Until the mid-1980’s women with epilepsy were advised not to use oral contraceptives (OC). This contraindication was based on animal studies showing exacerbation of seizures by estrogen. However, not only do the low estrogen doses in currently-used OCs make this unlikely, but the concept has never been proven in patient studies (Mattson & Cramer, 1985).

Unplanned pregnancy occurring during use of OCs is not uncommon among women taking enzyme inducing antiepileptic drugs (AED). Carbamazepine, oxcarbazepine, phenobarbital, phenytoin enhance cytochrome P450 microsomal oxidative enzyme activity, thereby increasing steroid hormone clearance (as does topiramate to some extent). Epilepsy and hormone experts (Mattson et al, 1986) jointly reported this problem with a recommendation that women taking enzyme inducing AEDs should be prescribed higher-dose OCs if breakthrough bleeding is noted, follow a back-up plan if pills were missed, or consider use of a contraceptive without estrogen (e.g., medroxyprogesterone).

In recent years, the concern about morbidity and mortality related to use of steroid hormones has dampened enthusiasm for use of high-dose OCs. Thus, women should preferentially be prescribed non-enzyme inducing AEDs (Cramer & Jones, 1991). Enzyme-inducing drugs also induce the clearance of folic acid. Valproate is not an inducer, being metabolized by omega oxidation. However, the risk of birth defects in children born to mothers taking valproate makes it a questionable choice unless careful compliance with the OC regimen can be assured (Cramer, 1996). Topiramate has some teratogenic effects in animals, but its effect in humans is not known. (see TABLE)

Lamotrigine, metabolized by hepatic glucuronic acid conjugation, is not an enzyme-inducer but is subject to induction and inhibition. Steroid hormones induce the metabolism of glucuronidated drugs such as lamotrigine. Sabers et al (2003) determined that lamotrigine blood levels were significantly decreased by OCs. Dose adjustments should be planned during initiation and discontinuation of an OC for women taking lamotrigine. The scope of this interaction is complicated by the typical cyclical pattern of OC use. Women take the inducing hormone preparation for 21 days, followed by a placebo for 7 days. That cycle could cause wide swings in lamotrigine blood levels with sharp increases a few days after stopping the hormone and sharp reductions a few days after restarting the hormone.

Where does that leave women with epilepsy? Awareness of drug interactions should be high for anyone using AEDs. Doctors who prescribe AEDs should consider all other treatments when selecting an appropriate drug for seizures. Although women are approximately half the epilepsy population, they should be considered a “special population” because of concerns about birth control and teratogenicity. Avoidance of enzyme-inducing and inducible drugs as well as drugs with high teratogentic risk leaves a small pool of AEDs for consideration – until we learn more about them.

Enzyme-inducers: Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, (topiramate) Inducible lamotrigine Teratogenic risk valproate Others gabapentin, levetiracetam, pregabalin, tiagabine, vigabatrin, zonisamide

References

Cramer, JA, Jones, EE. Reproductive function in epilepsy. Epilepsia 32(Suppl 6):S19-S26, 1991.

Cramer, JA. Compliance with oral contraceptives and other treatments. Obstet Gynecol 1996; 88 (Suppl):4S-12S.

Mattson, RH, and Cramer, JA. Epilepsy, Sex Hormones and Antiepileptic Drugs. Epilepsia 26(Suppl 1):S40-S51, 1985.

Mattson, RH, Cramer, JA, Darney, PD, and Naftolin F. Use of oral contraceptives in women with epilepsy. Journal of the American Medicine Association 256:238-240, 1986.

Sabers A, Ohman I, Christensen J, Tomson T. Oral contraceptives reduce lamotrigine plasma levels. Neurology 2003; 61: 570-571.