Epilepsy and Pregnancy
Over 90 % of women with epilepsy have a normal pregnancy.
Nonetheless, there are a number of fetal and obstetrical complications associated with women with epilepsy.
It is important for patients to be aware of these as careful planning and management of pregnancy can truly increase the odds of a favorable outcome.
A consultation with an experienced neurologist, such as Dr. Rosenkilde prior to or early on in pregnancy will allow you to ask questions and make the healthiest decisions for you and your baby. He and colleagues will follow you throughout your pregnancy and postpartum to ensure optimal outcome.
Dr Rosenkilde will consider the following issues when a woman with epilepsy becomes pregnant:
- Are antiepileptic drugs necessary?
- What effect do these drugs have on the fetus?
- What effect does epilepsy have on the fetus?
- What effect does pregnancy have on seizures?
- How should the patient be managed during pregnancy and later, during delivery?
- How should the patient be managed during the postpartum period?
Preconception Care is Primary Goal!
Epilepsy is not a contraindication for pregnancy. Over 90 % of women with epilepsy will have good outcomes.
Preconception counseling is important for all women of child bearing years because many pregnancies are unplanned (50%), and the risks of complications can be minimized by interventions before conception.
This includes educating the patient regarding risks associated with epilepsy and pregnancy, potential interactions with oral contraceptive therapy, and recommended folate supplementation. We routinely work closely with our Obstetric colleagues prior to planned pregnancy in these patients, including Dennis McGroary, MD and Susan S. Malley, MD at mcgroaryandmalley.com
Contraception
Women with epilepsy should be aware that hormonal contraceptive failure may occur with antiepileptic drugs (AEDs), and doses or types of contraception can be tailored to patients on AEDs.
Folic acid supplementation
Low serum folate levels in women with epilepsy are independently associated with an increased risk of major fetal malformations. It is believed that folic acid supplementation may decrease neural tube defects in women receiving AEDs.
Other vitamins had no protective effect, and folic acid supplementation had no demonstrable toxicity. An observational study in women with epilepsy found that the incidence of neural tube defects was similar in women who reported preconceptual use of folic acid compared to those who reported beginning folic acid supplementation later in pregnancy.
Folic acid supplementation is recommended for all women of child bearing potential to minimize the risk of neural tube defects. Published clinical guidelines regarding the dose of folate supplementation in women with epilepsy vary and are not definitive.
The 2009 American Academy of Neurology and American Epilepsy Society guidelines state that data are insufficient to determine whether doses higher than 0.4 mg offer greater protective benefits.
In contrast, the American College of Obstetricians and Gynecologists recommend 4.0 mg of folic acid daily for women at risk of having offspring with neural tube defects (including women taking AEDs) . The higher dose of folic acid has not been associated with adverse effects.
Necessity for antiepileptic drugs
There are two issues your neurologist will consider concerning the administration of antiepileptic drugs (AEDs) in any woman with a seizure disorder who wants to become pregnant:
- Is the diagnosis of epilepsy well established? In some patients, routine EEG recordings or continuous video/EEG monitoring may be warranted to confirm the diagnosis.
- Does the patient require AEDs and if so,
- Is she on the most appropriate medication(s)
- Is she at the minimum dose to maintain seizure control?
Withdrawing Seizure Meds Pre-Conceptually:
Only When Appropriate, Under A Doctor's Care
Many neurologists will consider withdrawal of AEDs after a period of five years without seizure. If a woman has been seizure-free for a satisfactory period, Dr. Rosenkilde often suggests a taper and withdrawal of AEDs at least six months prior to becoming pregnant.
Choice of antiepileptic drug
If it is felt that medications cannot be withdrawn, the patient should take the most suitable medication for the seizure type.
A number of pregnancy registries are beginning to accumulate data that should help guide therapy in the coming years.
At present, Dr. Rosenkilde recommends that AED therapy should be optimized prior to conception, if possible, before exposure of the fetus to potential teratogenic effects of AEDs.
Since there is no agreement as to which AED is most or least teratogenic, the AED that stops seizures in a given patient is the one that should be used.
An exception is valproate. Early results from pregnancy registries and most recent cohort studies suggest a trend toward higher teratogenicity with valproate than with other AEDs.
For these reasons, it is reasonable to avoid valproate in women planning to become pregnant if seizures can be adequately controlled with other AEDs.
Dr Rosenkilde also recommends:
- Use lowest effective dose: The AED should be administered at the lowest dose and lowest plasma level that protects against seizures.
- Follow plasma levels: The plasma drug level should be monitored regularly during pregnancy including, if available, the physiologically important free or unbound drug concentration.
- Monotherapy: The use of multiple agents should be avoided, if possible, especially combinations involving valproate, carbamazepine, and phenobarbital.
- No valproate, carbamazepine, or topiramate unless a patient's seizures cannot otherwise be controlled.
- Stick with AED that works: In established pregnancy, changes to alternate AED therapy should not be undertaken solely to reduce teratogenic risk for several reasons:
- Changing AEDs may precipitate seizures.
- Overlapping AEDs during the change exposes the fetus to effects of an additional AED.
- There is limited advantage to changing AEDs if pregnancy has already been established for several weeks.
Antiepileptic Drug Pregnancy Registry — The Antiepileptic Drug Pregnancy Registry (Toll-free:1-888-233-2334; online at www.massgeneral.org/aed) is a North American registry for pregnant women who are taking any AED. The registry's purpose is to collect data to assess the fetal risk from AEDs and to provide information about pregnancy issues to patients with epilepsy and their physicians.
Preconception counseling
It is important to emphasize the importance of:
- adequate sleep
- medical compliance
- minimizing stress
- folic acid supplementation
Once a woman with epilepsy who is taking AEDs becomes pregnant, serum and red cell folate levels can be monitored (goal is concentration above 4 mg/mL), especially important in the first trimester.
Screening for malformations
Screening for major anomalies provides the patient with the opportunity to terminate the pregnancy if a malformation is present.
Even if the patient would not consider termination, it may be helpful to know if a major defect is present in order to plan the optimum mode of delivery and to refer the patient to a center with specialty pediatric services for delivery.
There are two major screening modalities: serum alpha-fetoprotein (AFP) concentration and ultrasonography:
- Elevated serum AFP is associated with neural tube defects and other fetal abnormalities (eg ventral wall defects, congenital nephrosis). Measurement of the serum AFP concentration or amniocentesis for alpha-fetoprotein should be performed between 14 and 16 weeks, especially in women treated with valproate and carbamazepine.
- Real-time ultrasonography should be performed at 18 to 20 weeks to evaluate for neural tube defects, cleft lip and palate, heart anomalies, and for a general fetal anatomical survey.
Measurement of the serum alpha-fetoprotein level alone will detect most, but not all, cases of open spina bifida and anencephaly.
The detection rate increases if the serum level is measured in combination with high-resolution ultrasonography.
Drug levels and dose adjustment
Pregnancy is accompanied by many alterations in drug metabolism, including increased liver metabolism, renal clearance, and volume of distribution, and decreased gastrointestinal absorption and plasma protein binding.
As an example, for AEDs that are highly protein bound (eg, phenytoin, valproate), the total plasma drug level may decrease with impaired protein binding, but the physiologically important free or unbound drug concentration may not change.
As a result, free drug levels for these AEDs may be more reliable during pregnancy. However, medication dosage should be adjusted if the patient's seizures are not controlled, not because the free or total level has decreased.
Certain AEDs clear quickly in pregnancy and postpartum period, and need much closer monitoring.
Several studies suggest that lamotrigine clearance increases 65 to 94% and therefore should be monitored more frequently during the second and third trimesters to reduce the possibility of increased seizures, and during the early postpartum period to avert toxicity.
Vitamin K supplementation
Most physicians recommend administration of prophylactic vitamin K (10 to 20 mg/day) during the last month of pregnancy to women treated with AEDs to protect the child against severe postnatal bleeding due to a deficiency in vitamin K-dependent clotting factors.
Enzyme-inducing AEDs, such as phenobarbital, phenytoin, and carbamazepine, cross the placenta and may increase the rate of oxidative degradation of vitamin K in the fetus, an effect that can be overcome by large doses of vitamin K.
Despite the reports of excess bleeding and theoretical rationale for vitamin K administration, there has been limited systematic study of this issue.
On the other hand, oral vitamin K is relatively cheap and harmless. Currently, there is not sufficient evidence to recommend for or against this practice.
Dr. Rosenkilde generally recommend oral vitamin K supplementation (10 to 20 mg per day for the last month of pregnancy) in women with risk factors for premature delivery, in women taking multiple AEDs, enzyme-inducing AEDs (eg, phenobarbital, carbamazepine, phenytoin, topiramate, oxcarbazepine), and in women who abuse alcohol during pregnancy.
All newborns receive 1 mg of vitamin K intramuscularly at birth.
Fresh frozen plasma can be given if bleeding occurs.
Management During Labor and Delivery
Most women have a normal vaginal delivery. However, elective cesarean section may be justified in women with frequent seizures during the third trimester or a history of status epilepticus during severe stress.
Increased risk of seizures during Labor
With a neurologist's help, your obstetrician will maintain AEDs in labor at therapeutic dose. A tonic-clonic seizure occurs during labor in 1-2 % of women with epilepsy, and in another 1-2 % 24 hours after delivery.
It is therefore essential to maintain a plasma AED level known to protect against seizures during the third trimester and during delivery.
Doses must not be missed during the period of labor.
Treating seizures during labor and delivery
- IV lorazepam is considered the drug of choice.
- Intravenous phenytoin is also highly effective and has a longer duration of action. After delivery, phenobarbital, primidone, and benzodiazepines remain in neonatal plasma for several days. This can cause sedation and possibly a neonatal withdrawal syndrome.
- Magnesium sulfate is not an appropriate alternative for epileptic seizures. However, when seizures first present during the third trimester of pregnancy or the early postpartum period, it may be difficult to distinguish eclampsia from a new onset or late relapse of epilepsy. In these cases, treatment of eclampsia and evaluation of other etiologies for the seizure is warranted.
Generalized tonic clonic seizures can be associated with hypoxia; continuous fetal heart rate monitoring is recommended in the event of a seizure, as well as for a period of at least an hour after administration of benzodiazepines
Management in the Post-Partum
There are several basic principles of management of women with a history of seizures during the postpartum period:
- If the AED dose has been altered during pregnancy, a return to pre-pregnancy levels should be considered during the first few weeks after delivery. Lamotrigine clearance decreases quickly in the first week postpartum, and dose adjustments should be made sooner.
- In one case series, postpartum taper schedules of lamotrigine appeared to reduce the likelihood of maternal lamotrigine toxicity.
- The mother needs to be advised of the importance of adequate rest, sleep and compliance with drug therapy.
- Precautions need to be taken to protect the infant if the mother has a seizure. It is prudent, for example, to have another person present when the mother bathes the child. In addition, the baby should be changed on the floor or an alternative safe position.
Breast feeding: Benefits outweigh risk for most AEDs
All of the AEDs are measurable in breast milk. The maternal plasma levels in breast milk varies from 5-10 % with valproate to 90 % with ethosuximide.
Most experts believe that taking AEDs does not generally contraindicate breast feeding, as probable benefits outweigh risks. Problems tend to occur only with the sedative drugs, such as phenobarbital, primidone, or benzodiazepines.
Exposure to these drugs may cause the child to become irritable, fall asleep shortly after beginning to nurse, or fail to thrive. If this occurs, breast feeding may need to be discontinued but can be retried one week later.
Approach to a First Seizure In Pregnancy
Occasionally, a woman presents with a first seizure in pregnancy. With a few exceptions, the approach to diagnosis and management of a first seizure is the same as in a nonpregnant individual. Additional considerations in a pregnant woman include:
- Additional diagnostic considerations for new seizures might include pregnancy-associated conditions, such as eclampsia and cerebral venous thrombosis.
- Depending on the stage of pregnancy, there may be safety concerns regarding the use of neuroimaging procedures. Concern about the possible fetal effects of ionizing radiation should not prevent medically indicated diagnostic procedures using the best available modality for the clinical situation.
- The National Radiological Protection Board advises that magnetic resonance imaging (MRI) be avoided in the first trimester since there is limited experience assessing safety during organogenesis; however, MRI should be considered in the first trimester when the benefit exceeds the theoretic risk.
- Gadolinium, an intravenous contrast solution used for some MRI studies, is generally avoided because of adverse fetal effects in animal studies.
Summary and Recommendations
- Consulting an experienced neurologist to help manage antiepileptic medications during pregnancy can improve outcome.
- OCPs interact with antiseizure meds: Women of child bearing years should be counseled regarding the interactions between antiepileptic drugs (AEDs) and the pill, and the potential risks associated with epilepsy and pregnancy.
- Before conception: withdraw from meds, if possible. Patients who have been seizure free for two, preferably five years should be considered for AED withdrawal six months or more prior to planned conception.
- Use what works: Because there are no clear data indicating that any drug is without risk in pregnancy, patients planning pregnancy should be managed on the most effective medication for their seizures.
- Valproate probably should be avoided if an alternate effective drug regimen can be found.
- Monotherapy and the lowest possible drug dose may limit risk of teratogenicity with fetal abnormalities. The medication regimen should be optimized six months prior to planned conception.
- Don't change what works: We suggest NOT making changes to AED regimen for the purpose of reducing teratogenic risk in established pregnancy.
- Folic acid supplementation (0.4 to 0.8 mg per day) is recommended for all women of child bearing potential.
- Increase folate in certain patients: For women taking carbamazepine or valproate, or with a previously affected child, many recommend higher dose folate supplementation, 4 mg per day, prior to conception.
- Follow plasma drug levels at routine intervals: Both total and free plasma AED levels should be following regularly during pregnancy.
- Prenatal testing: AFP and ultrasound for fetal anatomy in patients being treated with AEDs.
- Oral vitamin K supplementation, 10 to 20 mg/day, in the last month of pregnancy for women taking enzyme-inducing AEDs (eg, phenobarbital, carbamazepine, phenytoin, topiramate, and oxcarbazepine.)
- Breast feeding safe with most AEDs: epilepsy is not considered a contraindication to breast feeding; however, use of lamotrigine or sedating drugs may be exceptions.
Leonardo da Vinci, Anatomical Study of the Foetus in the Womb, ca 1510, Windsor Castle, Royal Library
