Pregnancy and Disorders of the Nervous System

Neurologic disorders may present first 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 pre-existing diseases may be affected by pregnancy, and obstetric management may be influenced by the neurologic disturbance. These aspects are considered in this chapter.

Concerns about the use of imaging studies in pregnancy merit comment. In general, fetal exposure to ionizing radiation from computerized tomography (CT) is small, especially when the fetus is not in the imaged region. Magnetic resonance imaging (MRI) does not expose patients to ionizing radiation and may be necessary when the findings may influence clinical management during the pregnancy. Iodinated contrast may be administered during pregnancy when necessary for maternal care, but thyroid function tests should then be performed in the neonate in the first week of life. Gadolinium contrast passes into the placenta and may harm the fetus, so its use should be avoided when possible; otherwise, the smallest possible dose is given when required for maternal care.

Epilepsy

Birth rates are lower and maternal mortality during pregnancy, delivery, or the postpartum period are higher among women with epilepsy that among nonepileptic women. 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. Many pregnancies are unplanned, so that regular counseling of women with epilepsy during the reproductive years is important.

Effect of Pregnancy on Maternal Seizures

An increase in seizures occurs during pregnancy in 23 to 75 percent of cases depending on the series; seizure control is unchanged in between 53 and 67 percent. 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, for example, lamotrigine, levetiracetam, phenytoin, and, to a lesser extent, carbamazepine, and of the active oxcarbazepine metabolite, the monohydroxy derivative. Zonisamide serum concentration may decline by more than 40 percent during pregnancy, especially in the last trimester, but there is much interindividual variability. 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.

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 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 different 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 and genetic 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. A greater teratogenic risk exists with polypharmacy, but specific antiepileptic drugs in the regimen may actually be more important than whether multiple drugs are taken.

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 or ventricular septal defect, developmental delay, and other disorders; it is also associated with cognitive impairment and autism spectrum disorder. Its teratogenicity is dose dependent. Other antiepileptic drugs have different teratogenic risks. Phenytoin, phenobarbital, carbamazepine, and topiramate have been associated variously with cardiac anomalies and cleft palate, and carbamazepine with neural tube defects. A longitudinal, prospective cohort study showed that the risks of major congenital malformation are lowest with lamotrigine and levetiracetam. Gabapentin, oxcarbazepine, and zonisamide are not associated with an increased risk, but the data concerning these medications are limited. There are no or very limited data for newer drugs such as eslicarbazepine, lacosamide, perampanel, and brivaracetam. Vagal nerve stimulation therapy has not been associated with teratogenicity. These findings should guide the rational selection of medication in women with epilepsy, taking into account comparative risks and treatment alternatives.

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 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. Bleeding has 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. However, it has 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 intramuscular administration of vitamin K ₁ (1 mg) to all newborns (regardless of maternal epilepsy) is sufficient to reduce the incidence in infancy of late vitamin K deficiency bleeding (previously designated hemorrhagic disease of the newborn), with its high morbidity and mortality.

Withdrawal Symptoms

Maternal use of certain anticonvulsants may be associated with withdrawal symptoms in the neonate, with restlessness, irritability, tremulousness, difficulty in sleeping, and vasomotor instability, usually beginning a few days after birth.

Breast-Feeding

Although certain anticonvulsant drugs (primidone, ethosuximide, gabapentin, lamotrigine, levetiracetam, topiramate, and zonisamide) taken by the mother may be present in breast milk, there is no evidence that these have symptomatic effects on the newborn or affect development. 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. There is no evidence that phenobarbital, phenytoin, valproate, and carbamazepine 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, lamotrigine and levetiracetam seem to have the least teratogenic risk, and women of childbearing age should be managed on one of these drugs when feasible, depending on seizure type. 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 may help, however, to reduce the risk of teratogenicity and of certain malformations (such as neural tube defects), although the optimal dose is unclear. Some prescribe 0.4 mg folate daily for all women of childbearing age from a month before conception to the end of the first trimester, whereas others prescribe 4 mg daily for 3 months before and after conception for those at particular risk because of family and past medical (including spousal) history, a previous baby with a neural tube defect, or because they are taking valproate or carbamazepine. Folate supplementation is followed by routine prenatal vitamin supplementation for the remainder of the pregnancy and during lactation.

Anticonvulsant drug treatment should be monitored during pregnancy by serial (monthly) 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 after delivery to prevent toxicity, but at a time that must be determined individually based on clinical evaluation and plasma drug levels. In general, lamotrigine and levetiracetam can be tapered over 2 to 3 weeks, and other antiseizure medications over about a month or longer, beginning 3 or 4 days after delivery.

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

Most women with epilepsy will have a normal pregnancy and delivery. It is rare for seizures to occur during labor and delivery, but when they do occur it is usually in women who have continued to have seizures during the pregnancy.

Increased incidences of vaginal hemorrhage and toxemia and an increased stillbirth rate have been reported in epileptic women by some authors but not others. For those taking antiepileptic medication, the risk of cesarean delivery or late-pregnancy bleeding is increased but is less than double the expected risk, while the risk of premature contractions or premature labor and delivery is increased only mildly. The increase in cesarean 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 Anticonvulsants

Certain anticonvulsants (including phenytoin, carbamazepine, felbamate, topiramate, oxcarbazepine, eslicarbazepine, perampanel, 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, such as a condom, intrauterine device, or depot injection. 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. Oral contraceptives may also affect seizure frequency or blood levels of anticonvulsant medication (e.g., lamotrigine).

Migraine

Migraine is more common in women than men and is often influenced by pregnancy. Most commonly, the frequency and severity of attacks improve after the first trimester, but occasionally migraine worsens or occurs for the first time during pregnancy. Occasionally, attacks are changed so that auras occur without headache. 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. The association between migraine and oral contraceptive preparations is discussed in Chapter 20 .

Acute Treatment

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 (NSAIDs) also are best avoided. Some but not other studies in animals suggest that they may lead to congenital malformations and miscarriage when given in early pregnancy; after 30 weeks, they may cause premature closure of the ductus arteriosus and other adverse fetal outcomes.

Although early studies showed that sumatriptan in extraordinarily high doses led to death or malformations in fetal rats and rabbits, later retrospective studies and meta-analyses in humans provided no evidence either for teratogenicity or for prematurity or spontaneous abortions. When acute treatment for migraine is required during pregnancy, sumatriptan (unless contraindicated for other medical reasons) is best taken by nasal spray or injection as nausea and gastric stasis might well limit the utility of oral administration. The safety of other triptans in pregnancy is less clear.

Partial opioid agonists may be used on a limited basis if the response to other medications is inadequate. Prochlorperazine may help both nausea and headache.

Ergot-containing preparations should be avoided because of possible teratogenicity and the effect this drug may have on the gravid uterus.

Preventive Treatment

Preventive measures can usually be discontinued during pregnancy as migraine tends to improve spontaneously, but they may be required for women who experience frequent, prolonged, and severe attacks that respond poorly to treatment. Patients should avoid known precipitants of attacks, eat regular meals, use relaxation techniques, and maintain good sleep hygiene.

Memantine is well tolerated, appears to be safe during pregnancy, and may be effective for migraine prophylaxis. Propranolol is also effective for migraine prophylaxis but should be avoided during pregnancy when possible or used in the lowest effective dose. This is 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.

Topiramate and valproic acid, which are effective for migraine prophylaxis, are not recommended during pregnancy because of their teratogenic effects, discussed in an earlier section.

The tricyclic antidepressant amitriptyline is sometimes used in low dose (25–50 mg daily) and seems to be safe during pregnancy. It is best discontinued during the third trimester because of possible effects on the fetus (respiratory distress, drowsiness, hypoglycemia).

Many women, often with a past or family history of migraine, experience mild bifrontal headaches in the week after delivery, sometimes accompanied by photophobia, nausea, and anorexia. These headaches usually respond to simple analgesics or to sumatriptan and settle spontaneously.

Treatment During Lactation

Acetaminophen, NSAIDs (especially ibuprofen), and sumatriptan can be used safely during lactation.

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. 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.

Idiopathic Intracranial Hypertension

Idiopathic intracranial hypertension 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. Topiramate is also effective but should be avoided during pregnancy. 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.

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