Keywords
epilepsy, neonates, neurologic disorders, neuromuscular disorders, obstetric complications, pregnancy
Neurologic disorders may first present during pregnancy, and their investigation and treatment may be complicated by concerns for the safety of the developing fetus. Furthermore, the natural history of certain preexisting diseases may be affected by pregnancy, and obstetric management may be influenced by the neurologic disturbance. These aspects are considered in this chapter.
Epilepsy
Many of the pregnancies that occur in the United States are unplanned, so that regular counseling of women with epilepsy during the reproductive years is important. Pregnancy may affect the natural history and management of patients with epilepsy in several ways. In addition, antiepileptic management may affect the developing fetus and obstetric management.
Effect of Pregnancy on Maternal Seizures
In recent series, an increase in seizures occurred during pregnancy in 23 to 75 percent of cases ; between 53 and 67 percent had unchanged seizure control. It is not possible to predict in advance whether or how seizure frequency will be altered during pregnancy, but certain general points can be made. Seizure frequency is more likely to increase in poorly controlled epileptic patients than in those with infrequent seizures, and in those with focal seizures ; any increase is most likely to occur during the first trimester. Any change in seizure frequency usually reverses after the birth of the infant, although occasional patients whose seizures increase during pregnancy remain more difficult to control thereafter. For patients without seizures for at least 9 months prior to conception, the likelihood of remaining seizure-free during pregnancy ranges between 84 and 92 percent in different series. The influence of a particular pregnancy cannot be predicted by the outcome of previous pregnancies, any relationship between seizures and the menstrual cycle, or maternal age. Seizures may occur for the first time during or immediately after pregnancy and in some instances occur only in relation to pregnancy. Even in patients with such true gestational epilepsy, however, it is not possible to predict the course of subsequent pregnancies from the occurrence of seizures during one pregnancy.
Status epilepticus may complicate pregnancy and sometimes occurs before there is any other evidence that seizures have become more difficult to control. It may take the form of tonic-clonic (major motor) or nonconvulsive status. The former is easy to recognize, but a transient alteration in mental status and level of arousal may not be attributed to nonconvulsive status epilepticus unless an electroencephalogram is performed. As in the nonparous woman, it is important to obtain control of the seizures rapidly, but therapeutic termination of pregnancy is usually unnecessary. There is no evidence that anticonvulsant drugs administered intravenously to treat status epilepticus affect the fetus adversely.
The reason that seizure frequency sometimes increases during pregnancy is not clear, but a change in drug requirements during the gestational period may sometimes be responsible. Pregnancy probably causes an increase in the clearance and a decrease in the blood concentrations of lamotrigine, phenytoin, and, to a lesser extent, carbamazepine, and possibly decreases the blood level of levetiracetam and the active oxcarbazepine metabolite, the monohydroxy derivative (MHD). Evidence of a change in clearance or blood level of phenobarbital, valproate, primidone, and ethosuximide is inadequate to permit a definite conclusion to be reached. Other possible reasons for the increased dose requirements of anticonvulsants during pregnancy include poor compliance with the drug regimen, changes in drug absorption and excretion, and the dilutional effects of increasing plasma volume and extracellular fluid volume. Changes in drug absorption may relate to nausea, vomiting, or reduced gastric motility. Antacids are frequently prescribed during pregnancy and are known to adsorb to medications, preventing absorption. An increased metabolic capacity of maternal liver and metabolism of part of the anticonvulsant dose by the fetus, placenta, or both may also be important. Folic acid therapy (which may reduce the risk of major congenital malformations when taken preconceptionally ), prescribed routinely by many obstetricians, sometimes lowers the plasma phenytoin level. The effects of pregnancy on the pharmacokinetics of other antiseizure agents, such as felbamate, gabapentin, pregabalin, zonisamide, topiramate, and lacosamide, have not been defined.
Whether hormonal factors contribute to an increase in seizure frequency during pregnancy is unclear, but estrogens are epileptogenic in animals, and progesterone is said to have both convulsant and anticonvulsant properties. Finally, fatigue and sleep deprivation may influence seizure frequency during pregnancy.
The reason that seizure frequency decreases in some epileptic patients is also unclear, but improved compliance with the anticonvulsant drug regimen may be responsible.
Effects of Maternal Epilepsy on the Fetus
Seizures
A major concern in the management of epileptic women during pregnancy is the possible effect of the seizure disorder and of anticonvulsant drugs on the developing fetus. It is difficult to determine the precise risk that a seizure disorder will also develop in the offspring of epileptic parents. The risk depends in part on whether the parental epilepsy is idiopathic (constitutional) or acquired; such risk appears to be increased among the offspring of epileptic mothers but not when only the father is epileptic. The reason for the increased risk is unclear, but genetic factors may be important, as may the consequences of maternal seizures or anticonvulsant drugs taken during pregnancy.
Fetal Malformations
For many years, concern has existed that anticonvulsant drugs are teratogenic. Epidemiologic studies are difficult to interpret because epilepsy occurs for many reasons, varies in severity between patients and in the same patient at different times, may itself increase the risk of fetal malformation, and is treated by many drugs in different doses and combinations; environmental factors also bear on the development of fetal malformations and are difficult to control. Nevertheless, numerous reports suggest that certain anticonvulsant drugs are indeed teratogenic in humans, and the risk of malformation among the offspring of epileptic women is approximately double that for nonepileptic women. In a prospective study involving the UK Epilepsy and Pregnancy Register, however, the rate of major congenital malformation was 3.5 percent for women with epilepsy who had not taken antiseizure medication during pregnancy compared with 4.2 percent among those who had (3.7% with monotherapy and 6% for those on polytherapy). The failure of this study to show an increased risk of major malformations among women on antiseizure medication may have been because the study was not sufficiently sensitive. It seems that a greater teratogenic risk exists when polypharmacy is used, and the combination of lamotrigine and valproate is particularly teratogenic. Cognitive and behavioral development may also be affected, and the evidence is most suggestive for valproate, phenytoin, and phenobarbital.
The older antiepileptic drugs taken during the first trimester of pregnancy are probably all teratogenic to some extent, especially when taken in combination. However, it cannot be determined whether the increased risk relates to all or to only some antiseizure medications. Trimethadione, which is now rarely used and should be avoided during pregnancy, is particularly dangerous and causes fetal malformations and mental retardation in more than 50 percent of exposed infants. The absolute risk of major congenital malformations is also especially marked for valproate, which is associated with a high (1%) rate of neural tube defects and may also cause cleft lip or palate, polydactyly, hypospadias, craniosynostosis, atrial septal defect, developmental delay, and other disorders. It is not clear whether the rates and types of major congenital malformations differ in epileptic women taking specific antiseizure drugs (other than valproate). Existing data suggest that phenytoin and carbamazepine are associated with cleft palate, and phenobarbital may be associated with cardiac malformations; a relationship probably exists between the risk of developing major congenital malformations and the dose of valproate or lamotrigine. The data concerning the teratogenic risks of monotherapy with the newer anticonvulsant drugs such as levetiracetam, topiramate, and oxcarbazepine are still unclear and incomplete.
A specific syndrome has been described among some of the offspring born to mothers taking phenytoin, phenobarbital, or carbamazepine during pregnancy and bears some resemblance to the fetal alcohol syndrome. It is characterized by prenatal and postnatal growth deficiency, microcephaly, a dysmorphic appearance, hypoplasia of the distal phalanges, and mental deficiency. A characteristic facial phenotype in children exposed to valproic acid or sodium valproate in utero has also been described. Some of these children may have educational difficulties.
The mechanisms involved in teratogenesis of anticonvulsant drugs are not known but may include folate deficiency ( Fig. 31-1 ) or antagonism and production of toxic intermediary metabolites during biotransformation of the parent compound. Specific oxidative intermediates such as epoxide, for example, have been suggested as the ultimate teratogen in patients receiving phenytoin.
Bleeding Disorders
A clinical or subclinical bleeding disorder may occur in neonates exposed to anticonvulsant drugs in utero, without evidence of coagulopathy in the mothers. Although a number of anecdotal cases have been reported, the evidence is insufficient to determine whether the risk is, in fact, substantially increased in the newborns of women with epilepsy. Factors II, VII, IX, and X are decreased, whereas factors V and VIII and fibrinogen are normal. Bleeding usually occurred within 24 hours of birth, sometimes in unusual sites (e.g., the pleural or abdominal cavities). Bleeding has also been reported to occur in utero, leading to stillbirth. It has been suggested that the bleeding disorder may be prevented by the maternal ingestion of vitamin K 1 during the last month of pregnancy. The recommended dose of vitamin K is 10 mg daily for 30 days before delivery. However, other studies suggest that this hemorrhagic disorder is rare and that routine prophylaxis by maternal treatment with vitamin K 1 is unjustified. Indeed, it has even been questioned whether maternal use of antiseizure medication leads to a coagulopathy at all, and certainly the evidence is insufficient to support or refute this association . In any event, the routine administration of vitamin K 1 (1 mg/kg intramuscularly) to newborns of women receiving anticonvulsant drugs during pregnancy is sufficient to prevent such a coagulopathy.
Withdrawal Symptoms
Maternal use of barbiturates may be associated with barbiturate withdrawal symptoms in the neonate, with restlessness, irritability, tremulousness, difficulty in sleeping, and vasomotor instability, usually beginning a week after birth.
Breast-Feeding
Although certain anticonvulsant drugs (primidone, ethosuximide, gabapentin, lamotrigine, levetiracetam, and topiramate) taken by the mother may be present in breast milk, there is no evidence that these have symptomatic effects on the newborn. Breast-feeding therefore need not be discouraged on this account; however, when obvious sedation develops in an infant that could relate to anticonvulsants in the maternal milk, breast-feeding should be discontinued and the child observed for signs of drug withdrawal. A literature review found evidence that phenobarbital, phenytoin, valproate, and carbamazepine do not penetrate the breast milk in a clinically important amount.
Management of Epilepsy
Little or no information is available in the published literature to guide decision making with regard to certain management issues in women with epilepsy. Epilepsy must be managed during pregnancy, as at other times, by prophylactic anticonvulsant drugs. Management should be by monotherapy whenever possible, with selection of the anticonvulsant that is most appropriate for seizure type. As indicated earlier, trimethadione and valproic acid are best avoided, but available data concerning relative safety and therapeutic utility of the various anticonvulsant drugs during pregnancy are insufficient to provide any more detailed guidelines at this time for the management of epileptic patients or of women wishing to become pregnant. Moreover, there is little point in substituting one anticonvulsant drug for another after the first 2 to 3 months of pregnancy because major fetal malformations will probably have occurred already if they are going to occur at all. Folate supplementation (4 mg daily) may help, however, to reduce the risk of teratogenicity, although the optimal dose is unclear.
Anticonvulsant drug treatment should be monitored during pregnancy by serial measurement of plasma drug levels, depending on the drug that is being taken, as discussed earlier. Patients should be seen monthly, and as the pregnancy continues the dose of medication may need to be increased to maintain plasma concentrations at previously effective levels. If increases are made during pregnancy, dose reductions will be necessary at some point (usually within 8 weeks) after delivery to prevent toxicity, but at a time that must be determined individually based on clinical evaluation and plasma drug levels.
If patients inquire, it is appropriate to indicate that there is a slightly increased risk of fetal malformation due either to the seizure disorder itself or to the drugs used in its treatment. Nevertheless, there is still a very good chance (90 to 95%) that offspring will be normal. It must also be emphasized that the risks to both mother and fetus of noncompliance with anticonvulsant drug regimen are considerable, in that an increased seizure frequency or even status epilepticus may occur, with its associated morbidity and mortality.
Obstetric Management
Increased incidences of vaginal hemorrhage and toxemia, and an increased stillbirth rate are reported in epileptic women by some authors but not others. For women with epilepsy taking antiepileptic medication, there is probably no substantially increased risk (greater than two times expected) of cesarian delivery or late-pregnancy bleeding, and no moderately increased risk (greater than 1.5 times expected) of premature contractions or premature labor and delivery. Any increase in cesarian deliveries has been attributed to uncertainty in guiding the delivery of epileptic women and the misperception of an increased risk of complications. An increased incidence of neonatal death has sometimes been reported, perhaps owing to an increased incidence of congenital malformations, iatrogenic neonatal hemorrhage, the metabolic or toxic effects of seizures or anticonvulsant drugs, or socioeconomic factors.
Targeted ultrasonography can be used to diagnose most neural tube defects at 12 to 22 weeks of pregnancy as well as other major structural abnormalities.
Interactions Between Oral Contraceptives and Anticonvulsant Agents
Certain anticonvulsants (including phenytoin, carbamazepine, felbamate, topiramate, oxcarbazepine, phenobarbital, and primidone) may alter the effectiveness of oral contraceptives, leading to unwanted pregnancy. Thus, the risk of contraceptive failure in patients taking these anticonvulsants should be discussed in advance and documented in the patient’s records; in some instances, use of an additional backup contraceptive method should be considered. The incidence of breakthrough bleeding is also increased in women taking these anticonvulsants and concurrent oral contraceptives, and such bleeding may point to the possibility of contraceptive failure. Valproic acid and the newer anticonvulsants, zonisamide, vigabatrin, gabapentin, lamotrigine, levetiracetam, pregabalin, and tiagabine (at low doses), have not been reported to cause contraceptive failure. When oral contraception is to be used in a woman taking enzyme-inducing anticonvulsants, a formulation that includes at least 50 μg ethinyl estradiol or mestranol should be used. Oral contraceptives may also affect seizure frequency or blood levels of anticonvulsant medication, but this is less clear.
Migraine
Migraine is often influenced by pregnancy. Most commonly, symptoms improve after the first trimester, but occasionally they worsen or occur for the first time during pregnancy. The influence of pregnancy on migraine does not depend on any relationship of migraine to the menstrual cycle. Similarly, it does not relate to the sex of the fetus or to differences in plasma progesterone levels, although there may be some relationship to changes in the pattern of circulating estrogens. Treatment of migraine during pregnancy is similar to that at other times, with emphasis on the avoidance of precipitating factors together with the use of simple analgesics as necessary. However, acetaminophen should be used in preference to aspirin because there is some evidence that aspirin use in large dosages in the later stages of pregnancy may prolong labor, increase the incidence of stillbirth, impair neonatal hemostasis, and cause premature closure of the ductus arteriosus. Nonsteroidal anti-inflammatory drugs are best avoided for similar reasons, except in severe cases. If acetaminophen is insufficient, partial opioid agonists may be used on a limited basis. Ergot-containing preparations should be avoided when possible because of possible teratogenicity and the effect this drug may have on the gravid uterus. Propranolol should similarly be avoided during pregnancy when possible because animal studies have shown that it may impair fetal growth and that β-adrenergic blockade may inhibit the normal responsiveness of the fetus to asphyxia or other stresses. Other reported complications in neonates include prematurity, respiratory depression, hypoglycemia, and hyperbilirubinemia. Triptans are also best avoided because they have been associated with premature labor.
Many women, often with a past or family history of migraine, experience mild bifrontal headaches in the week after delivery. These headaches usually respond to simple analgesics and settle spontaneously.
The association between migraine and oral contraceptive preparations is discussed in Chapter 20 .
Tumors
Although any type of intracranial tumor occasionally presents during pregnancy, pituitary adenomas, meningiomas, neurofibromas, hemangioblastomas, and certain vascular malformations sometimes exhibit relapses during pregnancy, with partial or complete remission occurring after delivery. The basis of this relationship is unclear, but it seems likely that pregnancy produces a slight increase in tumor size. The enlargement of certain pituitary adenomas during pregnancy may be due to the trophic effects of increased circulating estradiol. Similarly, an increase in size of meningiomas may relate to a direct trophic effect of gonadal hormones on tumor cells; sex steroid–binding sites have been found in human meningiomas, but there are marked differences in their reported prevalence and concentration. Tumors with symptoms that show a consistent temporal relationship to pregnancy are usually so situated that significant neurologic involvement, with the development of new symptoms or signs, occurs with only slight expansion of the underlying lesion. Thus, spinal meningiomas are more likely than convexity meningiomas to show a relationship of symptoms to pregnancy. Visual field defects are unlikely to develop during pregnancy in patients with pituitary microadenomas, but may certainly occur with larger tumors.
Patients with suspected intracranial neoplasms should be managed during pregnancy as at other times. Magnetic resonance imaging (MRI) is generally the best noninvasive means of establishing the diagnosis and does not involve exposing the fetus to irradiation. Essential operative treatment should not be delayed. However, surgery for pituitary adenomas or other benign tumors diagnosed toward the end of pregnancy can often be delayed until after delivery, provided that the patient is followed closely. Radiation therapy or chemotherapy may be required during pregnancy. Radiation therapy is associated with a risk of fetal loss or teratogenicity depending on the level of fetal exposure, especially if administered during the first trimester; in later pregnancy it carries an increased risk of childhood cancer or leukemia. However, tumors of the brain or head and neck can usually be irradiated satisfactorily without dangerous fetal exposure. Therapeutic abortion may need to be considered in some patients with malignant brain tumors, depending on the therapy required and especially when it cannot be delayed to the latter half of pregnancy or postponed until after delivery, or when significant symptoms, such as uncontrollable seizures, complicate the pregnancy.
The pregnancy itself can usually be managed normally in patients with intracranial tumors. Concerns that vaginal delivery may exacerbate any existing increase in intracranial pressure due to the tumor are usually misplaced, especially if adequate regional anesthesia is employed and low forceps are used, if necessary, to shorten the second stage of labor.
The long survival associated with low-grade gliomas suggests that some women with such tumors may wish to become pregnant after the diagnosis has been established. Such decisions need to be made on an individual basis, but patients with these lesions may certainly go through pregnancy without further complications.
Choriocarcinoma may develop after a normal pregnancy or follow a molar, ectopic, or terminated pregnancy. Intracranial metastases are common, and hemorrhage may occur into the cerebral lesions. Early diagnosis and treatment are important for survival.
Pseudotumor Cerebri
Idiopathic intracranial hypertension, also known as pseudotumor cerebri, has a clear association with pregnancy and is especially likely to occur during the first trimester or postpartum. It therefore seems sensible that women with this disorder should defer pregnancy until their disease is controlled and important that all pregnant patients with new-onset headaches be examined funduscopically to exclude the diagnosis. Headache and visual disturbances due to papilledema may be accompanied by diplopia from sixth nerve palsy. Investigations reveal no space-occupying lesion, but the cerebrospinal fluid (CSF) pressure is increased. The disorder is self-limiting, but it may not remit for weeks after delivery, and there may be recurrences during subsequent pregnancies. Treatment, as in the nonpregnant woman, consists of measures to lower the intracranial pressure to prevent secondary optic atrophy. It may require the use of acetazolamide, furosemide, corticosteroids, repeated lumbar punctures, or a surgical shunting procedure. Optic nerve decompression and early delivery of the fetus may have to be considered if the intracranial pressure remains high despite these measures. There are no specific obstetric complications, and a normal birth can be expected.
Intracranial venous sinus thrombosis may simulate pseudotumor cerebri and is discussed later.
Cerebrovascular Disease
A significant number of pregnancy-related maternal deaths result from stroke. An increased incidence of stroke has been associated particularly with the puerperium. Pregnancy itself appears to be associated with an increased risk of stroke, and this probably relates at least in part to various hormonal changes.
Sex steroids can affect several physiologic and metabolic factors that predispose to cerebral thromboembolic or venous infarction, as discussed in Chapter 20 . The association of stroke with oral contraceptives is well recognized. Estrogens increase blood coagulability and platelet aggregation. Sex hormones may also predispose to aneurysm formation or rupture, as suggested by observations that early menarche or oral contraceptive use is associated with an increased risk of subarachnoid hemorrhage, that the risk of hemorrhage is greatest in the perimenstrual period, and that premenopausal women are at reduced risk of subarachnoid hemorrhage. Whether pregnancy influences intracranial arteriovenous malformations (AVMs) is unclear, but it may certainly aggravate spinal arteriovenous fistulas (p. 667). Eclampsia or pre-eclampsia is the most common cause of stroke during pregnancy, and the microangiopathic syndromes of pre-eclampsia, thrombotic thrombocytopenic purpura, and hemolytic-uremic syndrome are considered on p. 677.
Occlusive Arterial Disease
Most cases of nonhemorrhagic hemiplegia developing during pregnancy or the postpartum period are due to arterial occlusion. As in nonpregnant patients, this may relate to thrombus formation on an atheromatous plaque; inflammatory disorders such as arteritis or meningovascular syphilis; hematologic disorders such as polycythemia and sickle cell disease; and cardiac disorders such as a cardiomyopathy, rheumatic or ischemic heart disease, intracardiac shunts, cardiac dysrhythmias, subacute bacterial endocarditis, use of prosthetic heart valves, and cardiac myxoma. It may be associated with diabetes, cigarette smoking, and migrainous headaches. During pregnancy, in addition, stroke may be predisposed to by anemia, hormonal factors, changes in blood coagulation factors (see Chapter 25 ), increased platelet aggregation, hypertension, and puerperal septicemia.
The blood is in a hypercoagulable state during pregnancy; there is a rise in all procoagulant factors except XI and XIII, and increased thrombin activity. Circulating inhibitors of coagulation, such as protein C and protein S, are reduced during normal pregnancy, and antithrombin III may be reduced, as is discussed in Chapter 25 . The activity of the fibrinolytic system is also reduced during pregnancy. These various changes predispose pregnant women to stroke. Hemoglobinopathies may also lead to significant maternal morbidity during pregnancy. Thus, women with sickle cell disease are especially likely to experience crises, usually vaso-occlusive, during pregnancy. Sickle cell disease is also associated with an increased incidence of obstetric complication—including abortion, growth retardation, preterm birth, and stillbirth—although fetal wastage has been reduced considerably by improved prenatal care.
The presence of circulating antiphospholipid autoantibodies (discussed in Chapter 11 , Chapter 25 ) is similarly associated with a high rate of maternal arterial and venous thrombotic events and transient ischemic attacks, as well as with obstetric complications such as an increased rate of spontaneous abortion and of early-onset, atypical pre-eclampsia. Pregnancy may represent an especially high risk of thromboembolic disease in patients with these antibodies. Treatment recommendations are limited by a lack of clinical evidence but may involve low-dose aspirin, unfractionated heparin, or low-molecular-weight heparin.
A peripartum cardiomyopathy may occur during the last trimester of pregnancy or the puerperium, especially in the presence of twinning, toxemia, or postpartum hypertension; it sometimes presents with embolic phenomena necessitating anticoagulation. Its precise cause is unclear, but nutritional, hormonal, viral, and immunologic mechanisms have been suggested. Subsequent pregnancies are associated with a significant reduction in left ventricular function and may lead to clinical deterioration and death.
A postpartum cerebral angiopathy may occur during an otherwise normal pregnancy or the postpartum period and lead to a fatal outcome. It has been associated with hypertension and use of vasoconstrictive drugs and may be mistaken for cerebral vasculitis. Presentation is commonly with thunderclap headache; focal deficits and seizures may also occur. Cerebral infarction, intracranial bleeding, or vasogenic edema may be associated. The disorder follows a self-limiting course. Treatment is with calcium-channel blockers, but benefit is uncertain. The outcome is variable; full recovery occurs in many patients, but in others the disorder has a fulminant course and may have a fatal outcome or lead to residual deficits.
A reversible intimal hyperplasia of the cerebral vasculature during pregnancy has been described as a rare cause of stroke or transient ischemic attack during the gestational period, but such cases are poorly documented and hard to interpret. There are rare reports of arterial occlusion by paradoxical embolization from a pelvic vein through a patent foramen ovale. Fat, air, or amniotic fluid embolism may also occur during childbirth but usually presents with dyspnea, shock, and acute encephalopathy. Amniotic fluid embolism is an important cause of stroke and maternal death. In the United Kingdom and France, it is the fifth and third highest direct cause of maternal death, respectively, and in Singapore an autopsy study revealed that it was responsible for more than 30 percent of direct maternal deaths. Hemodynamic collapse and disseminated intravascular coagulopathy may lead to focal neurologic signs from cerebral hypoperfusion or hemorrhage. Plasma exchange may be helpful after initial resuscitation.
The role of thrombolytic agents (e.g., tissue plasminogen activator) for treating acute ischemic stroke in pregnant women or nursing mothers is unclear. Hemorrhagic complications are more likely, especially in the first few days after delivery; any effects on the fetus and the extent to which these agents are excreted in breast milk are uncertain. Nevertheless, tissue plasminogen activator has been used safely and effectively during pregnancy although it may increase the risk of miscarriage.
As in nonpregnant women, transient cerebral ischemic attacks may precede occlusion of one of the major intracranial arteries. Neurologic investigation and management should not be influenced by the pregnancy, but special shielding during radiologic studies may help to protect the developing fetus. Angiographic delineation of degenerative atherosclerotic disease in a localized arterial segment that is surgically accessible may permit disobliterative surgery, especially when stenosis is severe (70 to 99% in the internal carotid artery). If surgery is decided against or there is more widespread atherosclerotic disease, treatment is with low-dose aspirin. A cardiac source of emboli usually necessitates treatment with warfarin (as also do certain hypercoagulable states or venous occlusive disease). This drug is associated with risks of teratogenicity and fetal wastage when used during the first trimester, and it crosses the placenta, thereby increasing the risk of hemorrhagic complications. Accordingly, patients requiring anticoagulation during pregnancy are best maintained on subcutaneous heparin, which is discontinued with the onset of labor and restarted approximately 12 hours after vaginal delivery (or 24 hours after cesarean section).
The optimal management of labor and delivery in patients who have had a stroke during pregnancy is unclear. In most cases, vaginal delivery assisted by forceps is probably satisfactory. The blood pressure needs to be monitored closely, however, to avoid excessively high or low levels.
Occlusive Venous Disease
Aseptic intracranial venous thrombosis may occur during pregnancy, during the puerperium, or with the use of oral contraceptives for reasons that are unclear. It has been attributed to coagulation abnormalities, changes in the constituents of peripheral blood, and intimal damage to dural sinuses (see Chapter 25 ). The extent to which it relates to hormonal changes is unknown, but such changes probably have an important etiologic role, as discussed in Chapter 11 , Chapter 20 . In many instances there is no evidence of thrombosis in the pelvic or leg veins. Inherited prothrombotic states associated with intracranial venous thrombosis include protein C, protein S, antithrombin III, and factor V Leiden deficiency, and hyperhomocyteinemia (see Chapter 25 ); the antiphospholipid antibody syndrome and systemic malignancy may also be associated, and thus require exclusion.
Intracranial venous thrombosis ( Fig. 31-2 ) occurs most commonly during the third trimester of pregnancy or the postpartum period, sometimes in relation to pre-eclampsia. Although it may, in fact, occur at any time during a normal pregnancy, when it develops during the first trimester it usually is in relation to some complication such as spontaneous or therapeutic abortion. It is characterized clinically by headache, seizures, obtundation, confusion, and sometimes focal neurologic disturbances. Examination commonly reveals papilledema, and there may be signs of meningeal irritation from subarachnoid bleeding secondary to cortical infarction. Cerebrospinal fluid pressure is often increased, and its protein or cell content may be increased. Radiologic imaging procedures (computed tomography [CT] scan, MRI, and arteriography) confirm the diagnosis and help to exclude arterial disease.
Treatment of intracranial venous thrombosis is controversial. Anticonvulsant drugs and antiedema agents may be helpful. Anticoagulation with dose-adjusted intravenous heparin may also be worthwhile despite the risk of provoking hemorrhagic complications. The role of thrombolytic therapy to prevent extension of the thrombus in pregnant or postpartum women is not clear. Different mortality rates have been reported in various series, but a rate of 15 percent is based on the pooled outcomes in a number of studies. Survivors may experience recurrence of thrombosis later in the same pregnancy or in subsequent ones. The outcome is better, however, than when intracranial venous thrombosis is a sequel to inherited thrombophilia or systemic disease.
Cesarean section may be necessary if venous thrombosis has occurred before or during labor. If it occurs early in the pregnancy, labor can generally be allowed to commence spontaneously, with forceps-assisted delivery if necessary.
Pituitary Infarction or Hemorrhage
Acute infarction or hemorrhage of the pituitary gland, especially around the time of delivery, is a well-recognized complication that leads to hypopituitarism if the patient survives the acute event. The disorder may occur in patients with preexisting diabetes or in those who experience such obstetric complications as postpartum hemorrhage with vascular collapse. It may also occur in patients with coagulopathies or a pituitary adenoma. The extent of pituitary damage governs the severity of pituitary hypofunction. The initial symptom may be failure of lactation. Emergency treatment with corticosteroids and trans-sphenoidal decompression of the intrasellar content may need to be considered to preserve life and vision. Management otherwise is with hormone replacement therapy.
Disseminated Intravascular Coagulation
Disseminated intravascular coagulation may occur in patients with a variety of obstetric complications. It is discussed in detail in Chapter 25 and further consideration here is unnecessary.
Subarachnoid Hemorrhage from Intracranial Vascular Anomalies
Subarachnoid hemorrhage may occur during pregnancy from an aneurysm or cerebral AVM ( Fig. 31-3 ). The morbidity and mortality rates are greater with the former. It is unclear whether intracranial AVMs are more likely to bleed during pregnancy, but recent data do not support this belief.
Symptoms and signs of subarachnoid hemorrhage are as in nonpregnant patients. The hemorrhage may be the first indication of the underlying lesion. An AVM is somewhat more likely than an aneurysm to be responsible if subarachnoid hemorrhage is accompanied by a major focal neurologic deficit (suggesting an intracerebral hematoma). CT scan of the head detects recent subarachnoid or intracerebral bleeding and may permit the causal lesion to be identified and localized. Arteriography confirms the identity of the lesion and provides information about its anatomic characteristics that is especially important in planning operative treatment. All of the major intracranial vessels should be opacified because feeders to AVMs sometimes arise from the contralateral side and aneurysms may be multiple. Special shielding during radiologic studies is necessary for pregnant women to protect the developing fetus.
The management of subarachnoid hemorrhage is as for nonpregnant women. Because of the high risk of rebleeding in survivors of a ruptured aneurysm, operative or endovascular treatment should not be delayed because of pregnancy if the clinical and arteriographic findings indicate its feasibility. Although ruptured AVMs may also bleed again, this may not be for months or years after the initial hemorrhage, and neurosurgical treatment can often be postponed until the pregnancy is over.
The obstetric management of survivors of a subarachnoid hemorrhage is controversial. In patients with aneurysms that have been successfully treated by surgery or in whom rupture occurred before the last trimester, pregnancy and delivery can generally be permitted to continue normally. In patients with unoperated or incompletely obliterated aneurysms that ruptured during the last trimester of pregnancy, cesarean section at 38 weeks’ gestation is probably appropriate. Some have also suggested delivery by cesarean section at 38 weeks for women with AVMs, but this measure seems more difficult to justify.
Intracranial hemorrhage during pregnancy or the postpartum period may also occur in association with hypertension, vasculitis, various hematologic disorders, mycotic aneurysms, cocaine abuse, and moyamoya disease and as a manifestation of choriocarcinoma. Treatment is of the underlying cause.
The relationship of oral contraceptive use to intracranial hemorrhage is considered in Chapter 20 .
Intracranial Dural Arteriovenous Fistulas
Dural arteriovenous fistulas may present during pregnancy, after abortion, or during the postpartum period. Some are developmental anomalies, but others are acquired in adult life, occasionally following trauma. The anomalous arteriovenous shunt may involve either the anterior-inferior group of dural sinuses (cavernous, intercavernous, sphenoparietal, superior and inferior petrosal, and basilar plexus) or the superior-posterior group (superior and inferior sagittal, straight, transverse, sigmoid, and occipital). Anomalies involving the former group lead typically to unilateral orbital or head pain, diplopia, a proptosed or red eye, tinnitus, or some combination of these symptoms. Malformations involving the superior-posterior dural sinuses may lead to subarachnoid hemorrhage, increased intracranial pressure, tinnitus, seizures, or focal neurologic deficits due to cerebral ischemia. In either case, there may be papilledema, and a bruit is often present either over the eye (with involvement of the anterior-inferior sinuses) or about the mastoid region or ear (superior-posterior sinuses involved).
Arteriography is necessary to localize the shunt with certainty and determine its anatomic features. With shunts to the anterior-inferior dural sinuses, embolization of feeding vessels may help preserve vision or relieve intolerable symptoms. Ligation or embolization of feeding vessels is often helpful in relieving symptoms from shunts to the superior- posterior dural sinuses, and a direct surgical approach is also sometimes feasible.
Spinal Arteriovenous Fistulas and Malformations
Spinal fistulas and AVMs are usually either dural or intradural in location. They may lead to spinal subarachnoid hemorrhage or to a myeloradiculopathy that can either present acutely or develop insidiously. Symptoms usually are progressive. At least one-half of the survivors of subarachnoid hemorrhage from these spinal lesions have further episodes of bleeding, and one-half of the subsequent survivors bleed again unless the underlying lesion is treated. Similarly, once there is any functional impairment in the legs due to the myeloradiculopathy, disability is likely to worsen, so that 50 percent of patients become unable to walk at all or require two sticks or crutches to do so, within 3 years. Spinal cord or root symptoms may show a characteristic relationship to exercise or posture and occasionally to pregnancy or the menstrual cycle.
Typically, examination reveals a mixed upper and lower motor neuron deficit in the legs, often with an associated sensory disturbance that occasionally has a radicular distribution. There may be a coexisting cutaneous malformation that sometimes relates segmentally to the spinal lesion. A spinal bruit may be present.
Unruptured dural arteriovenous fistulas and spinal AVMs probably produce symptoms by causing venous hypertension. Although they are usually extramedullary, their draining veins connect with veins draining the spinal cord. The increased venous pressure leads to a reduction in the arteriovenous pressure gradient across the cord and thus to a reduction in spinal blood-flow. Pressure on pelvic or abdominal veins by the gravid uterus could aggravate symptoms of caudally situated dural arteriovenous fistulas and AVMs by obstructing venous return to the heart, thereby reducing still more the arteriovenous pressure gradient across the cord. Whether anemia and hemodilution are also partly responsible for exacerbations of symptoms during pregnancy is unclear, and it is not known whether sex hormones exert direct trophic influences on these lesions.
Advances in imaging procedures have revealed that the nidus of many spinal vascular lesions is situated durally. Spinal MRI is an excellent screening procedure ( Fig. 31-4 ); if the findings suggest an arteriovenous fistula, spinal angiography is performed to determine its anatomy, the anatomy of the spinal circulation, and the precise level of the abnormal fistula. Treatment of dural lesions is indicated in patients with progressive symptoms, functional incapacity, or a history of hemorrhage, and consists of embolization, surgical excision, or both. Treatment is clearly more difficult for vascular anomalies located anteriorly or within the spinal cord, but in some of these, also, the actual nidus of the lesion is dural and thus operable.
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