Antiseizure drugs and women: Challenges with contraception and pregnancy

Introduction

In Canada, there are 300,000 people living with epilepsy, almost half of whom are women.^1,2 These women face particular challenges with the treatment of epilepsy. In addition to issues with reproductive fertility, changes in hormones increase the risk of catamenial epilepsy, where seizures can become more frequent or intense at certain phases of the menstrual cycle.³ Furthermore, antiseizure drug interactions can lead to contraceptive failure, which can result in an unplanned pregnancy.^3-6 During pregnancy, many antiseizure drugs increase the risk of teratogenicity^3,4,7 and can become less effective in controlling seizures.^3,4,8 We developed infographics to help pharmacists provide additional support to women who are taking antiseizure drugs, both for epilepsy and for other indications (Figures 1 and 2).

Figure 1.

Contraception and anti-seizure drugs

Figure 2.

Pregnancy and anti-seizure drugs

Before pregnancy

For women who take antiseizure drugs, there are 2 main drug interactions that can affect contraceptive choice. First, many antiseizure drugs decrease the effectiveness of hormonal birth control through enzyme induction (e.g., carbamazepine, phenytoin).^4-6,9 Estrogen is metabolized by the cytochrome P450 system, and enzyme inducers increase the first pass metabolism of estrogen, thereby contributing to subtherapeutic concentrations and contraceptive failure. For the second interaction, the estrogen in hormonal birth control can decrease the effectiveness of lamotrigine and valproate.⁹ When women who take lamotrigine or valproate are started on a new hormonal contraception or are switched to a higher estrogen dose, they will often experience a loss or worsening of seizure control.^3,8

The simplest option for many women is to use either the copper intrauterine device (IUD) or the levonorgestrel IUD, as the efficacy of IUDs is not affected by drug interactions.^3-6 Women who take enzyme-inducing antiseizure drugs and hormonal contraceptives have 2 options—they can change their antiseizure drug or they can change their choice of contraceptive. The Provincial Guidelines for the Management of Epilepsy in Adults and Children are useful for identifying alternative antiseizure drug options based on epilepsy type, and pharmacists can help prescribers identify which options are less likely to interact with oral contraceptives.¹⁰ Alternatively, women can choose to receive the medroxyprogesterone depot injection administered every 10 to 12 weeks or take a combined oral contraceptive with at least 30 to 50 µg of estrogen.⁶ Women who choose the lower dose combined oral contraceptive may also choose to take it in continuous cycles, where it is taken every day with a 4- to 7-day break every 3 months.^5,6,11 However, women who choose continuous cycle oral contraceptives should be advised to use a back-up method such as condoms or vaginal diaphragms, as 30 µg of estrogen may not provide adequate protection against pregnancy.¹¹

During pregnancy

Up to 6% of women with epilepsy who take antiseizure drugs while pregnant have a child with a fetal malformation—this is double to triple the incidence in the general population.⁴ The risk appears to be higher at higher doses.¹² While the risk also varies across different antiseizure drugs, it is clearly highest with valproate.^3,4,7,12 Valproate has been associated with congenital malformations and also with cognitive and behavioural problems for the child later in life. For example, children exposed to valproate in utero are more likely to face developmental delays and intellectual challenges and are 3 to 5 times more likely to be diagnosed with autism spectrum disorder.^12,13

Clinicians should educate women who take antiseizure drugs, especially valproate, to start planning for a pregnancy, ideally, at least 1 to 2 years before conception.^3,4,8,14-16 During this time, women can work with their health care team to switch to a safer option and then adjust the dose until complete seizure control is achieved.¹⁵ Preferably, women should be seizure-free for at least 9 months before pregnancy, as this significantly lowers the risk of seizures during pregnancy,¹⁷ which is critical, as some seizure types can lead to hypoxia and trauma to the fetus.⁴ For women who take antiseizure drugs other than valproate, the planning period allows time for the health care team to identify the lowest effective dose and stop any unneeded medications.^3,14-16 Folic acid, in doses between 0.4 and 5 mg once daily, can also be started to lower the risk of major congenital malformations and possibly autism.^3,8 During pregnancy, switching or discontinuing antiseizure drugs is generally not recommended, as it increases the risk of withdrawal seizures,⁷ with the exception of valproate, which some experts recommend stopping and/or replacing during pregnancy due to the high risk of malformations.¹³

Antiseizure drugs are also affected by the physiologic changes of pregnancy, although it is critical to adjust drug therapy based on seizure activity rather than on therapeutic levels alone. For example, the concentrations of levetiracetam and lamotrigine often decline as a pregnancy progresses, which can lead to more seizures.^3,4,18 Similarly, the total concentration of phenytoin may also decline during the pregnancy, but seizure frequency is unlikely to change unless there is a decrease in the free concentrations, and the free concentrations may stay the same.¹⁸ Therefore, if a woman experiences an increase in her seizure frequency or severity along with a decrease in her levetiracetam, lamotrigine or phenytoin free concentrations, she may need a higher dose. In cases where the drug dose was increased during pregnancy, the woman may experience supratherapeutic concentrations in the postpartum period once the physiological changes of pregnancy start to reverse.³ In those cases, the drug doses will likely need to be adjusted back down.

Most antiseizure drugs are considered moderately safe or safe for breastfeeding, with the exception of ethosuximide, benzodiazepines and zonisamide (not available in Canada). Women who are taking safe antiseizure drugs should be encouraged to breastfeed, should they desire to do so. The infant should still be monitored for signs of an adverse effect, such as poor suck, poor weight gain, drowsiness, hyperexcitability and missing developmental milestones.¹⁹

Beyond the childbearing years

The enzyme-inducing nature of many of the antiseizure drugs also affects women beyond the childbearing years. For example, enzyme inducers may decrease the effectiveness of hormonal therapy⁴ for hot flashes, and these women may require higher doses. Furthermore, enzyme inducers and valproate may cause decreases in vitamin D concentrations and bone mineral density, increasing the risk of fracture.^3,4 All women who take antiseizure drugs should ensure they get enough vitamin D and calcium, through either diet or supplementation. While this article focuses on women with epilepsy, similar challenges are also faced by women using antiseizure drugs for the treatment of various other conditions, including chronic pain, mood disorders and headache. These women should be offered the same options outlined in this article to mitigate these challenges.

Conclusion

Research indicates that women who use antiseizure drugs for the treatment of epilepsy and other medical conditions want more information to make more informed decisions. As pharmacists, we can assist our patients to become better informed about their antiseizure drugs to mitigate the risks associated with these drugs through their lifespan. ■