Hi, everyone. This is Marie Baldessari, Professor of Critical Care and Neurocritical Care at the University of Pittsburgh Medical Center. I actually began my career doing obstetrical critical care and became involved and very interested in the neurologic complications in pregnancy, and that led me to the world of neurocritical care. Before we begin the meat of today's discussion, I need to share with you my financial disclosures, but more importantly, my accomplishments, my three children and my daughter-in-law and my two grandsons. We'll talk about today some of the physiological changes which predispose and factor into the increased incidence of neurologic complications in pregnancy, eclampsia, cerebrovascular disease, intracranial hemorrhage, cerebral venous sinus thrombosis, and the reversible encephalopathic syndromes and the vasoconstriction syndrome. Severe preeclampsia and eclampsia. Eclampsia by definition is a variant of severe preeclampsia. It may present with preeclampsia. The sine qua non of preeclampsia is hypertension and proteinuria or hypertension and end organ disease. Keep in mind that eclampsia may present without the hypertension and the proteinuria, so the patient who is severely preeclamptic with eclampsia may present initially with grand mal seizures and no other earlier symptoms. The pathogenesis is complicated. We certainly know now that there is a placental endothelial factor which has been identified as a result of ischemia. Probably there are additional biochemical markers. We know that there's a disruption of the blood brain barrier as well as cerebral autoregulation is significantly influenced by the hypertension that's seen in preeclampsia leading to rupture of vessels, and we have generalized arteriolar constriction with certainly predilection for the cerebral and renal vasculature. We know that cerebral perfusion pressure probably is the most critical determinant of intracranial injury in preeclampsia and not cerebral blood flow. Eclampsia is probably more likely due to over perfusion rather than ischemia, secondary to the hypertensive encephalopathy. The diagnosis, as I mentioned before, and I alluded to, hypertension and proteinuria or hypertension and end organ disease, but eclampsia may present by itself, either postpartum or prepartum or antepartum with seizures and no hypertension or proteinuria. Now keep in mind that recurrent seizures will actually mandate cranial imaging. It is very, very unusual to see eclampsia with more than one or two seizures. If your patient has persistent recurrent and refractory seizures, you need further imaging and continuous EEG monitoring because more than likely this is not preeclampsia. CT findings, if you choose to get a CT, and obviously in all of our preeclamptics and eclamptics, we do not get CTs or MRs, but in that patient where you have a suspicion, there may be something else going on because of refractory seizures. What we do find is occipital lobe, white matter, cortical and subcortical edema. I've listed some of the changes here consistent with cerebral edema, cerebral hemorrhage, cerebral infarction may be seen, although these are less common than the bilateral occipital and parietal edema, which we usually see on CAT scans. So when you see an MR, there's usually increased signal at the T2, the T2 images. You see white matter edema, you may see hemorrhage angiography, you'll see a widespread diffuse arterial vasoconstriction of the vessels. So this is an MR, their first A is a photo of a flare image showing edema of the cortex and subcortical white matter of the occipital and parietal lesions, as well as the corpus callosum, the splenium. When you go to the DWI, you see corresponding hyperintensity of these areas. When you look at the ADC, you continue to see hyperdensity or hyperintensity, I should say in the bilateral occipital and parietal lobes, but hypodensity in the splenium of the corpus callosum. When you look at an additional view of the flare MRI, what you see here in this particular patient who had antepartum eclampsia, you see bilateral frontal parietal and cerebellar hyperdensities or hyperintensities consistent with edema of the cortical and subcortical white matter. So there've been several trials looking at what is the appropriate therapy for preeclampsia. Is it an anti-epileptic? Is it magnesium? Keep in mind that magnesium has been around for a very, very long time and obstetricians, I think at this point have proved their point. This was a very early study back in 1996, where they randomized patients to magnesium versus diazepam and magnesium versus phenytoin, dilantin. And they clearly showed that magnesium-treated patients had less recurrent seizures in both groups. No change in maternal death rate, however, in either group. Two follow-up studies by Belfort and Altgent. So treatment guidelines, avoid aerobic exercise, however, strict bed rest, not recommended. Patients at high risk should receive low-dose aspirin at 81 milligrams until delivery and intravenous magnesium for prophylaxis and treatment of seizures, level A evidence based on the 2020 ACOG, American College of Obstetricians and Gynecologists guidelines. So let's switch gears now and move on to cerebral vascular disease and pregnancy, infarction, hemorrhage, thrombosis, arterial occlusions. We won't spend any time in the last category, spend most of our time on these first three categories. So unfortunately, stroke is the main cause of neurological mortality, about 10% in pregnancy. 30 strokes per 100,000 deliveries. Remember, we are talking about relatively young, healthy women here, so this is quite devastating. Women in their 30s, 40s, even 20s. Highest risk of stroke is later in pregnancy, in the third trimester at the time of delivery and up to 12 weeks postpartum, which clearly underscores, once again, the fact that simply because you have delivered the fetus does not mean that you are no longer pregnant. The physiologic changes that occur with pregnancy do not resolve very quickly with delivery of the fetus. It can take up to 12 weeks postpartum. Most pregnancy strokes are secondary to uncontrolled systolic hypertension. All right, so there are lots of physiologic changes which predispose to stroke, both ischemic stroke and hemorrhagic stroke. Ischemic stroke, pregnancy is a hypercoagulable state with increased procoagulant factors. We have venous stasis, vascular wall changes, altered immunity, the hormones. All of these can produce hypercoagulability and an increase in the risk of ischemic stroke. Paradoxically, we also have a risk for hemorrhagic stroke. So we clot and we bleed. Hemorrhagic stroke, secondary to increased blood-brain barrier permeability, altered cerebral autoregulation. We have a tremendous increase, 40% to 60% increase in blood volume. It's a hyperdynamic state. And we certainly have vessel wall remodeling and dilatation, all leading to a higher incidence of hemorrhagic stroke in the pregnant woman. So this is a cartoon showing that, in fact, there is very much a consistency among several different disease processes in pregnancy, including reversible cerebral vasoconstriction syndrome, ischemic stroke, hemorrhagic stroke, the HELP syndrome, which is part of the severe preeclampsia syndrome or disease process, eclampsia, cardiomyopathy, heart failure, ARDS, all secondary to the hypertension seen in pregnancy as a result of the endothelial activation from both maternal risk factors, paternal risk factors, and placental triggers. So here is another list of just some of the risk factors for both ischemic and hemorrhagic stroke, with hypertension being the number one preexisting factor leading to both types of stroke. Pregnancy related, I think it's important for you to notice that 50%, that is half of all women who have stroke, have preexisting preeclampsia. General principles for stroke diagnosis, focal neurologic symptoms are not usually part of preeclampsia and eclampsia. Preeclampsia does not usually present with neurologic symptoms. Eclampsia will present with generalized tonic-clonic seizures, but not focal neurologic symptoms, as we see in our patients with acute stroke. Any acute condition that appears to be more than a simple migraine, headache, probably does require imaging, particularly if those patients have focal neurologic symptoms. In most instances, evaluation, diagnosis, and treatment are the same as they are for non-pregnant patients. So if you choose to do, and as well you should, follow cranial imaging in those patients you suspect having stroke, CT head, MRI brain, angiography are all permissible and acceptable and recommended in the field of stroke and pregnancy. Keep in mind that all of these have very minimal risk to the fetus. Fetal radiation exposure with the CT of the head, particularly if the abdomen is shielded, is quite low, we have no complications from this. MRI of the brain, although highly recommended in these circumstances, we have to be careful, particularly in that first trimester, and if we can avoid using gadolinium, we should. Angiography, although it presents a risk in terms of renal function, as it does to any patient, most of our patients have normal renal function in pregnancy and can tolerate the angiography. So the risk from either MR or CT or angiography is really quite small, and you really should not take precedence over maternal decision making. If you would do this for any other patient, if you recommend a CT, an MR, or an angio, or whatever test may be important in your diagnostic sort of armamentarium, you should not delay that, because the risk of a delayed or misdiagnosis of stroke of another neurologic problem far outweighs the radiation risk to the mother and the fetus. MRI is preferred, as I said, at any trimester, trying to avoid the gadolinium or at least use the lowest dose of gadolinium. Remember left lateral decubitus position during any time you place the patient's supine. You want to get the, um, get the IVC and the aorta to be non-compromised, that is you don't want compression of the IVC or the aorta, so you need to put the patient left side down. This is going to increase your cardiac output, which is what's important in these patients. So these patients can become markedly hypotensive if you place them completely supine, and it doesn't matter whether it's a stroke patient, it's any patient in their second and third trimester. If you're examining this patient or doing any kind of radiographic test, any time these patients are supine, you must put them in the left lateral decubitus position, or at least put a wedge under the right hip. Building the abdomen of course is recommended, and if you proceed with angiography to minimize the time to do a limited examination if possible, and exposure below the aortic arch. Thrombolysis in pregnancy has actually been very well studied now. We don't have a lot of human trials, in fact I'm not sure we have any, but we certainly have case reports. They have been used safely in pulmonary embolism, acute MI, and prosthetic cardiac valve thrombosis during pregnancy. It does not cross the placenta, so it doesn't really cause any harm to the fetus. Post-operatively or postpartum, either after a vaginal or cesarean delivery in particular, it may increase the risk of uterine or pelvic hemorrhage if it's close to the time of delivery. There are several studies here, and as I said, pretty much all of these are case reports, so the outcome for the mother and the child has been universally good. Endovascular thrombectomy and large vessel occlusions with moderate to severe stroke is absolutely considered acceptable. Obviously any procedure that you do on a pregnant woman, you're always concerned about blood loss and changes in blood pressure, but this has been well studied in the pregnant lady. Endovascular thrombectomy with or without previous thrombolytic administration is recommended. Careful with general anesthesia. As you know, any hemodynamic changes that happen usually happen around the time of general anesthesia, with the onset of surgery, with the onset of anesthesia, with the intubation, with the extubation. The mom doesn't tolerate these hemodynamic changes as well, and in particular, nor does the fetus. When the fetus, when profusion to the uterus is compromised, if the mother becomes hypotensive, the fetus usually does not like that. If you can get away without doing general anesthesia and neuroaxial anesthesia or local, certainly that is preferred. When we talk about post-stroke antiplatelet and anticoagulant therapy, we do have a lot of options. Aspirin has been used for quite some time in pregnancy. Plavix, clopidrogel, low molecular weight heparin has been used. It's very commonly used during pregnancy, during gestation. There are obviously a few problems with low molecular weight heparin, and the biggest problem is really not the bleeding risk. It's, well, it is the bleeding risk in terms of the time of delivery. As you know, with pregnancy, you can't always plan for a time delivery. So if a patient is coming in for a section or is going to be induced, that makes it a little bit easier. But for the woman that's taking a low molecular weight heparin and goes into labor spontaneously, this becomes problematic in terms of particularly administering any neuroaxial or epidural anesthesia. Very often, if a patient is on a low molecular weight heparin for a thrombotic event during pregnancy, as she is beginning to get closer to labor and delivery, oftentimes we will change her to unfractionated heparin. There's been a lot of debate about warfarin. It clearly is teratogenic, particularly in the first, say, 12 weeks of gestation because of the risk of changes in the fetus secondary to, this is the most important period of embryopathy. There are some obstetricians that will continue to use or do use warfarin in later gestation. But I think now since we have, you know, we have unfractionated, we have low molecular weight heparin, we have other antiplatelet agents, whether or not you're using it as an antiplatelet agent or an anticoagulant therapy, I think we have a large armamentarium. And if you can avoid warfarin, we prefer that you do not use it. When we talk about aspirin management, we really have good data. These are published recently in the 2008 Canadian Stroke Guidelines. There were two big trials, the EGAR and Asprey trials, where aspirin was looked at. And really there were no complications, no significant incidents of fetal and neonatal complications. It's not excluded in breast milk. We're not sure about higher doses. We've looked at 81 milligrams, but looking at higher doses, greater than 300, you know, there is a theoretical risk of Rey's syndrome or metabolic acidosis. So we probably are asking, we're asking you not to use higher doses in these patients. If the patient is on other antiplatelet agent, probably aspirin is the superior agent. Let us talk now about, all right, so we'll continue. We alluded to, and I alluded to warfarin, we really sort of frown on warfarin unless it's absolutely necessary, but most of the time it's not. Heparin, we have both unfractionated and low molecular weight heparin. I've told you about the risk with low molecular weight heparin, particularly when you're talking about epidural, neuroaxial anesthesia, you really want to stop it prior to delivery. We don't have a lot of data, very little data on DOACs in pregnancy. And since we have such as a pretty wide armamentarium of other agents, DOACs are not recommended for pregnant patients. All right. So let's switch gears now and talk a little bit about hemorrhagic stroke. So unfortunately, pregnancy, as I said, it's a paradoxical phenomenon. You have an increase in thrombosis, but you also have an increase in hemorrhage. Patients who are preeclamptic have vascularitis or have subarachnoids, AVMs, arterial dissection, all are predisposed to hemorrhagic stroke. The risk is quite high, almost six times that for the non-pregnant patient. Once again, hypertension is a big offending, important risk factor. Most common hemorrhagic strokes are due to subarachnoid and intracranial hemorrhage due to ruptured AVM. In fact, AVMs are the most common cause of hemorrhagic strokes in pregnancy. Treatment principles, very similar to non-pregnant patients, blood pressure management, gentle blood pressure management, general supportive measures, and all of the treatments that we follow for our patients or we use, depending upon the risk of rupture, et cetera, for AVMs and subarachnoid. Blood pressure control, try and get the blood pressure under 160 to 110. We prefer libetalol. Hydralazine is a very good antihypertensive drug, but it seems to be somewhat too good because it can lower the blood pressure too precipitously. As you know, in the treatment of hypertensive urgencies and emergencies, you don't want to lower the blood pressure too precipitously. Libetalol seems to be a kind of gentle drug. Nitrates, as you know, we try and avoid those in our neuro ICU because they can potentially, theoretically increase the risk of bleed or increase the size of the preexisting bleed. ACEs and ARBs, if the patient is gestational, that is antepartum, these are absolutely forbidden to use because of the risk of damage to the fetal cartilage. And since we have a wide armamentarium of antihypertensive drugs, it really never comes up that we absolutely have to use an ACE or an ARB. Correct your coagulopathies, anesthesia. There are many of these patients who will require general anesthesia. And I think what you need is a good obstetrical anesthesiologist who's aware of the hemodynamic changes which can happen with pregnancy. Remember, these pregnant women are anemic with hemoglobin is about 10 to 11. So any type of blood loss and any time of abrupt hemodynamic changes can cause a lot of problems, particularly for the fetus. As I said, when you decrease uterine perfusion pressure, the fetus suffers and you can tell that with fetal monitoring. So if the fetus is viable and you plan on doing a neurosurgical procedure, you consider doing a concurrency section or prior to the start of neurosurgery. If it's pre-viable, then unfortunately you proceed as you would in any non-pregnant patient and the fetus may or may not survive. Remember, the goal of therapy here is to save the mother. Surgical AVM management is very similar to all of our patients. It depends on the risk of bleed for these patients, the size of the AVM, whether it's ruptured, but certainly if the patient requires surgery, it needs to be done in the pregnant patient. And remember, as I alluded to in the previous slide, careful management of blood loss to avoid fetal compromise. Seboracnoid hemorrhage, usually due to ruptures of AVM, probably about 50% of our seboracnoids during pregnancy, AVM is the etiology. Certainly because pregnancy does cause more bleeding, we have a higher risk of bleeding and re-bleeds if they present with seboracnoid and aneurysmal seboracnoid. Proceeding with surgical procedures, whether it's a clip or a coil, interventional coiling, should be done as it is in the non-pregnant patient. Cerebral venous sinus thrombosis, as you know, is very common in pregnancy and probably accounts for more than half, and it's estimated maybe up to 64, 65% of all strokes in pregnancy. Most of these occur postpartum, once again, underscoring that these physiologic changes, which happen during pregnancy, do not disappear after delivery of the fetus, usually affecting the transverse or the superior sagittal sinus. And the risk factors of dehydration, hypertension, hypocoagulability are specific to pregnancy, and cerebral venous sinus thrombosis, the presentation is similar as it is in our non-pregnant patient's headache. They can present with focal neurologic signs, altered level of consciousness, ICP elevation, and diagnosis is with MR or CT or angio. This is two diagrams of, this is inclusion here with an angio of the left transverse sinus, and here on the non-con, you can see some hyperintensity or hyperdensity of the right transverse sinus. So the treatment is similar as it is with your non-pregnant patient's heparin, low molecular weight heparin. There's some debate about whether or not we should continue with long-term warfarin therapy. Local thrombolysis has been tried with TPA and the sinus. Anti-epileptic medications can be considered, particularly for those who seize. It has a, you know, up to a 30% in-hospital mortality if they survive, usually will not have any sequela. The two reversible syndromes, reversible posterior leukoencephalopathy, otherwise called PRESS, usually presents with seizures, can present with postpartum blindness, particularly if you have the occipital lobes affected, always secondary to malignant hypertension, encephalopathy. This makes the circulatory circulation clearly more vulnerable because it has less auto-regulation. Treatment of choice is blood pressure control, calm and controlled blood pressure control with resolution of symptoms, may result in infarct or intracranial hemorrhage, but usually has a good outcome. The other reversible syndrome I'll mention is the cerebral vasoconstriction syndrome, RCVS, where you usually present with headache. You may have some neurologic deficit. This is due to vascular narrowing of the circle of Willis, and this usually spontaneous resolves in four to six weeks and presents oftentimes in association with preeclampsia or PRESS and hypertensive encephalopathy. You can use vasodilators and steroids, although oftentimes it's just supportive therapy. So final thoughts, there is a higher risk and incidence of many neurologic conditions in pregnancy. We need to follow accepted standards for both ischemic and hemorrhagic stroke and pretty much all of the neurologic conditions in terms of diagnosis and treatment for our pregnant patients. Do not hesitate to perform the appropriate test, whether it's CT, MR, transcranial Doppler's, angiography. Do not delay your examination or a surgical procedure or an interventional procedure because you think you may be putting a fetus at risk. The fetus actually will have the best chance of survival if the mother survives. Thank you for your attention.

neurologic complications

pregnancy

eclampsia

cerebrovascular disease

intracranial hemorrhage

cerebral venous sinus thrombosis