Pregnancy in the Woman with Epilepsy: Maternal and Fetal Outcomes

Page B. Pennell, M.D.1

ABSTRACT

Pregnancy in women with epilepsy is associated with increased obstetric risks and increased adverse neonatal outcomes. Prior to conception, folic acid should be administered and the antiepileptic drug (AED) regimen should be optimized. Effective control of maternal seizures with the least risk to the fetus is the goal, preferably using AED monotherapy. Periodic monitoring of total and free AED levels is recommended. The fetal anticonvulsant syndrome has been described with all of the AEDs and includes major malformations, minor anomalies, microcephaly, cognitive impairment, intrauterine growth retardation, and infant mortality. The most common major malformations are cleft lip/palate, heart defects, and neural tube defects. Prenatal screening should be offered. Supplemental vitamin K1 should be given to the mother and newborn to prevent neonatal hemorrhagic disorder. Careful planning and management of any pregnancy in women with epilepsy are essential to increase the likelihood of a healthy outcome for the mother and infant.
KEYWORDS: Epilepsy, women, pregnancy, anticonvulsants, teratogenesis

Objectives: On completion of this article the reader will be able to outline the current principles in the management of women with epilepsy during pregnancy. Accreditation: The Indiana University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Credit: The Indiana University School of Medicine designates this educational activity for a maximum of 1.0 hours in category one credit toward the AMA Physicians Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity. Disclosure: Statements have been obtained regarding the authors relationships with financial supporters of this activity. There is no apparent conflict of interest related to the context of participation of the author of this article.

PREGNANCY IN WOMEN WITH EPILEPSY Approximately 1.1 million women with epilepsy are of childbearing age in the United States1 and give birth to over 20,000 babies each year. The vast majority of these pregnancies are uncomplicated, but there are increased obstetric risks and increased adverse neonatal outcomes compared with the general population. Careful planning and management of any pregnancy in a woman with epi-

lepsy are essential to minimize these risks. The reduction of these risks begins with preconceptional planning. Approximately 50% of pregnancies are unplanned in the United States, and because of higher oral contraceptive failure for many women with epilepsy,24 their rate of unplanned pregnancies may be even greater. Physicians treating women with epilepsy are often not appropriately knowledgeable about issues of pregnancy and

Epilepsy; Co-Editors in Chief, Robert M. Pascuzzi, M.D., Karen L. Roos, M.D.; Guest Editor, Martha J. Morrell, M.D. Seminars in Neurology, Volume 22, Number 3, 2002. Address for correspondence and reprint requests: Page B. Pennell, M.D., Emory University School of Medicine, WMB 6000, 1639 Pierce Drive, Atlanta, GA 30322. 1Emory Epilepsy Monitoring Unit, Emory University School of Medicine, Atlanta, Georgia. Copyright 2002 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662. 0271-8235,p;2002,22,03,299,308,ftx,en;sin00206x.

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epilepsy,5,6 and current recommended guidelines4 regarding preconceptional counseling are often not being followed in the United States or the United Kingdom.5,79 The initial visit between the physician and a woman with epilepsy of childbearing age should include a discussion about family planning. Topics should include effective birth control, the importance of planned pregnancies with antiepileptic drug (AED) optimization and folate supplementation prior to conception, obstetrical complications, and teratogenicity of AEDs versus the risks of seizures during pregnancy. The goal is effective control of maternal seizures with the least risk to the fetus.

SEIZURES DURING PREGNANCY The effect of pregnancy on seizure frequency is variable and unpredictable between patients. According to recent studies, approximately 20 to 33% of patients have an increase in their seizures, 7 to 25% a decrease in seizures, and 50 to 83% no significant change.1012 Unfortunately, which route an individuals course will take is impossible to know and cannot be predicted on the basis of factors such as age, ethnic origin, number of pregnancies, seizure type(s), AED(s), and seizure frequency during a previous pregnancy. Pregnancy is associated with several physiologic and psychologic changes that can alter seizure frequency, including changes in sex hormone concentrations, changes in AED metabolism, sleep deprivation, and new stresses. One study demonstrated that sleep deprivation or noncompliance played a clear role in up to 70% of women with an increase in seizures during pregnancy,13 yet these two factors are largely modifiable. It is important to inquire about both sleep patterns and compliance in pregnant patients with epilepsy. Sleep deprivation can be due to physical discomforts, movements of the fetus, and nocturia. Marital and financial stress and personal doubts and concerns can contribute to sleep deprivation as well as cause a more direct increase in likelihood of seizure occurrence. Noncompliance with medications is common during pregnancy and is in large part due to the strong message that any drugs during pregnancy are harmful to the fetus. Teratogenic effects of AEDs are well described, but risks to the fetus are often exaggerated or misrepresented. Proper education about the risks of AEDs versus the risks of seizures can be very helpful in ensuring compliance during pregnancy. During pregnancy, the risk of seizures to the fetus is important and should be discussed thoroughly with the patient and other family members. Generalized tonicclonic seizures (GTCSs) can cause maternal and fetal hypoxia and acidosis.1,14 After a single GTCS, fetal intracranial hemorrhages, miscarriages, and stillbirths have been reported.15 Status epilepticus is an uncommon complication of pregnancy, but when it does occur it carries

a high maternal and fetal mortality rate. In one series of 29 cases, there were 9 maternal deaths and 14 infant deaths.16 A single brief tonic-clonic seizure has been shown to cause depression of the fetal heart rate for more than 20 minutes,17 and longer or repetitive tonicclonic seizures are incrementally more hazardous to the fetus as well as the mother. It is not as clear what the effects of nonconvulsive seizures are on the developing fetus. One study demonstrated that maternal seizures of all types in the first trimester were associated with a higher malformation rate of 12.3% compared with a malformation rate of 4% for infants of epileptic mothers not exposed to seizures during the first trimester.18 No significant differences in malformation rates have been observed between offspring of women with different types of epilepsy.18,19 In one case report, a complex partial seizure during labor was associated with a strong, prolonged uterine contraction with fetal heart rate deceleration for 3.5 minutes.20 Many types of seizures can cause trauma, which can result in ruptured fetal membranes with an increased risk of infection, premature labor, and even fetal death.21 Abruptio placentae occurs after 1 to 5% of minor and 20 to 50% of major blunt injuries.22 Restrictions from driving and climbing heights should be reinforced with each patient with special emphasis on the risk to the fetus of a seemingly minor injury.

ANTIEPILEPTIC DRUG MANAGEMENT Management of AEDs during pregnancy can be complex. Plasma AED concentrations decrease significantly during pregnancy despite steady or increasing doses and tend to rise again postpartum.12,2325 A similar but even exaggerated effect is seen with lamotrigine (LTG).23,24,26 The changes in AED levels during pregnancy can vary widely and are not predictable for the individual on the basis of reported group changes or total levels only for moderately to highly protein-bound AEDs. Although the ratio of free to bound drug increases during pregnancy, the amount of free AED still usually declines.1,12 The optimal approach to monitoring AED levels during pregnancy is one that measures free levels of any AED that is highly or moderately protein bound.4 Total levels are sufficient for AEDs that are minimally protein bound. The ideal AED (free) level needs to be established for each individual patient prior to conception and should be the level at which seizure control is the best possible for that patient without debilitating side effects. Levels should be obtained at least at baseline prior to conception, repeated at the beginning of each trimester, and obtained again in the last 4 weeks of pregnancy.4 Some authors recommend monthly monitoring, given the possibility of rapid and unpredictable decreases in AED levels in an individual patient.12,23,27 The frequency

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of monitoring levels needs to be tailored to each situation, including increased monitoring for worsening seizure control, adverse effects, and compliance issues. Several factors contribute to the decline in AED levels during pregnancy.21 Impaired absorption is one cause, although relatively uncommon. The volume of distribution increases throughout pregnancy, but this would not account for the relatively lesser reduction in free levels compared with total levels. The most important contributing mechanisms are thought to be decreased albumin concentration, reduced plasma protein binding, and increased drug clearance. The decline in albumin concentration and plasma protein binding creates an increased percentage of unbound AED, which in turn provides an increased proportion of the drug available for metabolic degradation. In addition, the increased sex steroid hormone levels may cause an induction of the hepatic microsomal enzymes and contribute to the increased clearance of AEDs.

with epilepsy1,29 and is even more prevalent in infants exposed to polytherapy.33 Minor anomalies are defined as structural deviations from the norm that do not constitute a threat to health. Major malformations are defined as abnormalities of an essential anatomical structure present at birth that interfere significantly with function or require major intervention, or both.

Minor Anomalies Minor anomalies affect 6 to 20% of infants born to women with epilepsy, which is an approximately twofold increased rate compared with the general population.34 Minor anomalies include distal digital and nail hypoplasia, and the craniofacial anomalies including ocular hypertelorism, broad nasal bridge, short upturned nose, altered lips, epicanthal folds, abnormal ears, and low hairline.21,34 Many of the craniofacial anomalies are outgrown by age 5 years.

OBSTETRICAL COMPLICATIONS Women with epilepsy do have an increased risk of certain obstetrical complications. There is an approximately twofold increased risk of vaginal bleeding, anemia, hyperemesis gravidarum, abruptio placentae, eclampsia, premature rupture of membranes, induced labor, and cesarean section.1 Weak uterine contractions have been described in women taking AEDs, which may account for the twofold increased use of interventions during labor and delivery including induction, mechanical rupture of membranes, forceps or vacuum assistance, and cesarean sections.28

TERATOGENESIS Offspring of women with epilepsy are at an increased risk for intrauterine growth retardation, major congenital malformations, minor anomalies, microcephaly, cognitive dysfunction, and infant mortality.1,2931 The term fetal anticonvulsant syndrome is used to include various combinations of these findings and has been described with virtually all of the AEDs.32 Intrauterine growth retardation results in low birth weight (<2500 g) in 7 to 10% of infants born to women

Major Malformations Major malformations occur at a rate of 2 to 3% in the general population; reported rates in offspring of women with epilepsy range from 1.25 to 11.5%, with the combined estimates yielding a rate of 4 to 6%4,15,30,34,35 Major malformations (Table 1) associated with AEDs include congenital heart disease, cleft lip/palate, and neural tube defects.21,34 Urogenital defects also occur at a higher rate of 1.7% of newborns and commonly involve glandular hypospadias. The congenital heart defects include atrial septal defect, ventricular septal defect, tetralogy of Fallot, coarctation of the aorta, patent ductus arteriosus, and pulmonary stenosis. The neural tube defects usually consist of spina bifida and not anencephaly but tend to be severe open defects frequently complicated by hydrocephaly and other midline defects.36 Carbamazepine (CBZ) and valproate (VPA) are selectively associated with neural tube defects at a rate of 10 and 20 times that in the general population, respectively.37,38 One analysis of pooled data from five prospective studies suggested that the absolute risk with VPA monotherapy may be as high as 3.8% for neural tube defects and that offspring of women receiving

Table 1 Major Malformations in Infants of Women with Epilepsy

Malformation Congenital heart Cleft lip/palate Neural tube defect General Population 0.5% 0.15% 0.1% Infants of Women with Epilepsy 1.52% 1.4% 12% (VPA) 0.51% (CBZ)

CBZ, carbamazepine; VPA, valproate.

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VPA at >1000 mg/day were at particularly increased risk.19 More recent collaborative studies have supported the significant dose-response relationship for VPA, with cutoff values of 1000 mg/day and 70 g/mL.35,39,40

Mortality Fetal death (fetal loss at greater than 20 weeks gestational age) is another increased risk for women with epilepsy. Reported stillbirth rates vary between 1.3 and 14.0% compared with rates of 1.2 to 7.8% for women without epilepsy.1 Perinatal death rates are also up to twofold higher for women with epilepsy (1.3 to 7.8%) compared with controls (1.0 to 3.9%).1 Spontaneous abortions (<20 weeks gestational age) may also occur more frequently, although figures from different studies vary considerably.4,30,41

Neonatal Vitamin K Deficiency Offspring of women with epilepsy are also at an increased risk for a hemorrhagic disorder during the neonatal period because of deficiency of vitamin Kdependent clotting factors.42,43 AEDs that have been reported to induce a vitamin K deficiency in the fetus include CBZ, phenytoin, phenobarbital, ethosuximide, vigabatrin, primidone, diazepam, mephobarbital, and amobarbital.1,44 The mechanism is unclear. Infant mortality from this bleeding disorder is greater than 30% and is usually due to bleeding in the abdominal and pleural cavities leading to shock. Prophylactic treatment consists of vitamin K1 administered orally as 10 mg to the mother during the last month of pregnancy and 1 mg administered intramuscularly or intravenously to the newborn at birth.4 If the women has not received supplemental vitamin K1 prior to labor onset, she should receive parenteral vitamin K1. If two of the neonates coagulation factors fall below 5% of the normal values, intravenous fresh frozen plasma needs to be administered.30

VPA in utero.49 Compared with children of women with epilepsy receiving no AEDs, the odds ratios for additional educational needs were 1.49 for all children exposed to AEDs in utero and 3.4 for children exposed to VPA monotherapy. Autism was also reported by one research group in six patients with fetal valproate syndrome.50 Other studies of particular AEDs have reported that the childs level of IQ is negatively correlated with in utero exposure to primidone,51 phenobarbital,52 phenytoin,53 and polytherapy.51 Exposure during the last trimester may actually be the most detrimental.52 Microcephaly has been associated with in utero AED exposure.1,29 One multicenter, prospective study found that the risk for small head circumference was increased for polytherapy, phenobarbital, and primidone.54 The risk of epilepsy in children of women with epilepsy is higher (relative risk of 3.2) than in controls.55 Children of fathers with epilepsy do not demonstrate the same degree of increased risk. This may be related to the finding that the occurrence of maternal seizures during pregnancy, but not AED use, confers an increased risk of seizures in the offspring (relative risk 2.4).56

NEURODEVELOPMENTAL OUTCOME Results of studies investigating cognitive outcome have been as varied as the protocols employed, but the majority of studies reported an increased risk of mental deficiency, affecting 1.4 to 6% of children of women with epilepsy compared with 1% of controls.1,45 Associations between cognitive impairment and a variety of factors have been reported, including in utero AED exposure, seizures,46 a high number of minor anomalies, major malformations, decreased maternal education, impaired maternal-child relations, and maternal partial seizure disorder.47 Verbal scores on neuropsychometric measures may be selectively more involved.30,48 A retrospective survey suggested an especially high risk for the neurodevelopment of children exposed to

POTENTIAL MECHANISMS The causes of the anticonvulsant embryopathy are probably multifactorial. However, studies have supported the anticonvulsant drugs as the most significant offending factor, more so than actual traits carried by mothers with epilepsy, environmental factors, or possibly even seizures during pregnancy.40,57,58 A research group reported that infants whose mothers had a history of epilepsy but took no AEDs during pregnancy did not have a higher frequency of these abnormalities than control infants,57 including abnormalities of cognitive function.58 One criticism, however, is that the group of women with a history of epilepsy receiving no AEDs is not the same as the group of women requiring AED use during pregnancy. The fetal anticonvulsant syndrome has been described with virtually all of the AEDs,32 with no vast differences in teratogenic risk59 with the exception of VPA and CBZ for neural tube defects. It is clear that the risk for the development of the fetal anticonvulsant syndrome increases with the number of AEDs that the fetus is exposed to during pregnancy, especially during the first trimester. Previous studies have reported major malformations in 25% of infants of women receiving four or more AEDs.18 The American Academy of Neurology practice parameter summary statement in 1998 recommended that the AED most appropriate for seizure type and the drug producing optimal control with least side effects remains the AED of choice for women with epilepsy.4 If a woman is at high risk for bearing a child with a neural tube defect because of her personal or family history, then VPA and CBZ should be chosen only if other AEDs are ineffective.

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Ongoing prospective pregnancy registries hope to provide better information about the relative risks of each AED. The North American AED Pregnancy Registry has released its first outcome data for 40 pregnancies involving phenobarbital monotherapy: infants exposed to phenobarbital had a significantly increased risk of major malformations (12.5%) compared with the unexposed newborn infants (2.24%).60 Malformations identified included heart defects (3), cleft lip and palate (3), and eye anomaly (1). This information is especially helpful in light of the fact that obstetricians have traditionally considered phenobarbital one of the safest AEDs during pregnancy. Although AEDs do carry teratogenic risks, for most women with epilepsy withdrawal of all AEDs prior to pregnancy is not a realistic option. A decision to undergo a trial of withdrawing AEDs prior to a planned pregnancy should be based upon the same principles used for AED withdrawal in any person with epilepsy. The taper should be completed at least 6 months prior to planned conception to provide some reassurance that seizures are not going to recur.4 If a woman with epilepsy is in the more prevalent category of needing AEDs for seizure control, monotherapy at the lowest effective dose should be employed. If large daily doses are needed, frequent smaller doses may be helpful to avoid high peak levels. The teratogenic effects of most of the relatively newer AEDs are unknown at this time. Information from the International Lamotrigine Pregnancy Registry61 indicates that major malformations occurred in 4.7% of the prospectively collected cases with first-trimester exposure (n = 275 outcomes) but in only 2.5% of infants exposed to lamotrigine monotherapy during the first trimester (n = 120 outcomes). Human birth defects have been reported with oxcarbazepine, topiramate, and zonisamide, but accurate denominators are not available to calculate rates. Rodent studies have shown limb agenesis with topiramate, a common finding with other carbonic anhydrase inhibitors. Teratogenicity by AEDs is probably mediated by several mechanisms, including antifolate effects and reactive intermediates of AEDs. Phenytoin, carbamazepine, phenobarbital, and primidone are associated with folate deficiency, and valproic acid and lamotrigine interfere with folate metabolism.15,62,63 The beneficial effects of folic acid supplementation are clear for lowering the risk of neural tube defects.64,65 It may also reduce the risks of other major malformations.66 The maximal benefit of folate is achieved, however, only with folate supplementation beginning prior to and continuing after conception. Because of this as well as the high rates of unplanned pregnancies and of late contact with a physician, all women with epilepsy and childbearing potential should receive folate supplementation of at least 0.4 mg/day.4 Some authors even recommend folate supple-

mentation of as much as 5 mg/day.67 The American College of Obstetricians and Gynecologists recommends that women with epilepsy who are treated with VPA or CBZ receive folic acid at 4 mg/day.68 Reactive intermediates of AEDs include free radicals (via peroxidation reactions) and oxidative metabolites, both of which may contribute to AED teratogenesis.69 AED polytherapy may especially promote epoxide production and inhibit epoxide metabolism via epoxide hydrolase. Fetuses may benefit from AEDs that lack epoxide intermediates (such as oxcarbazepine and gabapentin) and avoidance of polytherapy.

PRENATAL SCREENING Prenatal screening should be offered to all women with epilepsy to detect any fetal major malformations. Neural tube defects should be screened for with a combination of maternal serum -fetoprotein at 15 to 22 weeks and expert, targeted level II (structural) ultrasonography at 16 to 20 weeks.4 When performed together, these tests can identify over 95% of fetuses with open neural tube defects.70,71 Amniocentesis (with measurements of amniotic fluid -fetoprotein and acetylcholinesterase) should be offered if these tests are equivocal, increasing the sensitivity for detection of neural tube defects to greater than 99%. Detailed sonographic imaging of the fetal heart can be performed at 18 to 20 weeks of gestation and may be followed by fetal echocardiography if visualization is suboptimal. This approach can detect up to 85% of prenatally diagnosable cardiac abnormalities.71 Careful imaging of the fetal face for cleft lip and palate can also be performed at 18 to 20 weeks gestational age, although the accuracy of prenatal diagnosis is less established.71 If the patients weight gain and fundal growth do not appear appropriate, serial sonography should be performed to assess fetal size and amniotic fluid.72

LABOR AND DELIVERY Although there is an approximately twofold increased use of interventions during labor and delivery,28 most women with epilepsy have a safe vaginal delivery. GTCSs occur during labor in 1 to 2% of women with epilepsy and in another 1 to 2% during the first 24 hours after delivery.59 Sleep deprivation may provoke seizures, and obstetric anesthesia may be used to allow some rest prior to delivery if sleep deprivation has been prolonged. During a prolonged labor, oral absorption of AEDs may be erratic and any emesis confounds the problem. Phenobarbital, (fos)phenytoin, and valproic acid can be given intravenously at the same maintenance dosage. Convulsive seizures and repeated seizures during labor should be treated promptly with parenteral lorazepam or valium.59 Benzodiazepines can cause neonatal depression, decreased heart rate, and maternal apnea if given in large

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doses, and these potential side effects need to be monitored closely. Administration of another, longer acting AED is controversial because of the inhibitory effects on myometrial contractions.59 Status epilepticus or even a single GTCS needs to be treated aggressively because of the high risk to the mother and fetus. Oxygen should be administered to the patient, and she should be placed on her left side to increase uterine blood flow and decrease the risk of maternal aspiration.72 Prompt cesarean section should be performed when repeated GTCS cannot be controlled during labor or when the mother is unable to cooperate during labor because of impaired awareness during repetitive absence or complex partial seizures.59 The analgesic meperidine is best avoided because of its potential to lower the seizure threshold.

must consider the mothers ictal semiology. If she is likely to drop objects she is holding but remain upright, such as with myoclonic seizures or many complex partial seizures, she should use a harness when carrying the baby. If she is likely to fall, a stroller within the house is an even better option. Changing diapers and clothes is best performed on the floor rather than on an elevated changing table. Bathing should never be performed alone, as a brief lapse in attention can result in a fatal drowning. The important role that sleep deprivation plays in exacerbation of seizures needs to be emphasized. Especially if the mother is breast-feeding, sleep deprivation may be unavoidable. The possibility of other adults sharing the burden of nighttime feedings through the use of formula or harvested breast milk should be considered, and the mother should attempt to make up any missed sleep during the infants daytime naps.

POSTPARTUM CARE Serum AED levels rise again after delivery and level off after 8 to 10 weeks. AED levels should be followed closely during the postpartum period.4 Perinatal lethargy, irritability, and feeding difficulties have been attributed to intrauterine exposure to AEDs, especially with barbiturates and benzodiazepines. Breast-feeding with barbiturates or benzodiazepines may prolong sedation and feeding problems, and the newborn needs to be monitored closely. However, most infants of women with epilepsy can breast-feed successfully without complications. The amount of AED excreted into the breast milk is in part based upon the (free) portion that is not protein bound (Table 2).75 The infants serum concentration is determined by this factor as well as the AED elimination half-life in neonates, which is usually more prolonged than that in adults.30,73 The benefits of breast-feeding are believed to outweigh the small risk of adverse effects of AEDs.70,73 The puerperium with its inevitable sleep disruption is often a time of seizure worsening, including seizure recurrence for some women with previously controlled seizures. Extra precautions should be taken during this time.74 Appropriate individualized safety issues

Table 2 Breast Milk to Maternal Plasma Ratio of Common Antiepileptic Drugs (AEDs)
AED CBZ PHT PB PRM VPA LTG Ratio 0.69 0.45 0.40.6 0.72 0.42 0.6

CBZ, carbamazepine; LTG, lamotrigine; PB, phenobarbital; PHT, phenytoin; PRM, primidone; VPA, valproate. Data from Hale.75

SUMMARY OF MANAGEMENT OF EPILEPSY AND PREGNANCY Comprehensive care of women with epilepsy during the reproductive years must include effective preconceptional counseling. The womans AED regimen should be optimized and folate supplementation should be begun prior to pregnancy. A common but erroneous reason to change medications is that the woman presents to the neurologist after she has discovered she is pregnant. In many cases, she is already in or past the critical period of organogenesis (Table 3).76 If a woman with epilepsy presents after conception and is taking a single AED that is effective, her medication should usually not be changed. The teratogenic risk is only increased by exposing the fetus to a second agent during a crossover period of AEDs, and seizures are more likely to occur with any abrupt medication changes. If a woman is receiving polytherapy and is seizure free, it may be possible to switch safely to monotherapy. However, changes in the total and free levels of the remaining drug will need to be monitored closely. Seizure control remains an important goal during pregnancy. Convulsive seizures in particular place the mother and fetus at risk. Nonconvulsive seizures may also be harmful, especially if they involve falling or other forms of trauma. Because each of the major AEDs is teratogenic, the medication that is most effective for the womans epilepsy and seizure type should be prescribed. AED monotherapy is recommended and should be used at the lowest effective dose. If a large daily dose is needed, frequent smaller doses may be helpful to avoid high peak levels. Folate supplementation should begin prior to conception and is crucial during the first 30 days of gestation to protect against neural tube defects. The optimal dosage has not been established for women with epilepsy (WWE), and recommendations vary between 0.4 and 5 mg/day.

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Table 3 Relative Timing and Developmental Pathology of Certain Malformations

Tissues Central nervous system Heart Face Malformations Neural tube defect Ventricular septal defect Cleft lip Cleft maxillary palate Postconceptional Age (days) 28 42 36 70

Data from Moore.76

Prenatal screening can detect major malformations in the first and second trimesters. Vitamin K1 is given as 10 mg/day orally during the last month of pregnancy, followed by 1 mg intramuscularly or intravenously to the newborn.4 With the preceding information and guidelines, most women with epilepsy will have healthy pregnancies without major maternal or fetal complications.

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