoretically cause transient affects on fetal thyroid function, but there has not been any animal or clinical data suggesting any sequelae reported from brief exposures. Oral contrast agents do not cross the placenta and will not cause any fetal harm. Thus, iodinated contrast materials may be used in pregnancy when indicated.
Considering these factors for pregnant patients who present with symptoms of an ischemic stroke, it is appropriate to consider CT/CT angiography (CTA) and MRI as per the usual standard of care. Cerebral angiography may also be beneficial for specific patients. For patients presenting with symptoms concerning for cerebral sinus thrombosis, a MR venography (without the use of gadolinium) would be the best first-line diagnostic test.
Tissue Plasminogen Activator
Recombinant tissue plasminogen-activator is considered a pregnancy Food and Drug Administration (FDA) category C medication as there have been numerous animal studies suggesting adverse effects to the fetus. It is important to recognize that many of the drugs that are routinely used in pregnant patients are category C drugs because of the lack of reliable drug studies in humans. There are very few human studies regarding tissue plasminogen activator (tPA), and the fears may be overstated as the high molecular weight of tPA prevents it from crossing the placenta. In one small case review of 26 patients, only 3 had pregnancy complications with 1 patient suffering a spontaneous miscarriage and another suffering an intrauterine hematoma. None of the live children born suffered any permanent deficit. Because the data regarding tPA use in pregnancy is sparse and of poor quality, if tPA is given, elective pregnancy termination is an option for the patient to consider. The indications and contraindications for the use of tPA remain the same as the general population.
For patients who are >24 weeks gestation, because the fetus is viable, the consideration of stroke treatment is slightly different. While tPA remains an option, there needs to be a significant discussion since there is the potential to cause fetal demise. For those patients with a large vessel occlusion, it is reasonable to consider proceeding directly to endovascular thrombectomy in lieu of tPA if interventional therapy is available.
As detailed in Chapter 3, there is strong level I evidence for endovascular thrombectomy in appropriately selected ischemic stroke patients with a large vessel occlusion presenting within 24 hours since last seen normal. While the initial studies that proved the effectiveness of revascularization therapy for ischemic stroke did not evaluate its use in pregnant patients, pregnancy should not be an exclusion for this highly efficacious therapy. Radiation exposure to the developing fetus can be minimized with appropriate shielding. Both unfractionated heparin and low molecular weight heparin can be safely used as neither of these agents crosses the placenta. Agents such as clopidogrel, warfarin, and rivaroxaban should not be given to pregnant patients routinely.
As detailed in Chapter 3, decompressive craniectomy can be life saving for ischemic stroke patients with malignant cerebral edema. The 2007 pooled analysis of 3 randomized controlled trials showed a significant mortality benefit (78% medical management, 29% surgical management—absolute risk reduction 50%) of decompressive surgery for patients 60 years old or younger with large hemispheric infarction who developed a decrease in their level of arousal within 48 hours. In these trials, pregnancy was generally an exclusion criteria. However, there is no reason to hypothesize that decompressive craniectomy would be any different in pregnancy, the clinician’s first priority is treating their patient, and the best way to save the fetus is by providing standard of care therapy to the mother. Thus, if the patient is appropriate for this procedure, it should be strongly considered regardless of pregnancy.
Risk of Recurrence (Ischemic Stroke)
For women who suffered an ischemic stroke either during pregnancy or immediately afterwards in the post-partum period, the risk of recurrence is low, at 1.8% in future pregnancies. However, there is still risk of recurrence even without subsequent pregnancies. The overall risk of recurrence within one year is 1% and within five years is 2.3%.
The mainstay of treatment for these patients is full-dose anticoagulation with low molecular weight heparin or unfractionated heparin. Small studies have demonstrated improved outcomes with low molecular weight heparin as compared to unfractionated heparin, but unfractionated heparin is sometimes preferred if there is a need for acute reversibility in those patients at high risk of hemorrhage or need for surgical intervention. As mentioned previously, low molecular weight heparin does not cross the placenta and thus is safe to use. The duration of therapy should continue for a minimum of six weeks postpartum for a total minimal duration of therapy of six months.
The use of mechanical thrombectomy or direct thrombolysis as salvage therapy for the unstable patient has conflicting data in all patients with cerebral venous sinus thrombosis, regardless of pregnancy. There is no data specifically looking at this intervention in the pregnant patient. Thus, this intervention should be reserved only for patients who have failed anticoagulation therapy and are experiencing progressive decline with expected poor prognostic outcome and have access to experienced interventionists.
Risk of Recurrence in Future Pregnancies
An analysis of 441 women revealed no recurrent cases of cerebral venous thrombosis in two women who developed recurrent ischemic stroke during pregnancy. Thus, this condition is not a contraindication to future pregnancies. If there is a high concern, low-dose aspirin and/or low molecular weight heparin can be utilized for prophylaxis in future pregnancies.
Reversible Cerebral Vasoconstriction Syndrome
Reversible Cerebral Vasoconstriction Syndrome has a high prevalence in pregnant women and can occur along a spectrum with eclampsia or as an isolated syndrome. Please review Chapter 6 for a full discussion on the diagnosis and management of this condition.
There is no current evidence that is consistent with an increased risk of aneurysmal subarachnoid hemorrhage (SAH) in pregnancy. Those with vascular lesions that rupture during pregnancy are most likely to experience this during their third trimester. It is important to recognize this condition as a potential cause of headache and hypertension in the pregnant patient as initial symptoms can mimic preeclampsia. SAH will not have the same laboratory abnormalities as those patients suffering from preeclampsia.
Diagnosis with CT, CTA, and/or cerebral angiography should be utilized the same as in nonpregnant patients, with the only difference being to shield the fetus during testing. Case reports have demonstrated endovascular coiling of ruptured aneurysms to be a safe and effective treatment modality in pregnancy. Blood pressure control, prevention of dehydration, sodium control, and treatment of hydrocephalus with a ventricular drain should all be performed in the pregnant SAH patient. The decision to treat with nimodipine to prevent potential cerebral vasospasm should be seriously considered since it is a FDA category C medication. Nimodipine crosses the placenta, and animal studies have displayed adverse events related to this medication administration. For patients who develop cerebral vasospasm, intra-arterial therapy with verapamil has been safely utilized with successful results.
Although some clinicians will recommend vaginal delivery, others may recommend prophylactic cesarean delivery to prevent hemodynamic fluctuations and increased ICP during labor and delivery. Prophylactic cesarean delivery is preferred in the patient with an unsecured aneurysm.
Preeclampsia and Eclampsia
Definition and Pathophysiology
Preeclampsia refers to the acute onset of hypertension (>140/90) and end-organ dysfunction that occurs after 20 weeks of gestation. Eclampsia refers to the development of seizures in the setting of preeclampsia. The proposed pathophysiology is abnormal development of the placenta vascular system resulting in placenta underperfusion and hypoxia with release of factors that cause widespread maternal endothelian dysfunction.
Diagnosis and Clinical Symptoms
Patients are diagnosed with preeclampsia if they develop hypertension and proteinuria (no longer considered an absolute criteria for preeclampsia). Hypertension is defined as a blood pressure of ≥ 40/90 on two occasions at least four hours apart or a single value of ≥160/110. Proteinuria is defined as a dipstick value ≥+1 or ≥0.3 g in a 24-hour collection specimen or a protein to creatinine ratio ≥0.3 mg/mg. In the patient without proteinuria but hypertension, it is still possible to be diagnosed with preeclampsia if she develops any of the following: low platelet count (<100,000), serum creatinine greater than 1.1 mg/dL, liver transaminases twice the upper limit of normal, pulmonary edema, visual symptoms (blurred visions, flashing lights, etc.), or cerebral symptoms (such as headache). These patients commonly develop HELLP syndrome (hemolysis, elevated liver function tests, and low platelets).
In addition to the aforementioned symptoms noted in the diagnostic criteria, patients often complain of nausea, vomiting, right upper quadrant pain, and/or epigastric pain, or they may be asymptomatic. Physical examination can reveal ankle clonus and reproducible right upper quadrant abdominal pain. Some patients with severe symptoms may experience disseminated intravascular coagulopathy, acute renal failure, placental abruption, and/or death.
Patients who develop seizures and thus eclampsia most often have tonic-clonic activity. It is important to note that women who develop generalized tonic-clonic seizures in the setting of preeclampsia without persistent neurologic deficits do not require any further diagnostic evaluation. Headaches often precede seizure activity by a day, and seizure activity has been reported to occur in the postpartum period as well. However in those women with persistent and refractory seizures and other neurologic symptoms, it is recommended to obtain a diagnostic CT scan of the brain or MRI of the brain to rule out other potential etiologies of seizures. In patients who develop symptoms after delivery, the majority of symptoms will occur within one week after delivery. The majority of patients suffer from only one seizure episode although some patients will have recurrent seizure activity and can develop partial seizure activity. Additional physical exam findings in these patients can include symmetric or asymmetric increased deep tendon reflexes, cranial nerve deficits, memory deficits, and altered mental status.
The definitive management of preeclampsia and especially eclampsia is delivery, with severe symptoms as an indication for emergent delivery regardless of gestational age. For women with a gestational age of <34 weeks, betamethasone is recommended to help promote fetal lung maturity prior to delivery. Fluids should be kept to a minimum due to the risk of developing pulmonary edema. Blood pressure is best managed with labetalol, hydralazine, or nifedipine, all of which are safe in pregnancy. Blood pressure management, however, does not decrease the risk of developing eclampsia. Magnesium sulfate however does reduce this risk by 58%. For women who develop eclampsia, it is recommended to start and/or continue magnesium sulfate as opposed to starting a traditional anticonvulsant or benzodiazepines. Those treated with magnesium have a 67% lower risk of recurrent seizures as compared to phenytoin and a 52% lower risk as compared to diazepam. Magnesium is provided in a loading intravenous dose of 4 to 6 grams over 15 to 20 minutes followed by a maintenance infusion at 2 gms/hour. Those who have recurrent seizures should receive an additional intravenous bolus with magnesium (2–4 grams intravenously) and/or intravenous benzodiazepines. The optimal duration of magnesium therapy is unclear at this time but typically continues at least through the postpartum period.
Seizure Management in the Epileptic Pregnant Patient
While pregnancy in itself does not increase seizure risk, use of a single antiepileptic medication on average doubles the rate of major fetal malformations, and polytherapy can triple this risk. All antiepileptic medications have the risk of teratogenicity, and thus women who are seizure-free for a prolonged period may choose to taper off these medications prior to conception. Other strategies prior to a planned pregnancy include tapering to monotherapy, folic acid supplementation, and avoiding valproate, which has higher neurodevelopmental teratogenicity as compared to alternative agents. Avoidance of phenytoin and phenobarbital is also recommended (but with lower quality evidence as compared to valproate) to prevent reduced cognitive outcomes. For those with unplanned pregnancies, it is recommended to continue their current medication regimen without alterations.
Pregnant patients who develop status epilepticus should be treated with the same algorithm approach as nonpregnant patients. Benzodiazepines should be given for abortive therapy followed by loading with an AED. As noted earlier, loading with valproate should not be used as first-line AED therapy due to its high teratogenicity; levetiracetam is a better first-line agent in this population. For those patients with severe symptoms, intubation with continuous electroencephalography monitoring and infusion therapies with propofol and/or midazolam can and should be utilized in the pregnant patient.
Management of Elevated Intracranial Pressure (ICP) During Pregnancy
Increased ICP may occur in these patients due to hemorrhagic lesions, infarcts, and/or edema. Temporizing measures such as mannitol or hypertonic saline can be considered. Hypertonic saline is arguably safer to use in pregnant patients as mannitol is considered a category C medication, and there have been no animal or human studies to investigate its safety. Measures such as hyperventilation should be used with extreme caution as women in their second and third trimesters normally hyperventilate with a PaCO2 between 30–35; thus, this intervention will likely not be as useful in this patient population.
As mentioned above, in patients with impending herniation due to a unilaterial hemispheric lesion, a decompressive craniectomy can be lifesaving.
Pregnancy and Brain Death
While a majority of hospitals have developed protocols regarding brain death, 93% do not provide any guidance about fetal management after brain death, and 99% do not clarify who is responsible for making decisions for the fetus. This is a complex social, legal, ethical, and economic situation, and one that arguably should include a hospital’s ethical and legal teams. While state laws address keeping the mother alive through life support in the event of a severe brain injury, most are not clear about maintaining cardiopulmonary support after brain death.
If the decision is made to keep the mother on supportive care after declaration of brain death, it is important that this care is provided in a center with 24-hour capability for emergent caesarian delivery and neonatology intensive care.
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