CHAPTER 30 Peter W. Kaplan Emily L. Johnson and Payam Mohassel Johns Hopkins Bayview Medical Center, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA Neurologic disease is common, affecting at least 1 in 200 pregnancies; the physiologic changes of pregnancy may also temporarily alter the course of chronic neurologic disease. Some of the most widespread neurologic disorders include epilepsy, stroke, multiple sclerosis (MS), and myasthenia gravis (MG). We present a case‐based approach to these common neurologic problems seen in pregnancy. Epilepsy is a chronic neurologic condition, affecting approximately one million women of childbearing age in the United States alone, and 3–5 pregnancies out of 1000 [1]. Much progress has been made over the last decades in our understanding of the risks related to antiepileptic drugs (AEDs), and women with epilepsy are no longer routinely counseled against having children. Ischemic or hemorrhagic strokes are rising in frequency over the past decades; stroke‐related hospitalizations have increased from 3 per 10 000 hospitalizations during pregnancy in 1994–1995, to 4.8 per 10 000 hospitalizations during pregnancy in 2010–2011 [2]. MS is often diagnosed in the childbearing years, and affects women nearly twice as frequently as men, which makes starting a family a significant concern of many MS patients. Twenty years ago, women with MS were told to avoid having children due to a belief that pregnancy would worsen the disease course [3]; this is now known to be untrue. MG is the most common disorder of the neuromuscular junction, affecting about 1 in 5000 people; as with MS and other autoimmune neurological disorders, the childbearing years are a frequent time of onset, and women are affected at a higher rate than men. Cooperation between the obstetrician and the neurologist is essential, including preconception counseling in cases of chronic neurologic disease whenever possible. With proper planning, good outcomes for pregnant patients with chronic neurologic disease are highly likely. Epilepsy is one of the most frequent neurological conditions. It may also complicate pregnancy. Seizures occur in 0.3–0.6% of all pregnancies [4–7]. Obstetric complications are increased in women with epilepsy, and include preterm delivery, pre‐eclampsia, placental abruption, hyperemesis gravidarum, and increased perinatal mortality. However, most women with epilepsy have good outcomes [8–10]. The aim of therapy during pregnancy should be to control convulsions with a single agent, using the lowest possible dose [11, 12]. The European Pregnancy Study Group using the International Registry of Antiepileptic Drugs and Pregnancy (EURAP) revealed that occasional partial seizures posed little risk to the mother and fetus; repeated convulsions on occasion could lead to fetal loss. Status epilepticus rarely caused maternal or fetal death, although clearly was to be avoided [13]. The most common causes of breakthrough seizures in pregnancy in women with epilepsy are similar to those seen in women who are not pregnant. The majority of women with epilepsy have similar seizure control during pregnancy, while approximately 20–30% experience more frequent or more severe seizures [13–15]. Mood changes and emotional stressors during pregnancy may have a major impact on seizure control [16]. Women may stop taking AEDs in pregnancy because of the fear of fetal malformations, thus emphasizing the need for an open dialogue between physician and patient regarding the relative safety of AEDs versus the risks of seizures [17]. Intractable nausea and vomiting during early pregnancy may decrease the amount of AED absorbed and hence adequacy of seizure control. Sleep deprivation may add to these physical and emotional stressors, leading to increased seizure frequency. Several factors, such as stress, pain, sleep deprivation, over‐breathing, and dehydration, may increase the risk of breakthrough seizures in the puerperium. While most women with epilepsy will have an uneventful labor and normal vaginal delivery, between 3.5% and 5% may have tonic‐clonic seizures or even status epilepticus during puerperium [13]. In one recent study, seizures occurred in four of 32 (12.5%) patients with primary generalized epilepsy during labor as compared to 0 of 57 women with partial epilepsy [18]. Therefore, women at risk for seizures should be followed closely around the time of delivery. Several factors can change the blood level of AEDs during pregnancy. Increased plasma volume may affect the “loading dose”, but not the daily dose. Reduced serum albumin concentrations, increased renal blood flow, and glomerular filtration rate, all may reduce the serum concentrations of AEDs [14, 19]. Different AEDs will be differently affected. The most pronounced decrease in AED concentration is reported with lamotrigine and oxcarbazepine (declines of up to 50%; increased clearance of up to 300%), likely due to their mode of elimination by glucuronidation [20–25]. Levetiracetam plasma concentrations may decline by 50% in the third trimester [26] and similar alterations are reported with almost all AEDs. Only the free level of valproate (not usually a drug of choice) may rise. Based on these observations, many experts advocate measuring maternal drug levels during pregnancy [27, 28], possibly monthly. In this way, AED blood levels can be titrated to drug dosage. Drug levels should also be obtained before pregnancy to document the patient’s individual AED target zone. The literature contains little Grade 1–2 evidence, and mostly includes case series, case reports, reviews, and expert opinions. In addition, outcome data are confounded by several factors including lack of control for other confounding factors known to affect fetal outcomes (such as drug use, smoking, diet, and maternal age), and concurrent use of multiple AEDs during pregnancy. Case studies report that partial seizures may affect fetal heart rate transiently with no known lasting effect. In the case of complex partial seizures, a few case reports showed prolonged uterine contraction or fetal heart rate deceleration [29, 30] but these are subject to publication bias toward adverse outcomes. The large prospective European and International Registry of Antiepileptic Drugs in Pregnancy (EURAP) study of 1956 pregnancies did not show any fetal loss due to non‐convulsive seizures (partial or complex) or non‐convulsive status epilepticus [13, 31]. Specifically, in this study, 406 of the women with known epilepsy developed non‐convulsive seizures during pregnancy (approximately 25%); however, no miscarriages, fetal death, or any maternal morbidity was linked to single seizures. Generalized tonic‐clonic seizures have been reported to be associated with fetal abnormalities such as bradycardia, intracranial hemorrhage, cardiac slowing, or reduced beat‐to‐beat variability. However, the EURAP study showed no maternal deaths, miscarriages, or fetal loss due to isolated tonic clonic seizures. EURAP revealed that 2% of all pregnancies were complicated by status epilepticus and only one‐third of these were convulsive status epilepticus with one stillbirth and no maternal mortality [13]. These studies suggest that the morbidity of status epilepticus in pregnancy is probably less than previously reported though controlled studies are lacking [31]. In principle women with epilepsy should continue the AED that was needed to control seizures, particularly if other agents were unsuccessful. The challenges come with the use of valproate which poses significant risks for both fetal malformations and for developmental delay. In 2009, the American Academy of Neurology and American Epilepsy Society (AAN/AES) released practice parameters for management women with epilepsy during pregnancy [32]. They reported an increased risk of major congenital malformations with AED exposure in the first trimester (which was clearly demonstrated with valproate and phenobarbital). AED polytherapy probably contributes to an increased rate of major congenital malformations as compared with monotherapy [33]. Carbamazepine and lamotrigine yielded much more reassuring levels of teratogenesis in several national and international registries. Switching AEDs during pregnancy carries the risk of break‐through seizures, but occasionally has been attempted if valproate is not essential for seizure control, or for example, has been used for migraine prophylaxis. If valproate or phenobarbital can be discontinued or switched prior to pregnancy, this should be considered. As noted above, AED use during pregnancy should be based on the given clinical situation [34]. Lamotrigine and carbamazepine are two of the most well‐studied AEDs in pregnancy. The Lamotrigine Pregnancy Registry did not detect an appreciable increase in major congenital malformation in patients treated with lamotrigine as monotherapy during their first trimester in over 1500 pregnancies [35]. While there are limited data, levetiracetam may have a low rate of malformations if used during pregnancy but this remains to be established [36]. In the Australian registry of pregnancies, levetiracetam was associated with no major congenital malformations [37]. In conclusion, therapeutic drug monitoring of serum AED levels should be considered during pregnancy as levels may change significantly, especially those of lamotrigine and oxcarbazepine (Class IIa, Level B). Valproate and phenobarbital have an increased risk of major congenital malformations, and if these drugs can be safely replaced or discontinued prior to pregnancy, this should be considered (Class III, Level B for risk of teratogenesis). Lamotrigine and levetiracetam have relatively low rates of associated major congenital malformations, and may be preferred in women who are planning pregnancy (Class I, Level B). Studies were reviewed and graded according to the American College of Cardiology (ACC) and the American Heart Association (AHA) clinical practice guidelines (available at www.acc.org and www.aha.org): Recommendation class was assigned based on the consensus (or lack thereof) and relative risks and benefits in the studies cited, classified as: Stroke is the third most common cause of death in the United States and is a leading cause of disability. During pregnancy and in the early postpartum period, stroke complicates approximately 1 in 6000 pregnancies. While different studies arrive at different estimates for stroke prevalence during pregnancy and puerperium [38], it is reported that 12–35% of cerebrovascular disease in those aged 15–45 years occurred during pregnancy or in the puerperium [39, 40]. Stroke is responsible for approximately 5–10% of all pregnancy‐related maternal deaths in the United States each year and the survivors of stroke routinely are left with a significant disability [41, 42]. As a result, diagnosis, prevention, and treatment of risk factors leading to stroke are of utmost importance. In addition, acute stroke management may reduce morbidity and mortality from strokes during pregnancy or the puerperium. Strokes are broadly categorized into two major groups: ischemic stroke, which comprise about 85% of all strokes; and hemorrhagic stroke accounting for the remainder. Cerebral venous thrombosis (CVT) and subarachnoid hemorrhage also are relatively common cerebrovascular complications seen during pregnancy or puerperium. Risk factors associated with atherosclerosis and stroke in general (such as age, hypertension, smoking, diabetes, hyperlipidemia, valvular heart disease, and hypercoagulable states) are also highly relevant in pregnancy [43]. In addition, most of the effect is seen in the puerperium [39]. Hypertension alone, which can be pre‐existing or associated with pregnancy, can increase the risk of stroke during pregnancy by a factor of 9 [44, 45]. In addition, several other pregnancy‐specific risk factors may add to these factors (see Question 2). Eclampsia or pre‐eclampsia is the most frequent risk factor for stroke related to pregnancy or the puerperium. Pregnancies complicated by eclampsia or pre‐eclampsia increase the risk of maternal strokes, both ischemic and hemorrhagic [45–47]. Some studies suggest that pre‐eclampsia was present in a quarter of all cases of hemorrhagic or ischemic strokes related to pregnancy [48]. The mechanism is not entirely clear but hypertension, lower socio‐economic class, and endothelial dysfunction are thought to play a role [44, 49]. Microthrombi formation and an activation of the coagulation cascades may also be another contributor [50]. CVT can commonly complicate pregnancies with an incidence of about 1 in 11 000 deliveries [51]. Furthermore, CVTs are more common in the postpartum period, especially the first week after delivery [43, 52]. Dehydration may be a risk factor. The major clinical symptoms of CVT include headache, focal neurological signs, papilledema, seizures, and altered sensorium. Headaches are sometimes the only symptom. An MRI of the brain and an MR venogram can help in diagnosis. Compared to other patients with CVTs, those in pregnancy generally occur in younger women and tend to have a better prognosis [53]. Cardioembolic disease: Cardioembolism due to peripartum cardiomyopathy is a relatively common cause of stroke in young women [54, 55]. In addition, paradoxical emboli can occur in the presence of a PFO and deep CVT may also occur, especially in the setting of decreased mobility and the relative hypercoagulable state seen in pregnancy [56]; however, given the high prevalence of PFOs in the general population, no causal relationship has clearly been established. Moreover, treatment of strokes associated with PFOs with closure of the defect do not seem to provide significant benefit compared to the use of aspirin alone [57]. Arterial dissections leading to stroke do not seem to occur with greater frequency during pregnancy, delivery, or the puerperium compared to the general population. Thrombolytic therapy with recombinant tissue plasminogen activator (rt‐tPA) has been shown to improve outcomes and mortality from ischemic strokes in non‐pregnant patients. However, no controlled trials are available that have evaluated the efficacy or safety of treatment with rt‐tPA of stroke during pregnancy. Rt‐tPA is a category C drug and its benefits should be weighed against the risk to both mother and fetus. Thrombolytics have been used during pregnancy relatively safely [58–62] with little risk to the mother or the fetus but randomized trials are needed to further establish whether thrombolytic therapy is relatively safe when used for acute ischemic stroke during pregnancy. In addition, interventional procedures with intra‐arterial tPA or mechanical clot retrieval may provide an alternative therapy for stroke during pregnancy while minimizing exposure to thrombolytic drugs. Experience with these interventions during pregnancy is also limited. No randomized controlled trials have evaluated the efficacy of antiplatelet therapy for treatment or prevention of stroke in pregnancy. In general, it is thought that in patients with several risk factors, antiplatelet therapy may be helpful in preventing strokes. There is experience with low‐dose aspirin and it can probably be safely used for primary and secondary stroke prevention during pregnancy, especially during the second and third trimester [63, 64]. The mainstay of stroke treatment during pregnancy is that of treatment of underlying risk factors. Atherosclerotic risk factors should be treated and hypertension and diabetes should be controlled. Dehydration should be avoided, and the preterm pregnancy monitored for signs of pre‐eclampsia. In addition, in patients with hematologic disease with a known hypercoagulable state, systemic anticoagulation may be required. Heparin and low molecular heparin are classified as category C drugs and there is substantial experience with their use during pregnancy without untoward effect. Protracted use of heparin does predispose to osteoporosis and thrombocytopenia in the mother, but no teratogenic effects are known. Warfarin is a category X drug with known adverse effects on the fetus and is not recommended for treatment during pregnancy. In conclusion, typical stroke risk factors including hypertension and diabetes should be In conclusion, typical stroke risk factors including hypertension and diabetes should be controlled (Class I, Level B). Dehydration should be avoided (Class I, Level C), and signs of pre‐eclampsia documented (Class I, Level B). Antiplatelet therapy with aspirin may be helpful in preventing strokes in patients with multiple risk factors, and can probably safely be used during the second and third trimester (Class IIb, Level C). Treatment with warfarin during pregnancy should be avoided (Class III, Level B for risk of harm from warfarin). Experience with tPA in pregnancy is limited. Studies were reviewed and graded according to the ACC and the AHA clinical practice guidelines (available at www.acc.org and www.aha.org): Recommendation class was assigned based on the consensus (or lack thereof) and relative risks and benefits in the studies cited, classified as:
Neurologic disease
Introduction
Background
Clinical questions
Search strategy for each question
Grading of evidence
Background
Clinical questions
Search strategy for each question
Grading of evidence
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