Seizure Disorders and Pregnancy
Women's Health & Education Center's ContributionRoughly one out of every 100 pregnancies occurs in a woman with epilepsy. These pregnancies present a unique challenge to obstetricians and neurologists due to the interrelationship of the effects of epilepsy and pregnancy, the variable effects of anti-convulsant medications on mother and fetus, and the changes in pharmacokinetics of these medications during pregnancy. The obstetricians and neurologist should work together prior to conception and throughout the patient's pregnancy to determine the safest and most effective medical therapy. Furthermore, the pediatrician selected by the patient to care for her baby should be included in pre-pregnancy discussions to address the potential increase in congenital malformations, the potential for neonatal sedation with certain medications, and questions concerning breast-feeding. The purpose of this document is to provide the current information on this issue and to offer practical advice on managing patients.Pre-Pregnancy Counseling:Women with seizure disorders should seek care from an obstetrician-gynecologist as soon as they become sexually active. The use of certain anti-epileptic medications may interfere with the action of oral contraceptive agents. Patients taking low-dose oral contraceptives and certain antiepileptic medications may have more breakthrough bleeding and may be at increased risk for unplanned pregnancy. This rapid clearance does not appear to be induced by use of valproate or benzodiazepines (1). Although fertility rates may be lower in patients with epilepsy, most patients with epilepsy are able to conceive without difficulty. Topics to address in pre-pregnancy counseling of women with epilepsy are the possibility that seizures will become more frequent during pregnancy and teratogenic potential of antiepileptic drugs. Importance of good seizure control and adherence to the antiepileptic drug regimen should be stressed upon. Monitor of plasma levels of anti-epileptic drugs should be given to the patients. Pre-conceptional and gestational folate supplementation and vitamin K supplementation are important part of counseling.Effects of Pregnancy on Epilepsy: For some women with epilepsy, changes in the frequency of seizures will occur throughout pregnancy, but the time of greatest risk for seizures is during labor and delivery. In about 48% to 57% of women with seizures disorders the frequency of seizures during pregnancy remains stable. Increase is seen in one quarter to one third, and actually decreases in 9% to 22% (2). Patients with seizure disorders may be treated with single medications or a combination of medicines, based on the type of seizure and side effects. Serum levels of the most frequently used anticonvulsant medications (phenytoin, carbamazepine, and phenobarbitol) can change dramatically during pregnancy, generally decreasing in total concentration as pregnancy progresses. Although total levels fall, the free (active) levels tend to decrease because of a decline in serum albumin and other proteins throughout pregnancy. The drug dosage should be adjusted according to the total serum level and the patient's condition. If drug levels are carefully monitored, pregnancy should have little effect on seizure frequency. Potential toxic effects of commonly used anticonvulsants:
Source: ACOG Educational Bulletin; Number 231.| Medication | Maternal Effects | Characteristic Potential Fetal/Neonatal Effects | | Carbamazepine Oxcarbazepine Levetiracetam | Drowsiness, leukopenia,Ataxia, mild heptotoxicity | Facial dysmorphisms, neural tube defects,Hypoplasia of distal phalanges | | Phenobarbital | Drowsiness, ataxia | Neonatal withdrawal, neonatal coagulopathy | | Phenytoin Gabapentin | Nystagmus, ataxia, hirsutism,Gingival hyperplasia, megaloblastic anemia | Facial clefting, hypoplasia of distal phalanges, hypertelorism, neonatal coagulopathy | | Primidone Tiagabine | Drowsiness, ataxia, nausea | Neonatal withdrawal, neonatal coagulopathy | | Valproic acid | Ataxia, drowsiness, alopecia,Hepatotoxicity, thrombocytopenia | Facial dysmorphisms, neural tube defects |
Effects of Epilepsy on Pregnancy: Most women with seizure disorders who become pregnant will have an uneventful pregnancy with an excellent outcome. Several complications have been reported; these are: preeclampsia, still-birth, depressed Apgar scores, low birth-weight, diminished head circumference. However, studies are reassuring, that, there is no increase in the rates of perinatal mortality, preeclampsia, preterm labor, or cesarean delivery in women with epilepsy. Fetal and Neonatal Effects: Vitamin Deficiencies: all anticonvulsants interfere with folic acid metabolism. Folic acid deficiency during embryogenesis has been associated with neural tube defects and other congenital malformations. Pre-conceptional and during pregnancy the folic acid dose of 4 mg per day is appropriate for the patients taking anticonvulsants. Neonatal hemorrhage due to decreased vitamin K dependent clotting factors (II, VII, IX, X) has occurred in infants born to mothers taking phenobarbital, phenytoin, and primidone. It is recommended these infants be given 1 mg of vitamin K intramuscularly at birth. Some authors recommend prophylactic oral vitamin K during last month of pregnancy. Therapy with phenobarbital, phenytoin and primidone may also result in increased metabolism of vitamin D. Patients should be encouraged to take prenatal vitamins that include an adequate amount of vitamin D. Congenital Malformations: in literature it appears to be a 6-8% chance of birth defects in infants born to women taking anticonvulsant medications. This represents a risk two to three times that of the general population. Predominate malformations are cleft lip/palate and cardiovascular malformations. A specific fetal hydantoin syndrome has been identified consisting of growth and performance delays, cranial facial abnormalities (including clefting), and limb abnormalities (including hypoplasia of nails and distal phalanges). Approximately 10-30% of infants born to women taking these drugs have been reported to have some aspects of the syndrome (3). The proportion of exposed infants having the complete syndrome is much smaller. Teenagers with seizure disorders are often treated with valproate because it has few side-effects in this age group. It has, however, been associated with specific fetal valproate syndrome of cranial-facial defects and neural tube defects. Researchers have found a statistically significant difference in IQ among children of mothers with seizure disorders compared with controls. There appears to be a small, undefined risk of a slightly decreased IQ in children born to mothers with epilepsy. 
Fetal hydantoin syndrome: facial features - upturned nose, mild midfacial hypoplasia, long upper lip with thin vermilion border and lower distal digital hypoplasia. |
Possible mechanisms by which anti-epileptics may cause birth defects are:- The conversion of antiepileptic drugs in the embryo into highly unstable toxic metabolites (bio-activation process) may damage fetal DNA.
- Anti-epileptics may alter the endogenous concentrations of retinoids (which modulate embryonic growth, differentiation, and morphogenesis).
- Anti-epileptics like phenobarbital and phenytoin can cause folic acid deficiency by impairing its absorption, metabolism, or both. Deficiencies of folic acid can raise homocysteine levels (which are thought to underlie neural tube defects).
Management: During Pregnancy: The patients with anti-convulsant level should be monitored periodically and dosages adjusted accordingly. Good seizure control during pregnancy is important in ensuring the well-being of the woman with epilepsy and that of the fetus. If at all possible, maintain a pregnant patient with epilepsy on mono-therapy at the lowest effective dose, which ideally should be established before conception. Monitor anti-epileptic drug levels to ensure the therapeutic drug levels. Lamotrigine may require a two-fold increase by the third trimester in order to maintain stable serum concentrations, but metabolism returns to the pre-pregnancy baseline within 48 hours after delivery, necessitating a rapid postpartum reduction in dosage. Patients taking anticonvulsants should be evaluated for possible fetal neural tube defects with a combination of maternal serum alpha-fetoprotein determination and ultrasound. Amniocentesis should be offered if preceding tests are equivocal. At 16-18 weeks of gestation, the patients should undergo a comprehensive ultrasound examination to look for congenital malformations. Antepartum fetal surveillance tests should be done for obstetric indications. Monitoring and controlling risk factors like sleep deprivation or non-adherence that may provoke more frequent seizures during pregnancy are helpful in good outcome. If a woman is adhering to the therapeutic regimen and her risk factors are well controlled, but seizures increase anyway, consider increasing the dosage of her anticonvulsants. Labor and Delivery: With appropriate fetal monitoring, the availability of good obstetric anesthesia, the ability to measure maternal anticonvulsant levels, vaginal delivery can be accomplished safely in the patient with a seizure disorder. The delivery plan should include the availability of personnel to perform neonatal resuscitation if necessary. During labor, oral absorption of medications is erratic; if the patient vomits, it is almost negligible. When administration of anticonvulsant is necessary during labor, levels should be determined to help ascertain the appropriate dosage. If the patient's phenytoin level is normal, the usual daily dose may be administered intravenously. In patients with therapeutic serum levels of phenobarbital, a single 60-90 mg intramuscular dose will usually be sufficient for maintenance throughout labor and delivery. The usual loading dosage is 10-15 mg/kg administered intravenously at a rate no faster than 50 mg/min. Patients taking carbamazepine can be given intravenously phenytoin because there is no parenteral form. Benzodiazepines also may be used for acute seizures, but they can cause early neonatal depression as well as maternal apnea. Occasionally seizures will be diagnosed for the first time during pregnancy. If the seizures occur in the third trimester, they may be confused with eclampsia. The diagnosis often becomes clearer over time, but in either case action must be undertaken to prevent additional seizures. In these cases, it is best to assume the patient has eclampsia. If patient has recurrent generalized seizures (status epileptics), immediate treatment is essential. Consultation with an anesthesiologist and neurologist may be helpful. The drug of choice is intravenous phenytoin, which is highly effective, has long duration of action, and has a low incidence of serious side-effects. Alternatively, phenobarbital or diazepam may be used. Status epilepticus may lead to maternal fetal hypoxemia. The patient should be placed on her left side if possible as this will increase uterine blood flow as well as decrease the risk of maternal aspiration. Oxygen should also be administered if possible. Risk of placental abruption also exists with prolong seizures. Breastfeeding: Most health organizations strongly recommend breastfeeding to promote mother-child bonding and reduce the risk of infection and immunological disorders in later life (4). Antiepileptic drugs cross into breast milk in varying degrees, usually through simple diffusion, and the ratio is determined by the drug's molecular weight, pKa, lipophilicity, and most importantly the degree of protein binding. Concentrations in breast milk of phenytoin, carbamazepine, valproate, and tiagabine are negligible because they bind tightly to proteins. The best advice for most women is to seriously consider breastfeeding, keeping in mind that once started, the infant can be observed for proper weight gain and sleep cycles. Anticonvulsant metabolism and clearance remains elevated as long as patient continues to breastfeed. When patient stops breastfeeding, the mother may experience an increase in serum anticonvulsant drugs concentrations requiring a dosage adjustment. If breastfeeding is suddenly stopped, some infants who had been exposed to these medications may experience withdrawal symptoms. These usually occur in the first few days after breastfeeding is stopped. Infants may need to be started on low-dose phenobarbital and undergo gradual withdrawal. Postpartum Period: the levels of anticonvulsant medications may rise rapidly during the first few weeks postpartum and should be monitored frequently. One approach is measure the serum level approximately 1 week postpartum to guide dosage adjustments. Women should be counseled about contraception. No method is contraindicated for patents with epilepsy, although if oral contraceptives are selected higher doses may be required. The patient should be encouraged to continue to receive care to control her condition and receive pre-conceptional care for a future anticipated pregnancy. Summary: Epilepsy posed unique challenges for both a pregnant woman and her clinician. Physiologic changes during pregnancy can influence epilepsy and conversely epilepsy and anticonvulsant medications can affect pre-pregnancy and its outcomes. Medical advances continue to help minimize fetal and maternal risk and have reduced the number of major birth defects and miscarriages among women with epilepsy. With continued vigilance among pregnant women with epilepsy and their healthcare providers, fetal and maternal outcomes will continue to improve. Reference:- Cramer JA, Jones EE. Reproductive function in epilepsy. Epilepsia 1991;32(Suppl 6):S19-S26 (Level III)
- Sabers A, Rogvi-Hansen B et al. Pregnancy and epilepsy: a retrospective study of 151 pregnancies. Acta Neurol Scand. 1998;97:164-170
- Dessens AB, Boer K et al. Studies on long-lasting consequences of prenatal exposure to anticonvulsant drugs. Acta Paeditr Suppl 1994;404:54-64 (Level III)
- American Academy of Pediatrics Committee on Drugs: The transfer of drugs and other chemicals into human milk. Pediatrics, 1994;93:137-150
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