Case Study: Why Epilepsy Need Not Preclude Pregnancy

By Nancy Foldvary-Schaefer, DO, MS, and Lara Jehi, MD

Presentation

“Sarah,” age 24, began having absence seizures at age 10, when she was diagnosed with generalized epilepsy. With valproate treatment, she remained seizure-free for 11 years.

At age 21, after starting to take oral contraceptives, she began having daily clusters of absence seizures in addition to rare generalized tonic-clonic seizures. She tried lamotrigine but soon discontinued it because of seizure exacerbation. Topiramate and phenytoin were found to be ineffective, but her seizures were brought under control with a combination of valproate, levetiracetam and primidone.

She presented to Cleveland Clinic’s Epilepsy Center at age 24 because she wanted to start a family but was distressed by advice from her gynecologist against getting pregnant due to risks from her epilepsy. To her relief, the epilepsy specialist expressed a different opinion and explained that with modern treatment and careful management, most women with epilepsy can safely give birth to a healthy baby.

Contraception in the setting of epilepsy

Perhaps counterintuitively, the first step toward Sarah’s pregnancy was a close look at contraception. Careful family planning would allow Sarah and her doctor some time prior to pregnancy to optimize her medications and seizure control.

Sarah’s oral hormonal birth control presented some challenges:

• Since estrogen activates seizures in one-third of women with epilepsy, the pills may have aggravated her seizure control.
• Furthermore, since oral hormonal contraception induces the metabolism of lamotrigine, it may have reduced the efficacy of this medication by lowering its blood level for most of the month.
• Finally, some antiepileptic medications induce the metabolism of sex steroids, setting the stage for contraceptive failure, and Sarah was taking one of them.

Strong enzyme inducers (associated with higher risk of contraceptive failure) include carbamazepine, oxcarbazepine, phenobarbital, phenytoin and Sarah’s drug, primidone. Weak inducers include eslicarbazepine, felbamate, lamotrigine, perampanel, rufinamide and topiramate. In contrast, noninducers include clonazepam, ethosuximide, lacosamide, levetiracetam, valproate and zonisamide.

In view of the above challenges, an intrauterine device is the preferred contraceptive for women with epilepsy and is recommended by the American Academy of Pediatrics for sexually active teenage girls with epilepsy. Some patients may prefer injectable medroxyprogesterone, a synthetic progestin that is not known to exacerbate seizures. Sarah’s personal choice was to use barrier methods.

Case continued: Preconception management

With appropriate family planning in place, Sarah and her doctor embarked on the following plan to optimize the chance of having a healthy baby:

• Step 1: Confirm epilepsy diagnosis. Before determining a treatment plan, it is imperative to ensure the correct diagnosis. An EEG confirmed that Sarah had generalized epilepsy.
• Step 2: Start folic acid supplementation to reduce risk of neural tube defects. Because this is a benign intervention that can have enormous benefit when used in the earliest weeks of pregnancy, we routinely recommend starting supplementation (1-5 mg/d) well before a woman intends to become pregnant. Sarah was started on folic acid 2 mg/d, as well as zinc and selenium supplementation. Although no strong data are available for the benefit of these elements, they have antioxidant properties and may also help avoid poor pregnancy outcomes.
• Step 3: Adjust medications to optimize seizure control and minimize teratogenicity. The primary goal of treatment during pregnancy is to avoid seizures. Generalized tonic-clonic seizures in pregnancy can be devastating to the fetus because of the risk of lack of oxygen and injury from a fall. The second goal is to minimize risk of teratogenicity from antiepileptic medications. General principles are to achieve seizure control using the fewest drugs at the lowest dosages, while avoiding certain drugs known to carry a high risk.

As illustrated in the table below, compared with lamotrigine or carbamazepine monotherapy, polypharmacy is not associated with a substantially increased risk of major fetal malformation — unless valproate is included in the mix. Once valproate is included, the risk for a major fetal malformation increases dramatically.

Valproate 1,000 mg/d (serum concentration, 75 µg/mL)We reviewed Sarah’s medications and checked baseline drug levels to enable us to make comparisons during pregnancy. Her current regimen was:

• Levetiracetam 3,500 mg/d (25 µg/mL)
• Primidone 400 mg/d (PEMA, 5.6 µg/mL; phenobarbital, 37 µg/mL)

The first priority was to wean drugs with high risk for teratogenicity and then attempt to obtain better seizure control with low-risk medications. Over a few months, Sarah’s antiepileptic medications were adjusted as follows:

• Lamotrigine, a low-risk drug, was introduced.
• She was then weaned off valproate and remained stable.
• Next we tried to wean her off primidone, another high-risk drug during pregnancy. Absence seizures increased, so zonisamide was introduced. Although there are not yet substantial data on zonisamide during pregnancy, it is rated more favorably than older antiepileptic drugs.

After one year, Sarah was stable on the following regimen and ready for pregnancy:

• Levetiracetam 3,500 mg/d (25 µg/mL)
• Lamotrigine 400 mg/d (7.5 µg/mL)
• Zonisamide 400 mg/d (22 µg/mL)

Pregnancy management in the setting of epilepsy

Pregnancy for a woman with epilepsy should be regarded as high-risk. Her obstetrician should work closely with her managing neurologist.

Because of physiological changes during pregnancy, metabolism of medications can vary widely, so it is important to monitor their levels. For highly protein-bound drugs, free levels should be followed. Levels of lamotrigine should be checked monthly, as this agent is metabolized largely through hepatic glucuronidation, a pathway that is particularly accelerated during pregnancy, making maintenance of therapeutic lamotrigine levels challenging.

Sarah’s serum lamotrigine levels fell during the ensuing weeks of pregnancy despite increasing dosage. By 25 weeks, she was taking 700 mg/d with a serum level of only 2.5 µg/mL.

Postpartum management

Sarah delivered a healthy baby boy at term, with no complications.

Following birth, it is critically important to swiftly reduce medication to preconception levels to avoid toxic levels in the mother. Sarah’s lamotrigine was down-titrated over one week from 700 mg/d back to her preconception dosage of 400 mg/d as follows:

• Days 1-3: 600 mg/d
• Days 4-6: 500 mg/d
• Day 7: 400 mg/d

A mother’s preconception drug dosage should be achieved within one to two weeks postpartum, so dosages should be altered proportionately to meet that goal.

Case highlights

This case underscores several key points:

• Epilepsy should not deter a woman from having a baby. Careful management before pregnancy is key to a successful outcome. Folic acid supplementation can begin in the preteen years, as can basic conversations about healthy habits, contraception and planning for pregnancy. Families are concerned about the future and are usually relieved to have the subject brought up.
• Seizure control takes precedence over avoiding teratogenicity. It is important to counsel women to not stop taking their seizure medications during pregnancy. While the risk for fetal malformations is increased for some drugs compared with others, the overall risk is still low. In fact, the chance of avoiding fetal malformations is greater than 95 percent during treatment with antiepileptic medications, with the exception of valproate. Data on teratogenicity are generated from the North American Antiepileptic Drug Pregnancy Registry, which encourages women to provide information about medications taken during pregnancy and their pregnancy outcome. With second- and third-generation antiepileptic drugs, it will take years to acquire enough data to detect trends with confidence, but reasonable decisions can be made based on the evidence at hand.
• Individualize care during and after pregnancy. Monitoring of serum drug concentrations for dosage adjustment is particularly important for lamotrigine and oxcarbazepine. Often patients give birth in a hospital that their regular physician may not be affiliated with, so a plan should be in place before delivery for postpartum medication management.

Dr. Foldvary-Schaefer is a staff neurologist in Cleveland Clinic’s Epilepsy Center and Director of Cleveland Clinic’s Sleep Disorders Center.

Dr. Jehi is a staff neurologist and epileptologist in the Epilepsy Center.

To view a webcast of this and nine other epilepsy cases in the “Hot Topics in Epilepsy for Children and Adults” CME-certified webcast series, visit ccfcme.org/EpilepsyCME. This activity has been approved for AMA PRA Category 1 Credit™.