Curr Cardiol Rep (2014) 16:532 DOI 10.1007/s11886-014-0532-1
STROKE (AB SINGHAL, SECTION EDITOR)
Cerebrovascular Complications of Pregnancy and the Postpartum Period Ali Razmara & Khamid Bakhadirov & Ayush Batra & Steven K. Feske
Published online: 21 September 2014 # Springer Science+Business Media New York 2014
Abstract Cerebrovascular complications of pregnancy, though uncommon, threaten women with severe morbidity or death, and they are the main causes of major long-term disability associated with pregnancy. In this review, we discuss the epidemiology, pathophysiology, presentation and diagnosis, and management and outcomes of ischemic and hemorrhagic stroke and cerebral venous thrombosis. We also discuss the posterior reversible encephalopathy syndrome, the reversible cerebral vasoconstriction syndrome including postpartum cerebral angiopathy, and their relationship as overlapping manifestations of pre-eclampsia-eclampsia.
Keywords Cerebrovascular complications . Pregnancy . Postpartum period . Ischemic stroke . Hemorrhagic stroke . Cerebral venous thrombosis . Pre-eclampsia-eclampsia
This article is part of the Topical Collection on Stroke A. Razmara : K. Bakhadirov Fellow in Vascular Neurology, Massachusetts General and Brigham and Women’s Hospitals, Boston, MA, USA
Introduction Stroke is the fourth leading cause of death in the USA and the leading cause of serious long-term disability [1, 2]. While ischemic and hemorrhagic stroke and cerebral venous thrombosis are all rare in women of childbearing age, late pregnancy and the early postpartum period increase the risk of all of these types of stroke, and stroke is the leading cause of pregnancyrelated long-term disability. Pre-eclampsia-eclampsia is an important complication unique to pregnancy. In addition to its contribution to ischemic and hemorrhagic stroke, preeclampsia-eclampsia underlies the occurrence of hypertensive encephalopathy, also known as posterior reversible encephalopathy syndrome (PRES), and reversible cerebral vasoconstriction syndrome (RCVS). These two disorders are overlapping manifestations of a shared pathophysiology, and they encompass the entity termed postpartum cerebral angiopathy. In this brief review, we discuss the epidemiology, pathophysiology, diagnosis, and management of these important cerebrovascular disorders of pregnancy.
A. Razmara e-mail: [email protected]
Ischemic Stroke
K. Bakhadirov e-mail: [email protected]
Epidemiology
A. Batra Resident in Neurology, Brigham and Women’s and Massachusetts General Hospitals/Harvard Medical School, Boston, MA, USA e-mail: [email protected]
There are no long-term prospective studies of the incidence of stroke in pregnancy. Various studies estimate the incidence of all types of stroke in pregnancy and puerperium between 25 and 34 per 100,000 deliveries [3–5]. In comparison, the incidence of stroke in non-pregnant women in the 15- to 45-year age group is 11 per 100,000 [6]. A population-based retrospective study conducted from 1988 to 1991 found no increase during pregnancy but a relative risk of 8.7 during the first 6 weeks postpartum [7]. Recent analysis of hospital discharge data from the Nationwide Inpatient Sample of the
S. K. Feske (*) Neurology Department, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA e-mail: [email protected] S. K. Feske Harvard Medical School, Boston, MA, USA
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Healthcare Cost and Utilization Project demonstrated that between 1994–1995 and 2006–2007, the rates of antenatal and postpartum hospitalizations for all types of stroke increased by 47 and 83 %, respectively [8•]. This increase was thought to be related to the increase in hypertensive disorders and heart disease. Pathophysiology Pregnancy is associated with a number of physiologic changes that can result in increased risk of ischemic stroke. These include hemodynamic changes (hemodilutional anemia, variations in blood pressure, venous stasis), vascular abnormalities (decreased collagen and elastin content in blood vessels, increased stiffness and relaxation response), endothelial dysfunction (increased vessel wall permeability and vasogenic edema), and, most importantly, changes in the coagulation system. A procoagulant state is created by alteration in levels of coagulation factors, most notably by increases in procoagulant levels (factors I, VII, VIII, IX, X, XII, and XIII) and decreases in levels of coagulation inhibitors (antithrombin III, protein S, functional resistance to activated protein C) [6]. A combination of congested venous flow and changes in coagulation factor levels contributes to a hypercoagulable state which is most significant in the third trimester and early postpartum period. Multiple risk factors have been associated with the increased risk of stroke, including hypertension, diabetes, heart disease, sickle cell anemia, thrombocytopenia, smoking, systemic lupus erythematosus, and complications of labor [5]. Pre-eclampsia-eclampsia is a well recognized risk factor and is present in 11–47 % of cases of stroke in pregnancy. Cesarean section has been associated with a 3- to 12fold increased risk of peripartum stroke [9]. Clinical Presentation and Diagnosis Stroke in pregnancy most typically presents, as does all stroke, with sudden onset of a focal neurologic deficit. Headache is an important and common symptom of stroke. Although more likely in hemorrhagic stroke, it occurs commonly with preeclampsia-eclampsia and may be a key symptom in early diagnosis of pregnancy-related stroke. Impairment of consciousness and seizures more commonly accompany hemorrhagic stroke and venous sinus thrombosis, but they may also occur with ischemic stroke. The most common mechanism of stroke in pregnancy appears to be embolism, either from a demonstrable cardiac source or cryptogenic. Other causes of stroke in young patients, such as arterial dissections, paradoxical embolism through a patent foramen ovale, moyamoya syndrome, and IV drug abuse must be considered. Causes unique to pregnancy include peripartum cardiomyopathy and embolization of amniotic fluid or air, the latter due to dissection through the placental planes and into uterine veins.
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Pre-eclampsia-eclampsia is a strong risk factor that underlies many pregnancy-associated strokes, although the mechanism of this association is not always clear. An understanding of the possible causes of stroke guides the diagnostic work-up. Appropriate choice and timing of neuroimaging help to confirm the diagnosis. Noncontrast CT is often the first choice, especially when acute thrombolysis is considered. The fetal exposure to radiation is very low, especially with proper precautions and shielding. IV iodinated contrast is classified as class B by the FDA and should be avoided if possible [10]. While it has not been shown to have teratogenic or mutagenic effects, it has been associated with neonatal hypothyroidism. The low concentrations of iodinated contrast agents in breast milk have not been shown to affect the infant, making it relatively safe during breastfeeding. MRI up to 3 T has not been shown to cause any fetal adverse effects. Absence of radiation and high safety index make MRI the imaging method of choice when the speed and availability of CT are not decisive. Gadolinium-based contrast is classified as class C by the FDA and should be avoided unless benefits of its use outweigh its risk of developmental abnormality and abortion. Gadolinium is safe to use during lactation [11]. As a general rule, informed consent should be obtained any time contrast imaging is used. Cerebral vessel imaging can be achieved using CT, MR, or catheter angiography. When use of contrast is contraindicated, time-of-flight MRI, carotid ultrasound, and transcranial Doppler imaging can be used safely for assessment of both the intra- and extracranial cerebral vasculature. Cardiac ultrasound is an essential part of the evaluation in cases of embolic stroke. The use of agitated saline is consider safe during pregnancy and is recommended in all patients to look for a right-to-left shunt from a patent foramen ovale (PFO) [12]. The presence of a PFO suggests the possibility of paradoxical embolism and calls for further testing for deep venous thrombosis in lower extremities and pelvis. Minimal laboratory screening for common causes and risk factors is indicated in all patients, including complete blood count and liver function tests to look for features of HELLP syndrome (a severe form of pre-eclampsia with hemolytic anemia, elevated liver function tests, and low platelets), fasting glucose and hemoglobin A1C, fasting lipid panel, and serum and urine for toxicologic screening. Additional testing may be needed to search for specific disorders in particular cases, for example, hemoglobin electrophoresis when sickle cell disease is considered. Testing for thrombophilia should include lupus anticoagulant assay, antibodies to anticardiolipin IgG and IgM and to beta-2-glycoprotein I. Other testing for underlying thrombophilias, protein C and S levels and activity, antithrombin III, and factor V Leiden screening with activated protein C resistance assays are best done no sooner than 6 weeks after delivery, because these studies, most reliably protein S, will be affected by the pregnancy state. Genetic testing for the
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prothrombin G20120A mutation and the methylene tetrahydrofolate reductase C677T mutation in patients with hyperhomocysteinemia will round out testing for common causes of thrombophilia.
Management and Outcome Intravenous thrombolysis with tPA is the only FDA-approved treatment for acute ischemic stroke. Since pregnant women were excluded from the clinical trials of acute stroke therapies, there are no controlled data on which to base treatment decisions in this population. The real concern for thrombolysis in pregnancy is not efficacy but safety given potential hemorrhagic complications, such as placental hemorrhage and abruption, fetal loss, and preterm delivery. Animal data suggest that tPA, a large molecule, does not cross the placenta and is unlikely to have teratogenic effects [13]. Moreover, the halflife of tPA in the circulation is only 5 min, although the effect lasts for hours when bound to fresh thrombus. Evidence for efficacy and safety of acute IVor IA thrombolysis in pregnancy comes from a limited number of case reports in the literature. Recent case reports [14–22] of nine women who received IV tPA for acute ischemic stroke demonstrated generally good outcomes for both mothers and fetuses while showing minimal hemorrhagic risk apart from expected asymptomatic hemorrhagic transformation of stroke. Although the interpretation of these data is complicated by the small numbers and by decisions to terminate pregnancy after stroke, we believe that pregnancy alone should not serve as a contraindication to IV tPA for treatment of a potentially disabling stroke in a pregnant woman. Data are even more limited for acute endovascular thrombolysis or thrombectomy; however, these therapies should be considered in particular circumstances as they would for non-pregnant patients, such as in women who cannot be given IV tPA. Treatment decisions are best made jointly with obstetric consultants and the patient herself or a proxy and with careful assessment of all risks. When considering treatment choices, it is important to define the mechanism of stroke. Ischemic stroke from amniotic fluid embolism or from vasoconstriction secondary to pre-eclampsiaeclampsia will not be expected to benefit from thrombolysis. Choice of therapy for secondary prevention depends on the etiology of the stroke. Aspirin is a reasonable choice for most patients. Safety of low-dose aspirin (50–150 mg/day) after the first trimester has been demonstrated in several meta-analyses [23]. Higher doses of aspirin should be avoided due to increased risk of maternal and fetal hemorrhage, premature closure of the ductus arteriosus, and oligohydramnios. In high-risk patients that require anticoagulation (e.g., mechanical heart valves, atrial fibrillation, hypercoagulable states), unfractionated and low-molecular-weight heparin are acceptable. They appear to be safe in the first trimester and can be
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replaced by either aspirin or warfarin after the first trimester [24•].
Pre-eclampsia-Eclampsia, Posterior Reversible Encephalopathy Syndrome, and Postpartum Cerebral Angiopathy The pathophysiologic changes that occur within the cerebrovascular system in the setting of pre-eclampsia and eclampsia predispose pregnant women to ischemic and hemorrhagic stroke. Additionally, eclampsia itself leads to posterior reversible encephalopathy syndrome (PRES), a form of hypertensive encephalopathy that may lead to brain edema, seizures, and both ischemic and hemorrhagic strokes. Understanding the underlying mechanisms and addressing symptoms early may help prevent acute vascular events before delivery and in the postpartum period. Epidemiology Pre-eclampsia and eclampsia are major risk factors for both ischemic and hemorrhagic stroke during pregnancy. Hemorrhagic and ischemic stroke remain the most disabling complications of pregnancy. The incidence of hypertensive disorders of pregnancy is approximately 2.7 %, with the incidence of pre-eclampsia and eclampsia at about 2.1 and 0.3 %, respectively [25]. Risk factors for developing pre-eclampsia include obesity, nulliparity, multiple gestations, extra-uterine and molar pregnancies and pre-existing hypertension, diabetes mellitus, and thrombophilia [26]. Of the women that develop eclampsia, more than 95 % also develop PRES [27]. The incidence of hemorrhage in patients who develop PRES is estimated to be between 10 and 15 % [28, 29]. Unfortunately, the rapid identification of PRES in pregnancy has remained challenging, and the actual incidence during pregnancy may be much higher than initially recognized [27]. Pathophysiology The pathophysiologic basis of pre-eclampsia-eclampsia remains poorly understood. Dysregulation of angiogenesis and placentation, genetic predisposition, and endothelial dysfunction have all been implicated as plausible mechanisms of disease. Dysfunctional remodeling of spiral arteries in preeclampsia leads to disruption of this low-resistance system, which subsequently leads to placental hypoperfusion. In conjunction with a heightened sensitivity to mediators of vasoconstriction such as angiotensin I, systemic vascular tone is increased resulting in systemic hypertension, vasospasm, and end-organ hypoperfusion. Various signaling pathways, including VEGF-mediated and placental growth factor-
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mediated pathways, converge to contribute to the development of systemic endothelial dysfunction, hypertension, and proteinuria [30]. Endothelial dysfunction results in increased vascular permeability, which promotes cerebral edema and breakdown of cerebral autoregulation. PRES follows from the failure of cerebrovascular autoregulation with hypertension and increased vascular permeability resulting in cerebral edema. The most common pattern of hyperperfusion is most pronounced posteriorly. The predilection for edema in the subcortical white matter of the occipital lobes and other areas supplied by the posterior circulation is thought to be due to the relative low density of vasoconstricting sympathetic receptors in the vessels of the posterior circulation [31]. As the vasogenic edema progresses, oncotic forces in conjunction with hydrostatic forces may lead to intraparenchymal hemorrhage and, less frequently, vasospasm with ischemic infarction. Seizures mark the late stage of disease and develop secondary to cerebral edema and break down of the blood-brain barrier with disruption of the normal ionic gradients. The same pathophysiologic mechanisms that lead to preeclampsia-eclampsia and PRES likely also lead to postpartum cerebral angiopathy (PPA). PPA is a term used to describe one of the reversible cerebral vasoconstriction syndromes [32]. PPA is characterized by reversible narrowing of intracerebral arteries, often accompanied by reversible cerebral edema, seizures, parenchymal hemorrhage, and non-aneurysmal subarachnoid hemorrhage. The mechanisms remain incompletely understand, but PPA is a non-inflammatory vasoconstrictive disease which is reversible. The specific findings of cerebral artery narrowing on vascular imaging studies is seen in over half the patients who also present with PRES, thus the two conditions likely represent different but overlapping manifestations of the same underlying disease process. Clinical Presentation and Diagnosis Pre-eclampsia is clinically defined as hypertension (with diastolic BP greater than or equal to 90 mmHg or systolic BP greater than or equal to 140 mmHg on two occasions at least 4 h apart) and proteinuria (>300 mg/24 h or protein/creatinine ratio greater than or equal to 0.3 or urine dipstick reading of 1+ ). In the absence of proteinuria, pre-eclampsia may also be diagnosed in the setting of new-onset hypertension with the new onset of one of any of the following: thrombocytopenia (defined as platelet count less than 100,000/μL), renal insufficiency (serum creatinine greater than 1.1 mg/dL or doubling of the baseline creatinine in absence of renal disease), impaired liver function (defined as at least double normal transaminase levels), pulmonary edema, and cerebral or visual symptoms [33]. Eclampsia is defined as the preceding plus the onset of convulsions in woman with no coincidental neurologic disease that would account for the seizures.
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Patients typically present with manifestations of cerebral edema, including headache, nausea and vomiting, cortical visual phenomena consistent with occipital lobe dysfunction, and lastly seizures [34]. Other features of encephalopathy, such as confusion and depressed level of consciousness may be seen. Patients with isolated PPA (without PRES) usually present with recurrent sudden-onset severe headaches (thunderclap headaches). Some patients go on to develop visual deficits, confusion, and other focal neurological deficits from vasoconstriction-associated infarctions (usually bilateral, in posterior watershed locations) or lobar hemorrhages. Diagnostic testing for pre-eclampsia-eclampsia/PRES is driven by the search for hypertension and proteinuria and cerebral edema. CT or MRI of the brain reveals evidence of vasogenic edema, while Tc-SPECT imaging may demonstrate cerebral hyperperfusion. MRI remains the best imaging test for the confirmation of PRES, and FLAIR and postcontrast T1 MRI often demonstrate evidence of cerebral edema with blood-brain barrier dysfunction (Fig. 1) [35]. Vascular imaging by CT or magnetic resonance angiography may reveal evidence of cerebral arterial narrowing, defining cerebral angiopathy. Routine EEG is typically abnormal with diffuse or focal slowing, with occasional focal sharp waves in parietooccipital and temporal regions, correlating with imaging findings [36]. Unless there is accompanying hemorrhage or infarct, neuroimaging and EEG abnormalities typically resolve completely with clinical improvement. Management and Outcome Key management goals target aggressive normalization of systemic blood pressure and minimization of risk for seizures. In the setting of late-trimester pregnancy, delivery of the fetus is definitive treatment for eclampsia, although it is important to note that manifestations of PRES may arise only after delivery. Magnesium sulfate (MgSO4) remains the mainstay of therapy for eclamptic seizures and reduces the risk of progression from pre-eclampsia to eclampsia by more than 50 %. MgSO4 has been shown to be superior to traditional anticonvulsants such as phenytoin in reducing seizures in this setting [37]. Dosing is typically 4–6 g over 20–30 min followed by continuous infusion of 2 g/h. Additional 2-g boluses of MgSO4 may be given if seizures occur during this infusion setting [26]. Patients should be monitored closely while receiving MgSO4 infusion, and early loss of deep tendon reflexes or depressed respirations should alert clinicians to toxicity. Acute toxicity can be reversed with calcium gluconate, typically 1 g IV in severe cases. Intravenous antihypertensive agents should be liberally used to achieve normotension. Patients with ongoing seizures should be given anticonvulsant therapy when MgSO4 is not enough. However, these patients rarely go on to develop epilepsy [38], and most should be discontinued from chronic antiepileptic therapy after 3 months
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Fig. 1 The clinical and radiographic overlap of postpartum PRES and RCVS: A 36-year-old woman presented 9 days after uncomplicated delivery with thunderclap headache, photophobia, and nausea. BP was 130/108. Neurologic examination was normal. Head CT (not shown) showed a small left convexity subarachnoid hemorrhage (SAH). MRI FLAIR sequence shows features typical of RCVS, the non-aneurysmal SAH seen here as hyperintensity in sulci of the left frontal convexity (d, arrow), and features typical of PRES, the gray and white matter
hyperintensities most prominent posteriorly (a–d), here including the splenium of the corpus callosum (c) but also extending anteriorly (d). Diffusion-weighted images (not shown) showed no evidence of infarction. Conventional angiogram showed no aneurysm, no evidence of vasoconstriction, and no evidence of venous thrombosis. She was treated with intravenous MgSO4 and antihypertensive agents and had a full recovery
unless there is ongoing seizure activity or there are concerning abnormalities on EEG [34]. Anecdotal evidence for the role of glucocorticoids has not been supported in clinical studies, and corticosteroids have been associated with a trend toward poorer outcomes [32]. In most patients who receive treatment, these disorders have a self-limited course with complete resolution of clinical and imaging abnormalities; however, 5– 12 % can develop progressive vasoconstriction, cerebral edema, and strokes resulting in persistent neurologic deficits [39]. While PPA is included among the clinical syndromes that most commonly have benign outcomes, some patients with PPA develop rapidly progressive clinical deterioration from progressive infarcts, so close observation is prudent until the clinical stability becomes apparent and thunderclap headaches resolve. The presence of pre-eclampsia-eclampsia associated with one pregnancy increases the subsequent risk for future pregnancies, and close monitoring and screening are warranted with future pregnancies.
Cerebral Venous Thrombosis Cerebral venous thrombosis (CVT) is often a difficult diagnosis and may account for 6 to 64 % of all pregnancy-related strokes [40]. The main underlying cause of thrombosis in the cerebral venous circulation is presumed to be the underlying physiologic hypercoagulable state of pregnancy combined with pathophysiologic changes commonly accompanying pregnancy and delivery. Alterations in platelet function and levels and function of pro- and anti-thrombotic proteins, iron deficiency anemia, and changes due to the acute trauma and hemorrhage of labor and delivery increase the risk of abnormal thrombosis during the early postpartum period, corresponding to the peak incidence of cerebral venous thrombosis [41]. When a pregnant woman presents with sudden-onset headaches, focal neurologic deficits, altered level of consciousness, or seizures, it is critical to have a heightened index of suspicion for CVT. Neuroimaging findings range from normal to
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overt visualization of a thrombosed sinus and associated hemorrhagic infarction. Noncontrast head CT may be normal or may show parenchymal hypodensity from edema or infarction, or hyperdensity from hemorrhage; noncontrast CT often shows a hyperdensity in the area of the thrombosis. With contrast, a filling defect may be seen within the enhanced dural wall of the thrombosed sinus, the empty delta sign. A contrast-enhanced CT venogram may show a filling defect at the site of the thrombosed sinus. MRI has a higher resolution than CT and can directly demonstrate the thrombosed venous sinus with signal characteristics consistent with the time having elapsed since onset. Typically, in acute venous thrombosis, MRI T1 sequence is isodense and T2 sequence is hypodense, whereas in the subacute phase, T1 sequence first turns hyperintense followed by the T2 sequence so that the thrombus appears bright on both sequences. MR venography, showing a sinus filling defect, is particularly useful during pregnancy and nursing since it can be performed without contrast. Because of its higher sensitivity, absence of ionizing radiation, and lack of need for contrast, MRI is the preferred diagnostic study for CVT during pregnancy and breastfeeding. Based on limited available evidence and clinical experience, anticoagulation treatment for cerebral venous thrombosis appears to be safe and associated with a potential reduction in risk of death or dependency [42, 43]. A randomized, controlled trial of heparin therapy for CVT by Einhäupl et al. [44], although small, appeared to show a clear benefit for anticoagulation in CVT; the trial was terminated early, because there was evidence of benefit in favor of heparin anticoagulation after enrollment of only 20 patients. A larger Dutch study by de Bruijn et al. [45] using low-molecularweight heparin showed a trend in favor of early anticoagulation but did not reach statistical significance. This study was limited since patients in both the control and treatment groups received warfarin therapy after the first 3 weeks of study treatment, possibly accounting for the small differences between the groups. Based on this limited evidence, we, along with many clinicians, treat CVT with anticoagulation, although controversy remains. Approximately half the patients with CVT have concurrent intracerebral hemorrhage before treatment. In the Einhäupl study [44], 3 of 10 patients treated with heparin had hemorrhages before treatment with anticoagulation; none of these patients had expansion or new hemorrhage, and all recovered completely. Einhäupl et al. [44] also retrospectively reviewed 102 patients. Of 43 patients with hemorrhage, 27 received full-dose heparin while 13 patients received no heparin after hemorrhages. Those who received heparin had a lower mortality of 15 versus 56 %. Additionally, Bruijn et al. [45] found no worsening of already present hemorrhage in patients who received therapeutic anticoagulation. Our practice is to treat with full heparin anticoagulation during the acute phase of CVT followed by a period of warfarin therapy whether or not there is associated
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intracerebral hemorrhage. However, since warfarin is contraindicated during early pregnancy, low-molecular-weight heparin is recommended and then held during the period of labor and delivery. There are no studies that determine the optimal duration of anticoagulation. Extrapolating from the experience with systemic venous thromboembolism and to continue therapy beyond the period of postpartum hypercoagulability, which may extend at least 12 weeks after delivery [46], it is recommended that anticoagulation continue for 3–6 months after delivery. In patients found to have antiphospholipid antibody syndrome or underlying genetic predisposition to thrombosis, extended anticoagulation may be indicated.
Hemorrhagic Stroke and Vascular Malformations Hemorrhagic stroke is an important cause of pregnancyrelated mortality. Although hemorrhagic stroke is relatively uncommon during pregnancy and the postpartum period with an incidence of up to 6 per 100,000 in reported series [7, 47], pregnancy increases the risk of hemorrhage more than that of ischemic stroke (relative risk of 2.5 and 28.5 during pregnancy and the postpartum period, respectively) [7]. Underlying mechanisms of pregnancy-related hemorrhage are likely consequences of physiologic changes including blood volume expansion and vascular tissue remodeling in pregnancy with added risk from the strain and trauma of labor and delivery. Major causes of pregnancy-related hemorrhage are preeclampsia-eclampsia, which contributes to a large proportion of cases, followed by intracerebral aneurysms and arteriovenous malformations [47]. Additionally, in a large proportion of cases, the cause is unclear, though often related to preeclampsia-eclampsia. The risk of intracerebral aneurysmal rupture increases with gestational age, peaking at 30 to 34 weeks [48]. It has been reported that the maternal mortality of pregnancy-associated aneurysmal subarachnoid hemorrhage may be as high as 35 %, while fetal mortality may be up to 17 % [48]. Notably, the rate of recurrent hemorrhage and associated mortality is very high, maternal mortality of 63 % and fetal mortality 27 %, if a ruptured aneurysm remains unsecured. These rates are significantly decreased after early surgical intervention to 11 % maternal mortality and 5 % fetal mortality [48]. Thus, if aneurysmal subarachnoid hemorrhage occurs during pregnancy, then it is critical that surgical control by clipping or endovascular coiling be accomplished as soon as possible [49]. Since the morbidity and mortality of subarachnoid hemorrhage are high, and risk of rupture is increased near term, it is recommended that known unruptured aneurysms with high risk of rupture be secured before pregnancy. The risk of rupture depends on size and morphology, and screening MRA and CTA for headache and other conditions often find
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incidental small, uncomplicated aneurysms. In such cases, no rigorous studies guide therapy; however, it may be best to pursue delivery methods that avoid the second stage of labor to decrease chances of rupture. It is less clear that pregnancy predisposes to an increased risk of rupture of arteriovenous malformations (AVMs). The most common manifestation of AVMs is hemorrhage. An influential study in 1974 [50] suggested that pregnancy increased the rate of bleeding in AVMs; however, a later analysis in 1990 found the annual rate of hemorrhage in women with AVMs and no prior hemorrhage to be 3.5 % and in those with AVMs and prior hemorrhage 5.8 %, and that pregnancy did not have an impact on risk [51]. However, analysis of rupture risk per day has found increased risk by several-fold on the day of delivery [52, 53]. Also, when an AVM bleeds during pregnancy, the rebleeding rate is higher than in nonpregnant women. One study found a 25 % rate of recurrent hemorrhage from AVMs during pregnancy, significantly higher than the 6 % rate in non-pregnant women [54]. In most cases, AVMs can be conservatively observed until after delivery; however, if there is hemorrhage during pregnancy, then low-grade AVMs may benefit from early surgical or endovascular intervention [55]. If subarachnoid or intracerebral hemorrhage occurs during pregnancy, then prompt evaluation and management should follow based on neurosurgical principles with proper shielding protection of the unborn fetus for radiologic studies and hydration when iodinated contrast is given, typically for conventional four-vessel cerebral angiogram, to provide clear diagnostic information for therapeutic planning.
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Conclusion Ischemic and hemorrhagic stroke, cerebral venous thrombosis, and cerebrovascular manifestations of pre-eclampsiaeclampsia are all uncommon but serious complications of pregnancy and the puerperium. So that evaluation and diagnosis are rapid and focused, it is important to maintain a high level of suspicion for these disorders when pregnant and postpartum women present with headaches and focal neurologic symptoms. Although special precautions must be taken to insure the safety of mother and child, practitioners should pursue aggressive measures to minimize risk to life and functional disability in this special group of patients.
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Compliance with Ethics Guidelines Conflict of Interest Ali Razmara, Khamid Bakhadirov, Ayush Batra, and Steven K. Feske declare that they have no conflict of interest.
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Tassi R et al. Systemic thrombolysis for stroke in pregnancy. Am J Emerg Med. 2013;31:448.e441–3. Li Y, Margraf J, Kluck B, Jenny D, Castaldo J. Thrombolytic therapy for ischemic stroke secondary to paradoxical embolism in pregnancy: a case report and literature review. Neurologist. 2012;18:44–8. Coomarasamy A, Honest H, Papaioannou S, et al. Aspirin for prevention of preeclampsia in women with historical risk factors: a systemic review. Obstet Gynecol. 2003;101:1319–32. Furie KL et al. Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011;42:227–76. doi: 10.1161/STR. 0b013e3181f7d043 . Updated AHA/ASA guidelines for the prevention of stroke in patients with stroke or transient ischemic attack. Abalos E et al. WHO Multicounty Survey on Maternal and Newborn Health Research Network. Pre-eclampsia, eclampsia and adverse maternal and perinatal outcomes: a secondary analysis of the World Health Organization Multicounty Survey on Maternal and Newborn Health. Br J Gynecol. 2014;121 Suppl 1:14–24. Feske SK, Singhal A. Cerebrovascular disorders complicating pregnancy. Continuum. 2014;20:80–99. Brewer J et al. Posterior reversible encephalopathy syndrome in 46 of 47 patients with eclampsia. Am J Obstet Gynecol. 2013;208: 468.e461–6. Hefzy HM, Bartynski WS, Boardman JF, Lacomis D. Hemorrhage in posterior reversible encephalopathy syndrome: imaging and clinical features. AJNR Am J Neuroradiol. 2009;30:1371–9. Singhal AB. Postpartum angiopathy with reversible posterior leukoencephalopathy. Arch Neurol. 2004;61:411–6. Craici IM, Wagner SJ, Weissgerber TL, Grande JP, Garovic VD. Advances in the pathophysiology of pre-eclampsia and related podocyte injury. Kidney Int. 2014. Beausang-Linder M, Anders B. Cerebral circulation in acute arterial hypertension—protective effects of sympathetic nervous activity. Acta Physiol Scand. 1981;111:193–9. Singhal AB et al. Reversible cerebral vasoconstriction syndromes: analysis of 139 cases. Arch Neurol. 2011;68:1005–12. doi: 10. 1001/archneurol.2011.68 . Pregnany, T. F. o. H. i. Hypertension and pregnancy: establishing the diagnosis of preeclampsia and eclampsia. Am J Obstet Gynecol.2013; 17–20. Roth C, Ferbert A. The posterior reversible encephalopathy syndrome: what’s certain, what’s new? Pract Neurol. 2011;11:136–44. Weier K, Fluri F, Kos S, Gass A. Postcontrast FLAIR MRI demonstrates blood-brain barrier dysfunction in PRES. Neurology. 2009;72:760–2. Lee VH, Wijdicks EF, Manno EM, Rabinstein AA. Clinical spectrum of reversible posterior leukoencephalopathy syndrome. Arch Neurol. 2008;65:205–10. Duley L, Gulmezoglu AM, Henderson-Smart DJ. Magnesium sulphate and other anticonvulsants for women with pre-eclampsia. Cochrane Database of Syst Rev. 2003;2, CD000025.
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Kozak OS, Wijdicks EF, Manno EM, Miley JT, Rabinstein AA. Status epilepticus as initial manifestation of posterior reversible encephalopathy syndrome. Neurology. 2007;69: 894–7. 39. Fugate JE et al. Fulminant postpartum cerebral vasoconstriction syndrome. Arch Neurol. 2012;69:111–7. 40. Liang CC et al. Stroke complicating pregnancy and the puerperium. Eur J Neurol. 2006;13:1256–60. 41. Feske SK, Klein AM. Clinical risk factors predict pregnancyassociated strokes. Stroke. 2009;40:e183–4. 42. Bousser M-G. Cerebral venous thrombosis: diagnosis and management. J Neurol. 2000;247:252–8. 43. Coutinho J, de Bruijn SFTM, deVeber G, Stam, J. Anticoagulation for cerebral venous sinus thrombosis (review). Cochrane Database Syst Rev. 2011; CD002005. 44. Einhäupl KM, Villringer A, Meister W, et al. Heparin treatment in sinus venous thrombosis. Lancet. 1991;338:597–600. 45. de Bruijn SF, Stam J, Cerebral Venous Sinus Thrombosis Study Group. Randomized, placebo-controlled trial of anticoagulant treatment with low-molecular-weight-heparin for cerebral sinus thrombosis. Stroke. 1999;30:484–8. 46. Kamel H et al. Risk of a thrombotic event after the 6-week postpartum period. N Engl J Med. 2014;370:1307–15. doi: 10.1056/ NEJMoa1311485 . 47. Sharshar T, Lamy C, Mas JL, Stroke in Pregnancy Study Group. Incidence and causes of stroke associated with pregnancy and puerperium: a study in public hospitals of Ile de France. Stroke. 1995;26:930–6. 48. Dias MS, Sekhar LN. Intracranial hemorrhage from aneurysms and arteriovenous malformations during pregnancy and the puerperium. Neurosurgery. 1990;27:855–65. 49. Meyers PM et al. Endovascular treatment of cerebral artery aneurysms during pregnancy: report of three cases. AJNR Am J Neuroradiol. 2000;21:1306–11. 50. Robinson JL, Hall CS, Sedzimir CB. Arteriovenous malformations, aneurysms, and pregnancy. J Neurosurg. 1974;41:63–70. 51. Horton JC, Chambers WA, Lyons SL, Adams RD, Kjellberg RN. Pregnancy and the risk of hemorrhage from cerebral arteriovenous malformations. Neurosurgery. 1990;27:867–72. 52. Parkinson D, Bachers G. Arteriovenous malformations: summary of 100 consecutive supratentorial cases. J Neurosurg. 1980;53:285– 99. 53. Wier B, MacDonald RL. Neurosurg (eds R. H. Wilkins & S. S. REngachary) 2421–2427 (McGraw-Hill, 1996). 54. Sawin P. Neurol Asp pregnancy. (ed C. Loftus) 85–99 (American Association of Neurological Surgeons, 1996). 55. Ogilvy CS et al. Recommendations for the management of intracranial arteriovenous malformations: a statement for healthcare professionals for a special writing group of the Stroke Council, American Stroke Association. Stroke. 2001;32:1458–71. doi: 10.1161/01.STR.32.6.1458 .
STROKE (AB SINGHAL, SECTION EDITOR)
Cerebrovascular Complications of Pregnancy and the Postpartum Period Ali Razmara & Khamid Bakhadirov & Ayush Batra & Steven K. Feske
Published online: 21 September 2014 # Springer Science+Business Media New York 2014
Abstract Cerebrovascular complications of pregnancy, though uncommon, threaten women with severe morbidity or death, and they are the main causes of major long-term disability associated with pregnancy. In this review, we discuss the epidemiology, pathophysiology, presentation and diagnosis, and management and outcomes of ischemic and hemorrhagic stroke and cerebral venous thrombosis. We also discuss the posterior reversible encephalopathy syndrome, the reversible cerebral vasoconstriction syndrome including postpartum cerebral angiopathy, and their relationship as overlapping manifestations of pre-eclampsia-eclampsia.
Keywords Cerebrovascular complications . Pregnancy . Postpartum period . Ischemic stroke . Hemorrhagic stroke . Cerebral venous thrombosis . Pre-eclampsia-eclampsia
This article is part of the Topical Collection on Stroke A. Razmara : K. Bakhadirov Fellow in Vascular Neurology, Massachusetts General and Brigham and Women’s Hospitals, Boston, MA, USA
Introduction Stroke is the fourth leading cause of death in the USA and the leading cause of serious long-term disability [1, 2]. While ischemic and hemorrhagic stroke and cerebral venous thrombosis are all rare in women of childbearing age, late pregnancy and the early postpartum period increase the risk of all of these types of stroke, and stroke is the leading cause of pregnancyrelated long-term disability. Pre-eclampsia-eclampsia is an important complication unique to pregnancy. In addition to its contribution to ischemic and hemorrhagic stroke, preeclampsia-eclampsia underlies the occurrence of hypertensive encephalopathy, also known as posterior reversible encephalopathy syndrome (PRES), and reversible cerebral vasoconstriction syndrome (RCVS). These two disorders are overlapping manifestations of a shared pathophysiology, and they encompass the entity termed postpartum cerebral angiopathy. In this brief review, we discuss the epidemiology, pathophysiology, diagnosis, and management of these important cerebrovascular disorders of pregnancy.
A. Razmara e-mail: [email protected]
Ischemic Stroke
K. Bakhadirov e-mail: [email protected]
Epidemiology
A. Batra Resident in Neurology, Brigham and Women’s and Massachusetts General Hospitals/Harvard Medical School, Boston, MA, USA e-mail: [email protected]
There are no long-term prospective studies of the incidence of stroke in pregnancy. Various studies estimate the incidence of all types of stroke in pregnancy and puerperium between 25 and 34 per 100,000 deliveries [3–5]. In comparison, the incidence of stroke in non-pregnant women in the 15- to 45-year age group is 11 per 100,000 [6]. A population-based retrospective study conducted from 1988 to 1991 found no increase during pregnancy but a relative risk of 8.7 during the first 6 weeks postpartum [7]. Recent analysis of hospital discharge data from the Nationwide Inpatient Sample of the
S. K. Feske (*) Neurology Department, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA e-mail: [email protected] S. K. Feske Harvard Medical School, Boston, MA, USA
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Healthcare Cost and Utilization Project demonstrated that between 1994–1995 and 2006–2007, the rates of antenatal and postpartum hospitalizations for all types of stroke increased by 47 and 83 %, respectively [8•]. This increase was thought to be related to the increase in hypertensive disorders and heart disease. Pathophysiology Pregnancy is associated with a number of physiologic changes that can result in increased risk of ischemic stroke. These include hemodynamic changes (hemodilutional anemia, variations in blood pressure, venous stasis), vascular abnormalities (decreased collagen and elastin content in blood vessels, increased stiffness and relaxation response), endothelial dysfunction (increased vessel wall permeability and vasogenic edema), and, most importantly, changes in the coagulation system. A procoagulant state is created by alteration in levels of coagulation factors, most notably by increases in procoagulant levels (factors I, VII, VIII, IX, X, XII, and XIII) and decreases in levels of coagulation inhibitors (antithrombin III, protein S, functional resistance to activated protein C) [6]. A combination of congested venous flow and changes in coagulation factor levels contributes to a hypercoagulable state which is most significant in the third trimester and early postpartum period. Multiple risk factors have been associated with the increased risk of stroke, including hypertension, diabetes, heart disease, sickle cell anemia, thrombocytopenia, smoking, systemic lupus erythematosus, and complications of labor [5]. Pre-eclampsia-eclampsia is a well recognized risk factor and is present in 11–47 % of cases of stroke in pregnancy. Cesarean section has been associated with a 3- to 12fold increased risk of peripartum stroke [9]. Clinical Presentation and Diagnosis Stroke in pregnancy most typically presents, as does all stroke, with sudden onset of a focal neurologic deficit. Headache is an important and common symptom of stroke. Although more likely in hemorrhagic stroke, it occurs commonly with preeclampsia-eclampsia and may be a key symptom in early diagnosis of pregnancy-related stroke. Impairment of consciousness and seizures more commonly accompany hemorrhagic stroke and venous sinus thrombosis, but they may also occur with ischemic stroke. The most common mechanism of stroke in pregnancy appears to be embolism, either from a demonstrable cardiac source or cryptogenic. Other causes of stroke in young patients, such as arterial dissections, paradoxical embolism through a patent foramen ovale, moyamoya syndrome, and IV drug abuse must be considered. Causes unique to pregnancy include peripartum cardiomyopathy and embolization of amniotic fluid or air, the latter due to dissection through the placental planes and into uterine veins.
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Pre-eclampsia-eclampsia is a strong risk factor that underlies many pregnancy-associated strokes, although the mechanism of this association is not always clear. An understanding of the possible causes of stroke guides the diagnostic work-up. Appropriate choice and timing of neuroimaging help to confirm the diagnosis. Noncontrast CT is often the first choice, especially when acute thrombolysis is considered. The fetal exposure to radiation is very low, especially with proper precautions and shielding. IV iodinated contrast is classified as class B by the FDA and should be avoided if possible [10]. While it has not been shown to have teratogenic or mutagenic effects, it has been associated with neonatal hypothyroidism. The low concentrations of iodinated contrast agents in breast milk have not been shown to affect the infant, making it relatively safe during breastfeeding. MRI up to 3 T has not been shown to cause any fetal adverse effects. Absence of radiation and high safety index make MRI the imaging method of choice when the speed and availability of CT are not decisive. Gadolinium-based contrast is classified as class C by the FDA and should be avoided unless benefits of its use outweigh its risk of developmental abnormality and abortion. Gadolinium is safe to use during lactation [11]. As a general rule, informed consent should be obtained any time contrast imaging is used. Cerebral vessel imaging can be achieved using CT, MR, or catheter angiography. When use of contrast is contraindicated, time-of-flight MRI, carotid ultrasound, and transcranial Doppler imaging can be used safely for assessment of both the intra- and extracranial cerebral vasculature. Cardiac ultrasound is an essential part of the evaluation in cases of embolic stroke. The use of agitated saline is consider safe during pregnancy and is recommended in all patients to look for a right-to-left shunt from a patent foramen ovale (PFO) [12]. The presence of a PFO suggests the possibility of paradoxical embolism and calls for further testing for deep venous thrombosis in lower extremities and pelvis. Minimal laboratory screening for common causes and risk factors is indicated in all patients, including complete blood count and liver function tests to look for features of HELLP syndrome (a severe form of pre-eclampsia with hemolytic anemia, elevated liver function tests, and low platelets), fasting glucose and hemoglobin A1C, fasting lipid panel, and serum and urine for toxicologic screening. Additional testing may be needed to search for specific disorders in particular cases, for example, hemoglobin electrophoresis when sickle cell disease is considered. Testing for thrombophilia should include lupus anticoagulant assay, antibodies to anticardiolipin IgG and IgM and to beta-2-glycoprotein I. Other testing for underlying thrombophilias, protein C and S levels and activity, antithrombin III, and factor V Leiden screening with activated protein C resistance assays are best done no sooner than 6 weeks after delivery, because these studies, most reliably protein S, will be affected by the pregnancy state. Genetic testing for the
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prothrombin G20120A mutation and the methylene tetrahydrofolate reductase C677T mutation in patients with hyperhomocysteinemia will round out testing for common causes of thrombophilia.
Management and Outcome Intravenous thrombolysis with tPA is the only FDA-approved treatment for acute ischemic stroke. Since pregnant women were excluded from the clinical trials of acute stroke therapies, there are no controlled data on which to base treatment decisions in this population. The real concern for thrombolysis in pregnancy is not efficacy but safety given potential hemorrhagic complications, such as placental hemorrhage and abruption, fetal loss, and preterm delivery. Animal data suggest that tPA, a large molecule, does not cross the placenta and is unlikely to have teratogenic effects [13]. Moreover, the halflife of tPA in the circulation is only 5 min, although the effect lasts for hours when bound to fresh thrombus. Evidence for efficacy and safety of acute IVor IA thrombolysis in pregnancy comes from a limited number of case reports in the literature. Recent case reports [14–22] of nine women who received IV tPA for acute ischemic stroke demonstrated generally good outcomes for both mothers and fetuses while showing minimal hemorrhagic risk apart from expected asymptomatic hemorrhagic transformation of stroke. Although the interpretation of these data is complicated by the small numbers and by decisions to terminate pregnancy after stroke, we believe that pregnancy alone should not serve as a contraindication to IV tPA for treatment of a potentially disabling stroke in a pregnant woman. Data are even more limited for acute endovascular thrombolysis or thrombectomy; however, these therapies should be considered in particular circumstances as they would for non-pregnant patients, such as in women who cannot be given IV tPA. Treatment decisions are best made jointly with obstetric consultants and the patient herself or a proxy and with careful assessment of all risks. When considering treatment choices, it is important to define the mechanism of stroke. Ischemic stroke from amniotic fluid embolism or from vasoconstriction secondary to pre-eclampsiaeclampsia will not be expected to benefit from thrombolysis. Choice of therapy for secondary prevention depends on the etiology of the stroke. Aspirin is a reasonable choice for most patients. Safety of low-dose aspirin (50–150 mg/day) after the first trimester has been demonstrated in several meta-analyses [23]. Higher doses of aspirin should be avoided due to increased risk of maternal and fetal hemorrhage, premature closure of the ductus arteriosus, and oligohydramnios. In high-risk patients that require anticoagulation (e.g., mechanical heart valves, atrial fibrillation, hypercoagulable states), unfractionated and low-molecular-weight heparin are acceptable. They appear to be safe in the first trimester and can be
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replaced by either aspirin or warfarin after the first trimester [24•].
Pre-eclampsia-Eclampsia, Posterior Reversible Encephalopathy Syndrome, and Postpartum Cerebral Angiopathy The pathophysiologic changes that occur within the cerebrovascular system in the setting of pre-eclampsia and eclampsia predispose pregnant women to ischemic and hemorrhagic stroke. Additionally, eclampsia itself leads to posterior reversible encephalopathy syndrome (PRES), a form of hypertensive encephalopathy that may lead to brain edema, seizures, and both ischemic and hemorrhagic strokes. Understanding the underlying mechanisms and addressing symptoms early may help prevent acute vascular events before delivery and in the postpartum period. Epidemiology Pre-eclampsia and eclampsia are major risk factors for both ischemic and hemorrhagic stroke during pregnancy. Hemorrhagic and ischemic stroke remain the most disabling complications of pregnancy. The incidence of hypertensive disorders of pregnancy is approximately 2.7 %, with the incidence of pre-eclampsia and eclampsia at about 2.1 and 0.3 %, respectively [25]. Risk factors for developing pre-eclampsia include obesity, nulliparity, multiple gestations, extra-uterine and molar pregnancies and pre-existing hypertension, diabetes mellitus, and thrombophilia [26]. Of the women that develop eclampsia, more than 95 % also develop PRES [27]. The incidence of hemorrhage in patients who develop PRES is estimated to be between 10 and 15 % [28, 29]. Unfortunately, the rapid identification of PRES in pregnancy has remained challenging, and the actual incidence during pregnancy may be much higher than initially recognized [27]. Pathophysiology The pathophysiologic basis of pre-eclampsia-eclampsia remains poorly understood. Dysregulation of angiogenesis and placentation, genetic predisposition, and endothelial dysfunction have all been implicated as plausible mechanisms of disease. Dysfunctional remodeling of spiral arteries in preeclampsia leads to disruption of this low-resistance system, which subsequently leads to placental hypoperfusion. In conjunction with a heightened sensitivity to mediators of vasoconstriction such as angiotensin I, systemic vascular tone is increased resulting in systemic hypertension, vasospasm, and end-organ hypoperfusion. Various signaling pathways, including VEGF-mediated and placental growth factor-
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mediated pathways, converge to contribute to the development of systemic endothelial dysfunction, hypertension, and proteinuria [30]. Endothelial dysfunction results in increased vascular permeability, which promotes cerebral edema and breakdown of cerebral autoregulation. PRES follows from the failure of cerebrovascular autoregulation with hypertension and increased vascular permeability resulting in cerebral edema. The most common pattern of hyperperfusion is most pronounced posteriorly. The predilection for edema in the subcortical white matter of the occipital lobes and other areas supplied by the posterior circulation is thought to be due to the relative low density of vasoconstricting sympathetic receptors in the vessels of the posterior circulation [31]. As the vasogenic edema progresses, oncotic forces in conjunction with hydrostatic forces may lead to intraparenchymal hemorrhage and, less frequently, vasospasm with ischemic infarction. Seizures mark the late stage of disease and develop secondary to cerebral edema and break down of the blood-brain barrier with disruption of the normal ionic gradients. The same pathophysiologic mechanisms that lead to preeclampsia-eclampsia and PRES likely also lead to postpartum cerebral angiopathy (PPA). PPA is a term used to describe one of the reversible cerebral vasoconstriction syndromes [32]. PPA is characterized by reversible narrowing of intracerebral arteries, often accompanied by reversible cerebral edema, seizures, parenchymal hemorrhage, and non-aneurysmal subarachnoid hemorrhage. The mechanisms remain incompletely understand, but PPA is a non-inflammatory vasoconstrictive disease which is reversible. The specific findings of cerebral artery narrowing on vascular imaging studies is seen in over half the patients who also present with PRES, thus the two conditions likely represent different but overlapping manifestations of the same underlying disease process. Clinical Presentation and Diagnosis Pre-eclampsia is clinically defined as hypertension (with diastolic BP greater than or equal to 90 mmHg or systolic BP greater than or equal to 140 mmHg on two occasions at least 4 h apart) and proteinuria (>300 mg/24 h or protein/creatinine ratio greater than or equal to 0.3 or urine dipstick reading of 1+ ). In the absence of proteinuria, pre-eclampsia may also be diagnosed in the setting of new-onset hypertension with the new onset of one of any of the following: thrombocytopenia (defined as platelet count less than 100,000/μL), renal insufficiency (serum creatinine greater than 1.1 mg/dL or doubling of the baseline creatinine in absence of renal disease), impaired liver function (defined as at least double normal transaminase levels), pulmonary edema, and cerebral or visual symptoms [33]. Eclampsia is defined as the preceding plus the onset of convulsions in woman with no coincidental neurologic disease that would account for the seizures.
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Patients typically present with manifestations of cerebral edema, including headache, nausea and vomiting, cortical visual phenomena consistent with occipital lobe dysfunction, and lastly seizures [34]. Other features of encephalopathy, such as confusion and depressed level of consciousness may be seen. Patients with isolated PPA (without PRES) usually present with recurrent sudden-onset severe headaches (thunderclap headaches). Some patients go on to develop visual deficits, confusion, and other focal neurological deficits from vasoconstriction-associated infarctions (usually bilateral, in posterior watershed locations) or lobar hemorrhages. Diagnostic testing for pre-eclampsia-eclampsia/PRES is driven by the search for hypertension and proteinuria and cerebral edema. CT or MRI of the brain reveals evidence of vasogenic edema, while Tc-SPECT imaging may demonstrate cerebral hyperperfusion. MRI remains the best imaging test for the confirmation of PRES, and FLAIR and postcontrast T1 MRI often demonstrate evidence of cerebral edema with blood-brain barrier dysfunction (Fig. 1) [35]. Vascular imaging by CT or magnetic resonance angiography may reveal evidence of cerebral arterial narrowing, defining cerebral angiopathy. Routine EEG is typically abnormal with diffuse or focal slowing, with occasional focal sharp waves in parietooccipital and temporal regions, correlating with imaging findings [36]. Unless there is accompanying hemorrhage or infarct, neuroimaging and EEG abnormalities typically resolve completely with clinical improvement. Management and Outcome Key management goals target aggressive normalization of systemic blood pressure and minimization of risk for seizures. In the setting of late-trimester pregnancy, delivery of the fetus is definitive treatment for eclampsia, although it is important to note that manifestations of PRES may arise only after delivery. Magnesium sulfate (MgSO4) remains the mainstay of therapy for eclamptic seizures and reduces the risk of progression from pre-eclampsia to eclampsia by more than 50 %. MgSO4 has been shown to be superior to traditional anticonvulsants such as phenytoin in reducing seizures in this setting [37]. Dosing is typically 4–6 g over 20–30 min followed by continuous infusion of 2 g/h. Additional 2-g boluses of MgSO4 may be given if seizures occur during this infusion setting [26]. Patients should be monitored closely while receiving MgSO4 infusion, and early loss of deep tendon reflexes or depressed respirations should alert clinicians to toxicity. Acute toxicity can be reversed with calcium gluconate, typically 1 g IV in severe cases. Intravenous antihypertensive agents should be liberally used to achieve normotension. Patients with ongoing seizures should be given anticonvulsant therapy when MgSO4 is not enough. However, these patients rarely go on to develop epilepsy [38], and most should be discontinued from chronic antiepileptic therapy after 3 months
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Fig. 1 The clinical and radiographic overlap of postpartum PRES and RCVS: A 36-year-old woman presented 9 days after uncomplicated delivery with thunderclap headache, photophobia, and nausea. BP was 130/108. Neurologic examination was normal. Head CT (not shown) showed a small left convexity subarachnoid hemorrhage (SAH). MRI FLAIR sequence shows features typical of RCVS, the non-aneurysmal SAH seen here as hyperintensity in sulci of the left frontal convexity (d, arrow), and features typical of PRES, the gray and white matter
hyperintensities most prominent posteriorly (a–d), here including the splenium of the corpus callosum (c) but also extending anteriorly (d). Diffusion-weighted images (not shown) showed no evidence of infarction. Conventional angiogram showed no aneurysm, no evidence of vasoconstriction, and no evidence of venous thrombosis. She was treated with intravenous MgSO4 and antihypertensive agents and had a full recovery
unless there is ongoing seizure activity or there are concerning abnormalities on EEG [34]. Anecdotal evidence for the role of glucocorticoids has not been supported in clinical studies, and corticosteroids have been associated with a trend toward poorer outcomes [32]. In most patients who receive treatment, these disorders have a self-limited course with complete resolution of clinical and imaging abnormalities; however, 5– 12 % can develop progressive vasoconstriction, cerebral edema, and strokes resulting in persistent neurologic deficits [39]. While PPA is included among the clinical syndromes that most commonly have benign outcomes, some patients with PPA develop rapidly progressive clinical deterioration from progressive infarcts, so close observation is prudent until the clinical stability becomes apparent and thunderclap headaches resolve. The presence of pre-eclampsia-eclampsia associated with one pregnancy increases the subsequent risk for future pregnancies, and close monitoring and screening are warranted with future pregnancies.
Cerebral Venous Thrombosis Cerebral venous thrombosis (CVT) is often a difficult diagnosis and may account for 6 to 64 % of all pregnancy-related strokes [40]. The main underlying cause of thrombosis in the cerebral venous circulation is presumed to be the underlying physiologic hypercoagulable state of pregnancy combined with pathophysiologic changes commonly accompanying pregnancy and delivery. Alterations in platelet function and levels and function of pro- and anti-thrombotic proteins, iron deficiency anemia, and changes due to the acute trauma and hemorrhage of labor and delivery increase the risk of abnormal thrombosis during the early postpartum period, corresponding to the peak incidence of cerebral venous thrombosis [41]. When a pregnant woman presents with sudden-onset headaches, focal neurologic deficits, altered level of consciousness, or seizures, it is critical to have a heightened index of suspicion for CVT. Neuroimaging findings range from normal to
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overt visualization of a thrombosed sinus and associated hemorrhagic infarction. Noncontrast head CT may be normal or may show parenchymal hypodensity from edema or infarction, or hyperdensity from hemorrhage; noncontrast CT often shows a hyperdensity in the area of the thrombosis. With contrast, a filling defect may be seen within the enhanced dural wall of the thrombosed sinus, the empty delta sign. A contrast-enhanced CT venogram may show a filling defect at the site of the thrombosed sinus. MRI has a higher resolution than CT and can directly demonstrate the thrombosed venous sinus with signal characteristics consistent with the time having elapsed since onset. Typically, in acute venous thrombosis, MRI T1 sequence is isodense and T2 sequence is hypodense, whereas in the subacute phase, T1 sequence first turns hyperintense followed by the T2 sequence so that the thrombus appears bright on both sequences. MR venography, showing a sinus filling defect, is particularly useful during pregnancy and nursing since it can be performed without contrast. Because of its higher sensitivity, absence of ionizing radiation, and lack of need for contrast, MRI is the preferred diagnostic study for CVT during pregnancy and breastfeeding. Based on limited available evidence and clinical experience, anticoagulation treatment for cerebral venous thrombosis appears to be safe and associated with a potential reduction in risk of death or dependency [42, 43]. A randomized, controlled trial of heparin therapy for CVT by Einhäupl et al. [44], although small, appeared to show a clear benefit for anticoagulation in CVT; the trial was terminated early, because there was evidence of benefit in favor of heparin anticoagulation after enrollment of only 20 patients. A larger Dutch study by de Bruijn et al. [45] using low-molecularweight heparin showed a trend in favor of early anticoagulation but did not reach statistical significance. This study was limited since patients in both the control and treatment groups received warfarin therapy after the first 3 weeks of study treatment, possibly accounting for the small differences between the groups. Based on this limited evidence, we, along with many clinicians, treat CVT with anticoagulation, although controversy remains. Approximately half the patients with CVT have concurrent intracerebral hemorrhage before treatment. In the Einhäupl study [44], 3 of 10 patients treated with heparin had hemorrhages before treatment with anticoagulation; none of these patients had expansion or new hemorrhage, and all recovered completely. Einhäupl et al. [44] also retrospectively reviewed 102 patients. Of 43 patients with hemorrhage, 27 received full-dose heparin while 13 patients received no heparin after hemorrhages. Those who received heparin had a lower mortality of 15 versus 56 %. Additionally, Bruijn et al. [45] found no worsening of already present hemorrhage in patients who received therapeutic anticoagulation. Our practice is to treat with full heparin anticoagulation during the acute phase of CVT followed by a period of warfarin therapy whether or not there is associated
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intracerebral hemorrhage. However, since warfarin is contraindicated during early pregnancy, low-molecular-weight heparin is recommended and then held during the period of labor and delivery. There are no studies that determine the optimal duration of anticoagulation. Extrapolating from the experience with systemic venous thromboembolism and to continue therapy beyond the period of postpartum hypercoagulability, which may extend at least 12 weeks after delivery [46], it is recommended that anticoagulation continue for 3–6 months after delivery. In patients found to have antiphospholipid antibody syndrome or underlying genetic predisposition to thrombosis, extended anticoagulation may be indicated.
Hemorrhagic Stroke and Vascular Malformations Hemorrhagic stroke is an important cause of pregnancyrelated mortality. Although hemorrhagic stroke is relatively uncommon during pregnancy and the postpartum period with an incidence of up to 6 per 100,000 in reported series [7, 47], pregnancy increases the risk of hemorrhage more than that of ischemic stroke (relative risk of 2.5 and 28.5 during pregnancy and the postpartum period, respectively) [7]. Underlying mechanisms of pregnancy-related hemorrhage are likely consequences of physiologic changes including blood volume expansion and vascular tissue remodeling in pregnancy with added risk from the strain and trauma of labor and delivery. Major causes of pregnancy-related hemorrhage are preeclampsia-eclampsia, which contributes to a large proportion of cases, followed by intracerebral aneurysms and arteriovenous malformations [47]. Additionally, in a large proportion of cases, the cause is unclear, though often related to preeclampsia-eclampsia. The risk of intracerebral aneurysmal rupture increases with gestational age, peaking at 30 to 34 weeks [48]. It has been reported that the maternal mortality of pregnancy-associated aneurysmal subarachnoid hemorrhage may be as high as 35 %, while fetal mortality may be up to 17 % [48]. Notably, the rate of recurrent hemorrhage and associated mortality is very high, maternal mortality of 63 % and fetal mortality 27 %, if a ruptured aneurysm remains unsecured. These rates are significantly decreased after early surgical intervention to 11 % maternal mortality and 5 % fetal mortality [48]. Thus, if aneurysmal subarachnoid hemorrhage occurs during pregnancy, then it is critical that surgical control by clipping or endovascular coiling be accomplished as soon as possible [49]. Since the morbidity and mortality of subarachnoid hemorrhage are high, and risk of rupture is increased near term, it is recommended that known unruptured aneurysms with high risk of rupture be secured before pregnancy. The risk of rupture depends on size and morphology, and screening MRA and CTA for headache and other conditions often find
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incidental small, uncomplicated aneurysms. In such cases, no rigorous studies guide therapy; however, it may be best to pursue delivery methods that avoid the second stage of labor to decrease chances of rupture. It is less clear that pregnancy predisposes to an increased risk of rupture of arteriovenous malformations (AVMs). The most common manifestation of AVMs is hemorrhage. An influential study in 1974 [50] suggested that pregnancy increased the rate of bleeding in AVMs; however, a later analysis in 1990 found the annual rate of hemorrhage in women with AVMs and no prior hemorrhage to be 3.5 % and in those with AVMs and prior hemorrhage 5.8 %, and that pregnancy did not have an impact on risk [51]. However, analysis of rupture risk per day has found increased risk by several-fold on the day of delivery [52, 53]. Also, when an AVM bleeds during pregnancy, the rebleeding rate is higher than in nonpregnant women. One study found a 25 % rate of recurrent hemorrhage from AVMs during pregnancy, significantly higher than the 6 % rate in non-pregnant women [54]. In most cases, AVMs can be conservatively observed until after delivery; however, if there is hemorrhage during pregnancy, then low-grade AVMs may benefit from early surgical or endovascular intervention [55]. If subarachnoid or intracerebral hemorrhage occurs during pregnancy, then prompt evaluation and management should follow based on neurosurgical principles with proper shielding protection of the unborn fetus for radiologic studies and hydration when iodinated contrast is given, typically for conventional four-vessel cerebral angiogram, to provide clear diagnostic information for therapeutic planning.
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Conclusion Ischemic and hemorrhagic stroke, cerebral venous thrombosis, and cerebrovascular manifestations of pre-eclampsiaeclampsia are all uncommon but serious complications of pregnancy and the puerperium. So that evaluation and diagnosis are rapid and focused, it is important to maintain a high level of suspicion for these disorders when pregnant and postpartum women present with headaches and focal neurologic symptoms. Although special precautions must be taken to insure the safety of mother and child, practitioners should pursue aggressive measures to minimize risk to life and functional disability in this special group of patients.
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Compliance with Ethics Guidelines Conflict of Interest Ali Razmara, Khamid Bakhadirov, Ayush Batra, and Steven K. Feske declare that they have no conflict of interest.
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Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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