maternal and fetal implications of anticonvulsive therapy during pregnancy

~~ ~

PRESCRIBING IN PREGNANCY 0889-8545/97 $0.00 + .20

MATERNAL AND FETAL IMPLICATIONS OF

ANTICONVULSIVE THERAPY DURING PREGNANCY

Daniel P. Eller, MD, C. Anne Patterson, MD, and Gilbert W. Webb, MD

Seizure disorders represent the most frequent neurologic disorders in pregnancy, affecting 0.4% to 0.8% of patients and an estimated 1.1 million women of childbearing age in the United States. Approximately 85% of seizure disorders are idiopathic, whereas 15% are acquired as a result of metabolic disorders, space occupying lesions, infections, or trauma. Epilepsy is defined as the tendency for recurrent seizure activity (two or more) unprovoked by any known insult. A seizure can be defined as a paroxysmal disorder of the central nervous system in which abnormal neuronal discharge occurs, with or without the loss of consciousness.1o Idiopathic seizures can be classified as partial or generalized. Partial seizures originate from a focal area in the brain and may or may not progress secondarily to involve the entire brain. In contrast, generalized seizures involve the entire brain from the outset.

Pregnancy can have variable effects on seizure frequency. Yerby and Devinsky45 reviewed 30 studies evaluating this subject. They found that in the recent reports 5% to 25% of gravidas experience an increase in seizure frequency, whereas 60% to 85% experience no change.

Epilepsy may increase the risk of pregnancy to both mother and fetus. The literature evaluating the effects of epilepsy on p>egnancy is somewhat conflicting. Wilhelm and c011eagues~~ in a case control study

From the Northside Hospital, North Fulton Regional Hospital; and Gwinnett Medical Center, Atlanta, Georgia

~

OBSTETRICS AND GYNECOLOGY CLINICS OF NORTH AMERICA

VOLUME 24 * NUMBER 3 * SEPTEMBER 1997 523

524 ELLER et a1

compared 98 pregnancies complicated by epilepsy to controls. They confirmed the findings of Nelson and Ellenberg from 198235 suggesting a two- to threefold increase in the incidence of preeclampsia, cesarean delivery, preterm delivery, low birth weight, congenital malformations, and perinatal mortality. Other studies,21, 26 however, have been unable to demonstrate an increase in the rates of perinatal mortality, preeclampsia, preterm labor, or cesarean delivery.

Management of pregnant patients with seizure disorders may be challenging and requires cooperation among the obstetrician, perinatalo- gist, neurologist, and patient. The effects of epilepsy on pregnancy, the effects of antiepileptic medication on both mother and fetus, and the changes in pharmacokinetics of antiseizure medication during pregnancy require a multidisciplinary team approach to optimize outcome. Preconceptionally, one can evaluate the maternal neurologic status and explore the need for continued therapy. If ongoing anticonvulsive treatment is deemed necessary, the most appropriate medication should be used, the lowest effective daily dose should be determined, and the medication should be administered in divided doses. Discontinuation of an anticonvulsive medication should only be considered prior to pregnancy. Supplemental folate administration may minimize the risk of anomalies, primarily neural tube defects. Fortunately, despite the risks, most women with seizure disorders will experience an uneventful pregnancy and a normal outcome.

ANTICONVULSIVE THERAPY: PRECONCEPTIONAL CONSIDERATIONS

Epileptic patients seen preconceptionally should be counseled regarding the risk of seizures and the risk of anticonvulsants with pregnancy. All anticonvulsants have been associated with an increased risk of fetal malformation^.^, 7, 24 The literature remains contradictory when examining the association of specific therapies with malformations. An- dermann? in a preliminary report of 983 pregnant patients, found an overall 14.3% incidence of malformations associated with antiseizure medication. He reported malformation rates for specific anticonvulsants. The risk was 14.3% for those taking primidone, 11.1% for valproate, 9.1% for phenytoin, 5.7% for carbamazepine, and 5.1% for phenobarbital. Other investigators have found an association of polytherapy with congenital malformation^.^^, = A recent study,3O however, could not confirm an increased risk of anomalies in mothers receiving polytherapy compared to those taking a single agent. Nevertheless, most investigators agree that monotherapy is preferred if reliable seizure control can be obtained.

Often patients continue medication for many years without reassess- ment of the need for continued therapy. If a patient has been seizure-free for 2 to 5 years, one may consider planned withdrawal from anticonvulsant medication. Discontinuation or withdrawal is usually

MATERNAL AND FETAL IMPLICATIONS OF ANTICONWLSIVE THERAPY 525

accomplished over a 1 to 3 month period. As many as 50% of patients will relapse and require reinstitution of antiseizure medication. With- drawal of antiepileptics should only be attempted prior to pregnancy and under the supervision of a neurologist. The patient should refrain from driving during the withdrawal period. If the patient is on multiple anticonvulsants, consideration should be given to serial withdrawal of anticonvulsants over several months to attain a monotherapeutic regi- men prior to conception.

Despite the probability of an increased risk of fetal anomalies with anticonvulsants, seizure control prior to pregnancy is imperative. Mater- nal seizures during pregnancy are associated with an increased risk of miscarriage, preterm labor, intracranial hemorrhage, and possible developmental or learning diffi~ulties.~~ Increased seizure frequency during pregnancy is related to poor control prior to conception and is clearly associated with adverse perinatal outcome.

When it is necessary to initiate or change therapy in a patient planning pregnancy, choosing the most appropriate anticonvulsive agent is often challenging. There are inherent risks with virtually all known antiseizure medications; therefore, one must choose the most effective therapy based on the type of seizure disorder. If alternative therapies are effective, valproic acid should be avoided. Otherwise, no specific treatment can be recommended for pregnancy.

Patients should be encouraged to take folate supplementation to prevent neural tube defects. Neural tube defects have been most commonly associated with carbamazepine (1%) and valproate (1y0 to 2%). The risk may also be increased with other anticonvulsants. Some au- t h o r ~ ~ ~ recommend 4 mg daily during the preconception period and the first 3 months of pregnancy. The Centers for Disease Control* recommends this dose for patients who have a history of a previous child with a neural tube defect. The recommended dose for all others is 0.4 mg daily. Until further data are available, it would seem prudent to administer the larger dose preconceptionally and during the first trimester to patients taking carbamazepine and valproate.

Some investigators do not recommend high dose folate. Yerby et a1& found no difference in the incidence of major malformations between infants of patients with folate deficiency and infants of controls with normal folate levels. Increasing folate ingestion may stimulate hepatic microsomal enzymes and thus increase clearance of anticonvulsants and other medications. If folate supplementation is initiated, anticonvulsant levels should be monitored.

Patients should also be counseled that the efficacy of oral contraceptives may be altered by anticonvulsants, which themselves stimulate microsomal enzymes. Patients on low dose oral contraceptives may be at increased risk for breakthrough bleeding or unplanned pregnancyP These effects appear to be associated with carbamazepine, phenobarbital, and phenytoin, but not with valproate or benzodiazepines. The Ameri- can College of Obstetricians and Gynecologists in 1990 recommended

526 ELLER et a1

oral contraceptives containing 50 pg of estrogen for use in epileptic women taking anticonvulsants.2

Fertility rates may be lower in patients with epi lep~y.~ However, most are able to conceive without difficulty and infertility evaluation should be reserved for those who demonstrate difficulty achieving pregnancy.

Anticonvulsants are also known to interfere with the conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol, the active form of vitamin D. Therefore, it is important that these patients take prenatal vitamins containing vitamin D.

Many epileptic mothers are concerned with the risk to the child of developing a seizure disorder. Children of women who do not have a seizure disorder have a 0.5% to 1% risk of developing epilepsy. This risk increases approximately fourfold for the children of mothers with epilep~y.~ There does not appear to be an increased risk of epilepsy when the father has a seizure disorder.

EFFECTS OF PREGNANCY ON ANTICONVULSANT THERAPY

Multiple factors during pregnancy can dramatically affect the serum levels of anticonvulsant medications. These factors include altered protein binding, delayed gastric emptying, nausea and vomiting of pregnancy, changes in intravascular volume, and estrogen stimulation of the hepatic microsomal oxidative enzymes. Furthermore, increased intake of calcium through supplementation or antacids may bind to the drug and alter their levels.

While total levels of certain anticonvulsives such as phenytoin (90% protein bound), carbamazepine (76% protein bound), and phenobarbital (variable protein binding) are decreased, levels of the active nonprotein bound drug are actually increased in pregnancy. Therefore, it remains controversial whether total levels should be measured at all during pregnancy unless the patient displays signs of toxicity or seizure activity. Some authors'O suggest measuring serum levels only in women who are not controlled using standard empirical doses and in women suspected of being noncompliant or unable to tolerate their medications beause of nausea and vomiting. Lander and Eadie31 reported that seizure control was not improved by routine serum monitoring. Other investigators recommend routine monitoring of serum levels. The American College of Obstetricians and Gynecologists3 suggests monitoring drug levels in addition to evaluating the patient's clinical condition. While some advo- cate the measurement of free drug levels during pregnancy, these levels currently are not widely available and are therefore impractical.1°

EFFECTS OF ANTICONVULSANT MEDICATIONS ON THE FETUS

Seizure disorders not being managed with anticonvulsant therapy are associated with an increase in the rate of congenital malformations.

MATERNAL AND FETAL IMPLICATIONS OF ANTICONWLSIVE THERAPY 527

Anticonvulsants appear to amplify further the risk of malformations. The risk of a fetal malformation in those taking a single anticonvulsant medication appears to be in the 6% to 8% range, or a two- to threefold increase over the general population. The American College of Obstetri- cians and Gynecologists3 describes the specific potential fetal and neonatal effects of the most commonly prescribed anticonvulsants in Table 1. Many minor anomalies, such as facial (rotated ears, depressed nasal bridge, short nose, elongated upper lip) and hand (nail hypoplasia) abnormalities resolve with age.30

The medical literature is replete with studies reporting congenital malformations in infants of mothers taking anticonvulsant medications. Unfortunately, each study reports something somewhat different. Vary- ing reports have found different anticonvulsant medications to have the highest teratogenic potential, while other studies have found only a weak association of these medications with teratogenesis.

Other discrepancies found in the literature include discussions of specific anomalies such as facial clefting. Friis and colleag~es'~ reported a relative risk of facial clefting in untreated epileptic mothers of 2.7, while infants of mothers treated with anticonvulsants were 4.7 times more likely to have a child with facial clefting. These facial clefts were sometimes accompanied by cleft palate. Isolated cleft palate was not associated with epilepsy. Kelly and colleaguesz8 reported that facial clefting has a multifactorial inheritance pattern reflecting a combination of genetic and environmental factors and suggesting a lesser role of anticonvulsant medications. Other investigators, however,2O found no evidence of a familial association between epilepsy and clefting disorders.

A specific fetal hydantoin syndrome has been described, consisting of growth and performance delay, cranial and facial abnormalities, and limb anomalies. Hanson and SmithI9 first reported this association in 1975. Others have reported that 10% to 30% of infants born to mothers

Table 1. POTENTIAL TOXIC EFFECTS OF COMMONLY USED ANTICONVULSANTS

Characteristic Potential Medication Maternal Effects FetaVNeonatal Effects

Carbamazepine Drowsiness, leukopenia, ataxia, mild Facial dysmorphisms, neural tube hepatotoxicity defects, hypoplasia of distal

Phenobarbital Drowsiness, ataxia Neonatal withdrawal, neonatal

Phenytoin Nystagmus, ataxia, hirsutism, gingival Facial clefting, hypoplasia of distal

Primidone Drowsiness, ataxia, nausea Neonatal withdrawal, neonatal

Vaiproic acid Ataxia, drowsiness, alopecia, Facial dysmorphisms, neural tube hepatotoxicity, thrombocytopenia defects

phalanges

coagulopathy

phalanges, hypertelorism, neonatal coagulopathy

coagulopathy

hyperplasia, megaloblastic anemia

From American College of Obstetricians and Gynecologists: Seizure disorders in pregnancy. ACOG Educational Bulletin 231:2, 1996; with permission.

528 ELLER et a1

on phenytoin display some aspects of this syndrome.*6, l8 Gaily and coworkers,16 however, found no evidence of the full syndrome in 82 women exposed in utero to phenytoin. He conceded that some of the patients displayed some aspects of the syndrome, including hypertelorism and hypoplasia of the distal phalanges.

Carbamazepine was formerly the clear drug of choice in pregnancy; however, there is an approximate 1% incidence of spina bifida in infants born to women treated with carbamazepine during pregnancy.37 Jones and colleagues25 also reported a pattern of malformations in children of women taking carbamazepine, including cranial facial defects, fingernail hypoplasia, and developmental delay. One hypothesis as to the cause of this pattern of anomalies, which is similar to that found with phenytoin, involves the metabolism of these drugs through the arene oxide pathway. In fetuses with low levels of epoxide hydrolase, there may be an increase in potentially toxic epoxide intermediaries. Finnell and col- league~'~ described this pathway with phenytoin, phenobarbital, and, to a lesser extent, with carbamazepine. Carbamazepine also has been investigated for long-term effects. A recent study comparing children with and without histories of carbamazepine exposure did not demonstrate any adverse neurobehavioral

Valproic acid is also associated with a 1% to 2% risk of spina bifida in infants exposed in the first possibly as a result of alteration in embryonic folate metab~l ism.~~ Most cases of neural tube defects are associated with either valproate or carbamazepine. These neural tube defects are nearly always lumbosacral, unlike the general population in which the distribution of the level of neural tube defect is uniform. A fetal valproate syndrome has been describedz3 which includes brachy- cephaly with a high forehead; shallow orbits; ocular hypertelorism; small nose and mouth; low set, posteriorly rotated ears; long overlapping fingers and toes; and hyperconvex fingernails.

Phenobarbital has been recently associated with decreased cognitive performance when 114 phenobarbital-exposed men age 22 or older were compared with nonexposed controls.36 Other antiepileptic medications have been implicated in causing psychomotor delays or mental retardation; however, this issue is difficult to study as discussed by Dessens et al.13 Many other factors can contribute to psychomotor development in children of mothers with epilepsy, including the frequency of seizures during pregnancy, a nonoptimal psychosocial environment, and inher- ited neurologic di~0rders.l~ Phenobarbital has also been associated with some withdrawal symptoms of the infant after delivery. These symptoms may begin approximately 1 week after birth and usually last 1 to 2 weeks, characterized typically by irritability, but symptoms may be more severe.I2

MANAGEMENT DURING PREGNANCY

As previously described, the measuring of drug levels during pregnancy remains controversial. The American College of Obstetrics and

MATERNAL AND FETAL IMPLICATIONS OF ANTICONVULSIVE THERAPY 529

Gynecology3 recommends monitoring trough drug levels each trimester in patients who are well controlled. Care should be taken not to measure levels too soon after adjusting dosages. It takes four to five half-lives before a steady state is reached. The half-lives of the anticonvulsants range from 8 hours for primidone to approximately 100 hours for phenobarbital. Table 2 illustrates therapeutic levels, nonpregnant dosages, and half-lives of commonly prescribed anticonvulsants. Because levels may not be completely reliable during pregnancy, patients must be followed clinically for signs of toxicity. These signs may include ataxia, drowsiness, hepatotoxicity, anemia, or thrombocytopenia. If the patient displays any signs of toxicity, the dosage should be decreased or the medication discontinued and serum levels evaluated. Nonpharmacologic interventions such as avoiding high levels of stress and sleep deprivation will also help the patient to remain seizure-free during the pregnancy.

Patients should be properly screened for fetal neural tube defects, including maternal serum alpha-fetoprotein levels at 15 to 20 weeks, comprehensive ultrasonography at 16 to 20 weeks, and amniocentesis, if indicated. Special attention should also be given to the evaluation of the fetal heart and face. Facial clefting is more easily detected between 22 and 24 weeks.

The risk for fetal growth retardation is mildly increased. Serial sonography in the third trimester may be considered if one is not reassured by the usual clinical parameters of maternal weight gain and advancement of the fundal height. Antepartum fetal surveillance should be considered if fetal growth retardation is detected. If growth is appropriate and maternal reporting of fetal activity is reassuring, fetal heart rate assessment can be reserved for the usual obstetrical indications.

Phenobarbital, phenytoin, and primidone have been associated with neonatal hemorrhage because of a decrease in vitamin K-dependent clotting factors (11, VII, IX, X). Bleyer and SkinneI.6 thus recommend that such infants be given 1 mg of vitamin K intramuscularly at birth. The administration of a 10 mg oral daily supplement of vitamin K in the last month of pregnancy may be helpful in preventing neonatal hemorrhage,ll but this has not been definitively proven.

MANAGEMENT DURING LABOR AND DELIVERY

Patients should continue their anticonvulsant medication throughout labor. If they are unable to tolerate the medication orally, their anticonvulsant levels should be measured. If the patient is taking phenytoin, she can receive her usual daily dose intravenously. In patients taking phenobarbital, a 60 to 90 mg intramuscular dose is usually adequate. If the patient needs an alternative medication during labor, phenytoin can be given in a loading dose of 10 to 15 mg per kg intravenously at a rate no faster than 50 mg per minute. Cardiac activity should be monitored because of a small risk of dysrhythmias if the medication is

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administered too rapidly. Benzodiazepines can also be used for seizures; however, neonatal clearance is delayed, increasing the risk of respiratory depression. One must also monitor for maternal apnea.@

If the patient experiences new onset seizures in the third trimester, the most likely cause is eclampsia. Magnesium sulfate continues to be the most appropriate therapy for the prevention and treatment of eclampsia.4O Magnesium sulfate is commonly administered in a 4 to 6 g loading dose, followed by a 2 g per hour infusion. A recent multicenter randomized clinical trial confirmed that magnesium sulfate is superior to phenytoin in the treatment and prevention of eclampsia.33

Status epilepticus is an obstetric and neurologic emergency. Consul- tation with an anesthesiologist and neurologist is indicated. Intravenous phenytoin is the initial drug of choice, using the loading dose previously described. Phenobarbital and diazepam may be used as alternatives. The patient should be placed on her left side, if practical, and oxygen should be administered. A tongue blade should never be forced into the patient's mouth because this may further obstruct the airway. Fetal heart rate monitoring should be evaluated only after adequate control of maternal seizure activity is established.

POSTPARTUM

Anticonvulsant levels may rise postpartum. Serum levels should be evaluated approximately 1 week after delivery to guide continued therapy.

Carbamazepine, phenytoin, and valproic acid have been classified as compatible with breast feeding.', 33 The infant should be monitored for excessive sedation. If breast feeding is abruptly discontinued, some infants may experience minor withdrawal symptoms. These symptoms usually occur in the first few days and may require a low dose of phenobarbital and gradual w i t h d r a ~ a l . ~ ~ Concerns over these issues lead to a lower incidence of breast feeding initiation in epileptics when compared to Physicians are also less likely to recommend breast feeding in epileptic women even though published guidelines suggest compatibility.22

SUMMARY

A team approach with close communication among the obstetrician, neurologist, pediatrician, and patient will result in an uneventful pregnancy in most epileptic women. Women should be counseled regarding the greater than 90% likelihood of a favorable outcome. Maternal and neonatal outcome can be optimized by carefully evaluating the clinical necessity of anticonvulsant medications preconceptionally. One can then prescribe an appropriate choice based on seizure type and history of response, with a goal of achieving monotherapy at the lowest effective

532 ELLER et a1

dose. Nonpharmacologic intervention, such as avoiding high levels of stress and sleep deprivation, will also help the patient to remain seizure- free during the pregnancy. In addition, folic acid and vitamin K can help optimize neonatal outcome.

In short, most epileptic women will experience a normal pregnancy, labor, and delivery of a healthy baby and can breastfeed if desired. Although the incidence of congenital malformations with any anticonvulsant is increased, the actual incidence remains relatively low. Despite the shortcomings and risks of anticonvulsants, adequate therapy is clearly preferable to uncontrolled seizure activity. Women should be encouraged to optimize their anticonvulsive therapy prior to pregnancy, usually resulting in adequate therapy throughout the pregnancy and postpartum, with a happy and healthy outcome for mother and infant.

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maternal and fetal implications of anticonvulsive therapy during pregnancy

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