Neurologic Diseases in Pregnancy

Kathleen B. Digre

Michael W. Varner

In the United States, there are 4,000,000 live births per year. It is thus common to see neurologic conditions occur in association with pregnancy. Furthermore, the physiologic changes in pregnancy can mimic neurologic diseases and can affect the severity of neurologic signs and symptoms. Not only can neurologic conditions be affected by pregnancy, but also treatment frequently must be altered to accommodate a developing fetus. Finally, pregnancy-specific conditions can present with neurologic symptoms and signs.

I. NORMAL PHYSIOLOGIC CHANGES IN PREGNANCY

A. Cardiovascular.

1. Increase of 30% to 50% in cardiac output and blood volume with singleton pregnancy (70% with twins).

2. Midpregnancy decrease in blood pressure.

B. Pulmonary.

1. Increase of 20% to 30% in minute volume.

2. Increase in respiratory rate and partially compensated respiratory alkalosis.

C. Renal.

1. Increase of 30% to 50% in renal blood flow.

2. Decreased serum level of blood urea nitrogen and creatinine (due to increased renal clearance).

D. Gastrointestinal.

1. Decreased motility.

2. Elevated alkaline phosphatase level (placental). No pregnancy-associated changes in any other liver function tests.

3. Increased cytochrome P-450 activity.

E. Hematologic.

1. Decreased hematocrit (20% to 30% increase in RBC volume but 30% to 50% increase in blood volume).

2. Increased WBC count; decreased platelet count.

F. Coagulation factors.

1. Increased levels of plasminogen, fibrinogen, and factors VII, VIII, IX, and X.

2. No change in factor V, antithrombin, or platelet adhesion.

3. Thrombophilias (e.g., antiphospholipid antibodies, protein C and S deficiency, and factor V Leiden) are more likely to produce thromboembolic complications.

G. Connective tissue.

Thickening and fragmentation of reticular fibers with mild hyperplasia of smooth muscle cells.

H. Hormonal changes.

Progressive increase in estrogens and progesterone until delivery.

I. Serum osmolality.

Decreases from early in gestation, with resultant increase in extracellular fluid volume.

J. Neurologic.

Increase in pituitary size; slight decrease in brain volume that returns to baseline postpartum.

K. Evaluating neurologic conditions in pregnancy

(Table 57.1).

L. U.S. Food and Drug Administration (FDA) risk factor classification of drugs in pregnancy.

1. Class A. Controlled studies show no risk to fetus in the first trimester; fetal harm is remote.

2. Class B. No controlled studies have been completed, but there are no known risks.

3. Class C. Studies on animals may show effects on fetuses, but no results of controlled studies are available. The drug can be used if the risk is justified.

TABLE 57.1 Evaluating Neurologic Conditions in Pregnancy

Test	Risk to Mother	Risk to Fetus	Contraindications
MRI	None	None known	Metal, cardiac pacemaker, and otologic implant
MRI with gadolinium	None	None known	Same as above (risk category C)
CT	None	Minimal^a	None
CT with contrast	None	Minimal^a	Allergy to contrast medium
Angiography	Minimal in most	Minimal^a	Allergy to contrast medium
Lumbar puncture	None	None	Incipient herniation or mass lesion
Ultrasonography	None	None	None
EEG	None	None	None
NCV/EMG	None	None	None
Tensilon test	Minimal	Minimal	Heart failure
Visual fields	None	None	None
Dilated eye examination	None	None with punctal occlusion	Incipient glaucoma
Fluorescein angiography	None	Minimal	Allergies, FDA risk category C
^aAbdominal shielding. Abbreviations: NCV, nerve conduction velocity.

4. Class D. There are risks, but the drug may be used if serious disease or life-threatening conditions exist.

5. Class X. Human and animal studies show risk. The risk of use outweighs any benefit.

II. SEIZURE DISORDERS IN PREGNANCY

A. Frequency.

One percent of the population.

1. In an unselected population, frequency is 7 to 8 per 1,000 deliveries.

2. Antiepileptic drugs (AEDs) lower the efficacy of some oral contraceptives in some individuals making pregnancy more likely.

B. Heredity.

1. About 2% to 5% if parent has idiopathic epilepsy. Relatively higher if the parent is the mother; relatively lower if the parent is the father.

2. No significant transmission if disease is acquired.

C. Course of disease in pregnancy.

1. The best figures for disease activity during pregnancy include the following:

Improved, 22%.
Exacerbated, 24% (most likely to occur in the first trimester).
No change, 54%.

2. Postulated mechanisms for changes in frequency during pregnancy include the following:

Physiologic.
- Hormonal (estrogens decrease and progestins increase seizure threshold).
- Metabolic (increased cytochrome P-450 activity).
Sleep deprivation.
Noncompliance (e.g., fear of birth defects from taking medications).
Pharmacokinetic changes in drug levels caused by: impaired absorption, increased volume of distribution, decreased albumin concentration, reduced plasma protein binding, and increased drug clearance.
Folate supplementation can reduce anticonvulsant levels.
Stress, anxiety.
Alcohol or other drug use.

3. Seizure frequency during pregnancy does not correlate with maternal age, seizure type, drug regimen, and seizure frequency in previous pregnancies.

4. Fetal risks with generalized convulsive seizure include the following:

Physical injury from maternal abdominal trauma.
Hypoxic-ischemic injury due to maternal hypoxia.

D. Therapeutic options.

1. Pharmacologic.

Be certain of the diagnosis.
Be familiar with and use the few drugs that are the most effective for the various types of seizures.

2. Surgery in general should be addressed before or after pregnancy.

3. General.

Maintain good daily habits (regularly scheduled meals, adequate sleep, and minimize stress).
Avoid alcohol and sedatives.
Avoid hazardous situations.
Avoid ketogenic diet.

E. Drug dosages, plasma levels, and clinical management.

1. AED levels decline during pregnancy in almost all women. This does not necessarily equate with a need to increase dosage, unless seizures are not controlled.

Free (non-protein-bound) drug level equates best with clinical status (seizure control and side effects) and should be obtained in pregnancies complicated by persistent or recurrent seizures or side effects.
Total drug level (usual laboratory result) sufficient if the patient has good clinical control.
With the exception of valproic acid, the average decline in free levels is less than that for total levels.

2. Frequency of measurement of levels.

Ideally, preconceptional total and free levels should be obtained and optimized.
Obtain non-protein-bound (free) levels every trimester (3 months), and again 4 weeks before term when: seizure types do not interfere with activities of daily living, the epilepsy is well-controlled.
Obtain monthly free levels when: uncontrolled seizures interfere with activities of daily living during the year before conception, previously controlled seizures recur during pregnancy, seizures are controlled but total drug levels decrease >50% on routine screens, troublesome or disabling side effects develop, lack of compliance is suspected or confirmed.
Always check levels postpartum and adjust dosage because levels often increase as the physiologic effects of pregnancy resolve within 10 to 15 days after delivery.

3. Changing drug dosage.

Reasons not to change dosage.
- Total drug levels are declining in a woman with well-controlled seizures, unless there are >30% decline in free levels and a history of poor control.
- A woman taking two or more AEDs discovers that she is pregnant (the time to change to monotherapy is before conception).
Reasons to change dosage.
- Increased numbers of tonic-clonic seizures.
- Complex partial or other seizure types that interfere with activities of daily life and the patient wants better control.
- Troublesome or disabling side effects.
Discontinuation of AED therapy should ideally be accomplished before conception but can be considered cautiously during pregnancy if a patient has been seizurefree for more than 2 years, has normal findings on neurologic examination, normal electroencephalographic findings, no structural brain disorder, and no history of prolonged convulsive seizures.

4. AEDs used in pregnancy (Table 57.2); breast-feeding while taking AEDs does not appear to affect cognition.

5. Other drugs to add or consider for patients with epilepsy.

Folic acid.
- Requirements may be further increased because of malabsorption, competitive metabolism, and increased hepatic metabolism.
- Increased supplementation may precipitate seizures by lowering anticonvulsant levels.
- Best advice is to maintain usual supplementation.
- Compelling evidence links the folic acid antagonism properties of AEDs to relatively increased risk of fetal neural tube defects in women taking anticonvulsants during the first trimester (neural tube defects form, or do not form, 26 to 28 days after conception). Women of reproductive potential should take continuous folic acid supplementation (400 mg per day) whether or not they are considering pregnancy.
Vitamin K should be administered (10 mg by mouth daily) to all pregnant women receiving AEDs beginning 4 weeks before expected delivery until birth to minimize the risk of neonatal hemorrhage. If a woman has not received vitamin K before delivery, consideration should be given to parenteral vitamin K administration.
Vitamin D not routinely supplemented.

TABLE 57.2 Medications Used in Epilepsy

Drug	Indication	Dosage	FDA Category	Side Effects	Breast-Feeding^a
Phenobarbital	Generalized seizures	1-2 mg/kg/d; 90-120 mg/d	D	Sedation	Potential toxicity
Phenytoin	Generalized seizures	4-5 mg/kg/d; 300-600 mg/d	D	Gingival hyperplasia and hirsuitism	Compatible
Fosphenytoin	Status epilepticus	Maximum 100-150 mg	D	Infant risk possible PE/min IV	Compatible
Primidone	Generalized and partial complex seizures	500-2,000 mg/d in 2 or 3 divided doses	D	Fatigue, depression, nausea; folate deficiency	Potential toxicity
Carbamazepine	Generalized, partial complex seizures	10-30 mg/kg/d divided t.i.d. or q.i.d.; maximum 1,600 mg/d	D	Diplopia, dizziness, neural tube defect headache, nausea	Compatible
Oxcarbazepine	Partial complex seizures	Initial: 600 mg/d divided b.i.d. Maintenance: 1,200 mg/d divided b.i.d.	C	Hyponatremia, rash	Probably compatible
Valproic acid	Generalized and myoclonic seizures	15-60 mg/kg/d	D	1% neural tube defect	Compatible
Valproate IV	Status epilepticus, difficult-to-control	Loading dose of 20 mg/kg in 100 ml NS over 1 hr	D	Thrombocytopenia, injection site erythema	Compatible seizures
		Maintenance 15 mg/kg a day divided t.i.d.
Lamotrigine	Generalized seizures	Starting dose: 25 mg b.i.d. slow start	C	Insomnia or drowsiness, rash, and nausea	Potential toxicity
	Adjunctive therapy	Maximum 500 mg for partial seizures
Ethosuximide	Absence seizures	500-1,500 mg/d given as 1 or 2 doses	C-D	Nausea, vomiting, anorexia, agitation, and headache	Probably compatible
Felbamate	Partial onset with secondary generalization	300-400 mg t.i.d.	C	Aplastic anemia and liver failure	Potential toxicity
	Mostly used in Lennox-Gastaut syndrome
Gabapentin	Adjunctive for partial seizures	300-600 mg t.i.d.	C	Fatigue	Probably compatible
Tiagabine	Partial and tonic-clonic seizures	30-50 mg/d divided doses	C	Dizziness and sedation	Probably compatible
Topiramate	Adjunctive, partial, and tonic-clonic seizures	12.5-25 mg/d with gradual increase to 6 mg/kg or 400 mg/d	D	Mental dullness, renal calculi; cleft palate	Potential toxicity
Zonisamide	Partial, generalized, or myoclonic seizures	Initial: 100-200 mg/d	C	Hypersensitivity reaction and nephrolithiasis	Potential toxicity
		Maintenance: 400-800 mg/d divided b.i.d.		Probably compatible
Levetiracetam	Partial or generalized seizures	Initial: 1,000 mg/d divided b.i.d.	C	Fatigue and weakness	Probably compatible
		Maintenance: 1,000-3,000 mg/d divided b.i.d.
Trimethadione	Abscence Seizures	300-600 mg qid-tid (adult dosage)	X first trimester; D thereafter	Rash, sore throat, fever, drowsiness, fatigue, sunlight sensitivity	Probably Compatible
Vigabratin	Adjunctive in treatment resistant epilepsy, and refractory complex partial seizures	500 mg bid	C (D in Australia)	Watch vision; restricted use due to retinal toxicity	Possibly Compatible
Lacosamide	Adjunctive in treatment of partial seizures	50 mg bid (Max dose 400 mg daily)	C	Blurred vision, imbalance, mood or behavioral changes, suicidal thoughts, syncope	Unknown
^aWatch how infant does. Abbreviations: IM, intramuscular; t.i.d., three times a day; q.i.d., four times a day; b.i.d., twice a day; NS, normal saline solution. See text: Source: Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation. 7th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2005.

6. Birth defects in infants of epileptic mothers.

Should be discussed with all epileptic women of reproductive age, irrespective of whether or not they are planning pregnancy (50% of pregnancies are unplanned).
Other factors that may explain the increased incidence of anomalies in infants of epileptic mothers are as follows:
- Increased incidence of anomalies in infants of epileptic mothers not taking AEDs. The only anomalies that are more common in phenytoin-exposed fetuses are hypertelorism and digital hypoplasia.
- Increased incidence of characteristic malformations in infants of epileptic fathers, described as being intermediate between treated and untreated epileptic mothers.
- A specific metabolic defect (epoxide hydrolase deficiency) more common in persons with epilepsy may predispose to damage in some cases. Autosomal codominant and increased fetal anomalies.
- Epilepsy may represent an underlying genetic disease.
- The defects may result from an AED-mediated relative folate deficiency. (Folate antagonists are known abortifacients and teratogens; see discussion above.)

7. AED teratogenesis should be discussed with all epileptic women of reproductive age.

Fetal anticonvulsant syndrome occurs in 3% to 5% of epileptic women and can occur in association with use of any anticonvulsant medication. The relative risk is dose dependent. This syndrome is being seen with decreasing frequency as fewer women receive polytherapy and more receive monotherapy.
- Craniofacial (cleft lip and palate) and digital dysmorphic changes.
- Growth deficiency.
- Microcephaly.
- Cardiac defects.
- Mental retardation.
AEDs and neural tube defects.
- Risk is 1% to 2% for valproic acid and slightly less for carbamazepine. It is <1% for other anticonvulsants. However, these risks are >0.1% population-wide risk in the United States.
- The relative risk is dose related.
- If the medications are necessary for seizure control, the patient should be offered maternal serum α-fetoprotein and ultrasound screening.
Trimethadione is clearly teratogenic and is contraindicated in pregnancy.

8. Breast-feeding.

Most AEDs cross into breast milk, although at low levels; the higher the protein binding of the AED, the less that is passed into breast milk. Recent studies show no cognitive change in babies breast fed while mother takes AED.
Contraindications to breast-feeding include poorly controlled maternal seizures, rapid somnolence on the part of an initially hungry infant, which suggests a drug effect.

F. Onset of seizures during pregnancy: differential diagnosis.

1. Rule out eclampsia. The most common multisystem disease in late pregnancy is preeclampsia or eclampsia.

2. Cortical venous thrombosis, especially late in pregnancy and in the immediate puerperium.

3. Tumors are especially likely to manifest in the first trimester, because this is when the pregnancy-associated increase in extracellular fluid begins. Meningioma tends to expand during pregnancy (response to the progressive increases in estrogen and progesterone).

4. Intracranial hemorrhage.

5. Gestational epilepsy is a diagnosis of exclusion and represents only a small fraction of all women who have initial seizures while pregnant.

G. Status epilepticus during pregnancy (follow guidelines for non-pregnant patients).

1. Less than 1% of all pregnant epileptic women.

2. Not an indication for termination of pregnancy.

3. Management should follow standard treatment of status epilepticus. Hospitalize, securing the airway, intravenous (IV) access for normal saline solution and B vitamins, baseline laboratory studies including electrolytes, CBC, glucose, calcium, and arterial blood gases. Maternal and fetal vital signs, including ECG and fetal heart rate monitoring. In addition administer the following:

Glucose bolus (50 ml of D50).
Thiamine (100 mg intramuscularly or intravenously).
Begin lorazepam (0.1 mg per kg IV, not to exceed 2 mg per minute) or diazepam (5 to 15 mg IV in 5 mg boluses) and fosphenytoin (150 mg per minute) or phenytoin 18 to 20 mg per kg IV, not to exceed 50 mg per minute, with ECG and blood pressure monitoring, administered in nonglucose-containing fluids).
If seizures persist, intubate and begin either phenobarbital (20 to 25 mg per kg IV, not to exceed 100 mg per minute). Alternatives include midazolam, propofol, levtriacetam, or IV valproic acid (if absolutely necessary).
If seizures still persist, institute general anesthesia with halothane and neuromuscular junction blockade. (See Chapters 38 and 39.)

III. HEADACHE

A. The most common headache diagnoses are as follows:

1. Migraine (with or without aura) occurs in 10% to 20% of women of childbearing age. Unilateral or bilateral throbbing headaches associated with photophobia, phonophobia, nausea, or vomiting may be exacerbated by activity.

2. Tension-type headache is very common. Mild-moderate headache, without nausea and vomiting, may be relieved by activity.

B. Genetics of migraine. Migraine is more common in affected families. Hemiplegic migraine is autosomal dominant associated with calcium channel genes located on chromosomes 1 and 19.

C. Course of migraine in pregnancy.

1. The condition of most women with migraine improves when they are pregnant. This is especially true with menstrual migraine and migraine whose onset was at menarche.

2. About 10% to 20% of headaches worsen or have the initial onset during pregnancy, usually in the first trimester. Many of these may be migraine aura without headache.

3. Migraineurs have no increased risk of complications during pregnancy, but headaches usually recur near term and in the puerperium.

4. Multiparous migraineurs may have an increase in headaches in the third trimester, whereas nulliparous women report less headache activity in pregnancy and the puerperium.

D. The differential diagnosis of headache or migraine occurring for the first time in pregnancy includes the following:

1. Severe preeclampsia—headache with hypertension should bring this diagnosis to the forefront.

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