Family planning is of great importance to women with epilepsy because women with epilepsy are more likely than women in the general population to have babies with congenital malformations, i.e. abnormal development of the face, brain, heart or other organs. The risk for congenital malformations may be limited by taking steps before pregnancy to make sure that seizures are under the best possible control on the lowest dose and safest antiepileptic drug and by the use of folic acid supplement.
The timing of pregnancy can be regulated by abstinence or the use of birth control. Birth control (contraception) presents special challenges for women with epilepsy and their clinicians because the hormones in systemic hormonal contraception (birth control pills, vaginal ring, hormonal patch, injectable hormones such as depomedroxyprogesterone – DMPA, but not intrauterine devices) may affect seizures in some women with epilepsy and have reciprocal interactions with some antiepileptic drugs in ways that can adversely affect seizure control and/or effective contraception. In some women with epilepsy, there are also possible adverse interactions between some hormonal birth control methods and not only seizures but also conditions that are commonly associated with epilepsy such as emotional disorders (depression, anxiety) and migraine (headaches). Adverse interactions between non-hormonal forms of birth control and epilepsy specifically are not known to occur but have not been adequately investigated. Despite the great importance of birth control to women of reproductive age, there has been little formal investigation of contraception as it pertains to women with epilepsy and much of the available knowledge is not familiar to women with epilepsy and even to some healthcare professionals.
We have developed the Epilepsy Birth Control Registry, a web based survey and educational site, to gather data from women with epilepsy for women with epilepsy with the ultimate goal to develop guidelines for the selection of safe, well-tolerated and effective contraception for women with epilepsy with consideration of which contraceptive method works best with which antiepileptic drug. The Registry also gathers and provides valuable information regarding the availability of the best birth control methods for women with epilepsy and the decision-making process that goes into the selection of a birth control method.
Menstrual Cycles, Ovulation and Fertility in Women with Epilepsy
Overall, women with epilepsy have more disorders of menstruation, ovulation and fertility than women in the general population. It is estimated that perhaps one-third of women with epilepsy have menstrual disorders that include absence of menstruation for 3 or more months (amenorrhea), too few (more than 35 day intervals between periods) or too many (less than 21 day intervals between periods) menstrual cycles, irregular menstrual cycles (more than 4 days variability in menstrual cycle intervals), heavy menses and bleeding between periods (menometrorrhagia), and abnormally painful menses (dysmenorrhea). The significance for epilepsy of detecting abnormal menstrual cycles is that they often are associated with failure of ovulation (anovulation) and anovulation may be associated with more seizures. In women who have both ovulatory and anovulatory cycles, seizures may be 28% more frequent with anovulatory cycles. The greater frequency of anovulatory cycles found in women with epilepsy may be a cause for the lower rates of fertility found in women with epilepsy. Although fertility rates were substantially lower in the past, recent community studies show substantial improvement, perhaps related to better seizure control, newer antiepileptic drugs and better assisted reproductive technologies such as in vivo fertilization (IVF).
Birth Control in Women with Epilepsy
Although ovulation rates and fertility are reduced in women with epilepsy, birth control failure rates resulting in unplanned pregnancies are increased in comparison to the general population. One previous study found that women with epilepsy may not be using the best forms of birth control. Specifically, they may not be using forms of hormonal contraception as often as women in the general population. It is not yet clear, as yet, whether this is due to unproven fears of provoking seizures, concerns about unfavorable interactions with AEDs, or other reasons. One of the purposes of this registry is to find out if the best forms of birth control are available to and in use by women with epilepsy and, if not, whether it is because of a lack of adequate knowledge, ineffective medical counseling or socioeconomic reasons. Another purpose is to determine if certain forms of hormonal contraception may be less effective when combined with certain antiepileptic drugs.
Interaction Between Birth Control Hormones and Antiepileptic Drugs
The combined use of birth control pills (oral contraceptive pills, OCPs) and some antiepileptic drugs (AEDs) may have an important effect on the serum concentrations of both the birth control hormones and the antiepileptic drugs (see table below). Specifically, there is evidence that the older enzyme inducing AEDs (phenobarbital, primidone, phenytoin and carbamazepine) as well as some newer drugs (higher dosages of topiramate above 200 mg daily, perampanel, rufinamide), but not enzyme inhibiting (valproate) or enzyme neutral (clobazam, ethosuximide, gabapentin, levetiracetam, tiagabine, vigabatrin and zonisamide) AEDs, reduce substantially the serum levels of birth control pill hormones. The class of enzyme inducing AEDs acts on the liver to increase the breakdown of birth control hormones. This can result in irregular cycles, bleeding between periods, birth control pill failure and unplanned pregnancies. Higher-dose, rather than the lowest dose modern formulation, contraception pills have been recommended for women with epilepsy who take enzyme inducing AEDs, especially if they experience irregular cycles and breakthrough bleeding on the birth control pill. There is concern, however, that the potential benefit of increasing oral contraceptive pill (OCP) dosage on menstrual cycle control and risk of ovulation must be weighed against the potential adverse effects of these higher dosages on serum AED levels, seizures and potential OCP side effects such as venous blood clots (thrombosis, thrombophlebitis).
Reciprocally, birth control hormones may reduce the serum levels of certain AEDs. Specifically, the estrogens in birth control pills can act on the liver to increase the breakdown of certain so called glucuronidated AEDs, especially lamotrigine and valproate. This can result in increased seizures.
Reciprocal interactions between contraceptive hormones and AEDs may prove a barrier to prescription of highly effective birth control methods by clinicians who are unsure of the overall effects of these drug interactions. Investigations to compare the safety and effectiveness of various brands of birth control pill are lacking in the epilepsy community. Even less is known about the effects of contraceptive vaginal rings, patches, injectables and implants in women with epilepsy. The effects of continuous versus interrupted hormonal contraception on epilepsy, likewise, have not been investigated.
|Antiepileptic drugs that increase birth control pill metabolism||Antiepileptic drugs that do not increase birth control pill metabolism substantially||Antiepileptic drugs whose metabolism can be affected by birth control pills*|
|Topiramate over 200mg||Valproate|
* = theoretical consideration but no actual clinical reports
Effects of Birth Control Hormones on Seizures
The use of birth control pills by women with epilepsy has not been shown to affect seizure control although there are stories of seizure worsening in some women. In some animal models, estrogen treatment has been shown to make it easier to produce a seizure while progesterone may make it more difficult. While there are very preliminary reports to suggest that natural progesterone may lessen seizure frequency in some women with menstrually-related worsening of seizures, the synthetic progestins in oral birth control pills have not been shown to do so. Injectable depomedroxyprogesterone, a synthetic progestin, however, may lower seizure frequency by approximately one-third when it is given in sufficient dosage to induce stoppage of menstruation. Depomedroxyprogesterone use is often associated with hot flashes, irregular breakthrough vaginal bleeding and sometimes a delay of a few to many months in the return of regular ovulatory cycles. It may also be associated sometimes with headache, worsening of depression and some decrease in bone density.
Despite the great importance of birth control to women of reproductive age, there has been little formal investigation of contraception as it pertains to women with epilepsy and much of the available knowledge is not familiar to women with epilepsy and even to some healthcare professionals. We hope to gain knowledge about safe and effective birth control for women with epilepsy by asking women with epilepsy to share anonymously their past and future experiences with birth control on this website. The data we collect will characterize the use of contraception by women with epilepsy and compare the safety and effectiveness of various forms of contraception in this population. The data may also provide valuable information regarding the availability of the best birth control methods for women with epilepsy and the decision-making process that goes into the selection of a birth control method. The ultimate goal of this web based collection of birth control information in women with epilepsy is to determine what combinations of epilepsy characteristics, antiepileptic treatments and contraception methods provide the best tolerated and most effective contraception for women with epilepsy.
Importance of Folic Acid Use in Women of Reproductive Age
Folic acid is an important B vitamin (B9) that is important to make healthy new cells and for the DNA regulation of cell functions. Folic acid is of particular importance during early pregnancy because deficiency is associated with higher risks of fetal loss (spontaneous miscarriages) and neural tube malformations (major congenital malformations of the brain and spinal cord). In the USA, it is estimated by the Centers for Disease Control (CDC) that 3,000 pregnancies result in babies with spina bifida or anencephaly (incomplete closing of the spine or skull) each year. Of these, it is estimated that 50% to 70% could be prevented if women took 400 mcg of folic acid daily, before and during pregnancy. The CDC also estimates that 1,000 babies are protected from developing these malformations each year because their mothers take folic acid during pregnancy. We cannot make our own folic acid. It has to be included in our diet and/or a vitamin tablet. Since the malformations occur early in fetal development (i.e. starting in the first month of pregnancy), before women may even recognize that they are pregnant, the CDC recommendation is that all women of reproductive age take 400 micrograms of folic acid supplement daily and especially starting at least one month before pregnancy. Some foods (e.g. leafy vegetables) naturally contain abundant folic acid and some others (e.g. some cereals and breads) are now fortified with folic acid supplement. Taking an over- the-counter multivitamin preparation daily generally meets the minimal requirement. The folic acid content is usually printed on the label.
There are important special considerations for women with epilepsy (WWE). WWE who take antiepileptic drugs have lower blood levels of folic acid than untreated WWE or women in the general population. Lower levels are particularly likely to occur with the use of enzyme inducing antiepileptic drugs (EIAEDs) such as barbiturates, e.g. primidone, (Brand name: Mysoline), carbamazepine (Tegretol, Carbatrol), oxcarbazepine (Trileptal) or phenytoin (Dilantin). These medications may interfere with the absorption of folic acid or hasten its metabolic breakdown. The use of these medications during pregnancy may double the risk of brain and spinal cord malformations. Lower levels of folic acid also occur with the use of valproate (Depakene, Depakote), a folic acid antagonist that interferes with the body’s use of folic acid. It is associated with the highest rate of neural tube malformations. The general recommendation is that WWE take 1,000-4,000 micrograms (mcg) of folic acid supplement daily when planning a pregnancy (preconception) and during pregnancy and 400-1,000 mcg daily at other times.
The Epilepsy Birth Control Registry (EBCR) Folic Acid Preliminary Findings
We investigated the frequency of folic acid supplement use by WWE in the community and factors that may predict its use. These data come from the first 650 WWE, 18-47 years old, who completed the survey. The EBCR found that 277 (44.7%) of the 626 respondents took folic acid supplement. WWE at risk of pregnancy (i.e. those who were sexually active and not known to have infertility, hysterectomy, tubal ligation or male partners with vasectomy), regardless of which antiepileptic drug they took or method of contraception that they used were no more likely to take folic acid supplement than WWE not at risk and on no antiepileptic drug (Fig 1). Education (associate college degree or higher, 48.8% versus no degree, 39.0%) was the only statistically significant demographic predictor. There was no significant difference between WWE who did (44.4%) or did not (39.6%) see a healthcare provider during the year before the survey. Surprisingly, WWE who took antiepileptic drugs that are associated with higher risks of malformations, were not more likely to take folic acid.
Only about half of WWE in the community take folic acid despite the increased risk of WWE to have an unintended pregnancy (i.e. 80% of WWE of reproductive age report having at least one unintended pregnancy and 60% of pregnancies in WWE are unintended as compared to 49% in the general population). Rate of use is significantly higher among those with a college degree. Seeing a healthcare provider during the year before the survey did not have a significant effect. WWE who took an antiepileptic drug that put them at greater risk of having a baby with a major malformation were not significantly more likely to be taking a folic acid supplement. The findings highlight a striking gap in the dissemination of knowledge regarding the importance of folic acid supplementation among both WWE and healthcare providers.
Findings of the Epilepsy Birth Control Registry (EBCR):
Contraceptive Practices and Decision Making Process
- The EBCR is the largest study of contraceptive practices of women with epilepsy (WWE) in the community: 1,144 WWE report 2,712 contraceptive experiences
- 3% of WWE do not use highly effective contraception despite being at higher risk of having offspring with fetal malformations.
- Almost one-half (46.6%) of the WWE at risk of pregnancy use hormonal contraception which is considered highly effective in the general population but remains to be proven so in WWE.
- Insurance, race/ethnicity and age are significant demographic predictors of the use of highly effective contraception with younger and minority women without insurance being less likely to use highly effective contraception.
- Only a minority of WWE, 25.4%, consult their neurologist in selecting a contraceptive method.
The first two objectives of the Epilepsy Birth Control Registry (EBCR) are 1) to describe the existing contraceptive practices of women with epilepsy (WWE) in the community and predictors of highly effective contraception use and 2) reasons WWE provide for the selection of a particular method. The findings presented here (see Tables 1 & 2 below) come from 1144 WWE in the community, ages 18-47 years, who participated in the EBCR web-based survey regarding their contraceptive practices. We reported demographic, epilepsy and antiepileptic drug (AED) characteristics of the WWE, as well as their contraceptive use. We determined the frequency of use of highly effective contraception, i.e. methods with failure rates that are less than 10% per year in the general population, and determined demographic predictors of highly effective contraception use. We also reported the frequencies with which WWE consult various health care providers regarding the selection of a method and the reasons cited for selection of the various contraceptive methods. 69.7% of the 796 WWE at risk of unintended pregnancy use what is generally considered to be highly effective contraception (hormonal, IUD, tubal, vasectomy). Efficacy in WWE, especially for the 46.6% who use hormonal contraception, remains to be proven. Significant predictors of highly effective contraception use are insurance (insured – 71.6% versus non-insured – 56.0%), race/ethnicity (Caucasian– 71.3% versus minority – 51.0%) and age (38-47 years– 77.5%, 28-37 years – 71.8%, 18-27 years – 67.0%). 87.2% have a neurologist but only 25.4% consult them regarding selection of a method although concerns regarding the interactions between contraceptive hormones and AEDs is cited as the top reason for selection.
The EBCR web-based survey is the first large-scale study of the contraceptive practices of WWE in the community. The findings suggest a need for the development of evidence-based guidelines that address the efficacy and safety of contraceptive methods in this special population and for greater discourse between neurologists and WWE regarding contraception. The evidence to date is that a substantial minority of WWE do not use categories of contraception that are considered to be highly effective in the general population, especially among the uninsured and younger and minority WWE. Further, the effectiveness of what is generally considered to be highly effective contraception has not been proven to be so in WWE. This is particularly pertinent for the almost 50% of WWE who use hormonal contraception since hormonal contraception has been shown to have reciprocal interactions with some AEDs so as to compromise both the effectiveness of contraception and seizure control.
Table 1. Contraceptive categories and methods used by women with epilepsy at risk of unplanned pregnancy
|Contraceptive Categories||Number of WWE at Risk of Pregnancy||Percent of WWE at Risk of Pregnancy|
|N = 796||N = 796|
Contraceptive Methods Used Alone or in Combination
Number of WWE at Risk of Pregnancy
Percent of WWE at Risk of Pregnancy
|N = 1020||N = 796|
Abbreviations: WWE = women with epilepsy
Categories are listed for combinations by the generally more effective category
Table 2. Top Reasons for Selection of a Contraception Method
|Reasons Included Among
Top 3 Reasons
|Frequencies of the Reasons||% of all Reasons||% of WWE at Risk Selecting a Method|
|N = 2212||N = 796|
The 5 most frequently cited reasons listed among the top 3 reasons for selection of a contraceptive method by women with epilepsy at risk of unplanned pregnancy are presented in descending order. The frequencies of reasons are presented as percentages of all reasons cited for selection of contraceptive methods and as percentages of all WWE at risk who selected a contraceptive method. Abbreviations: WWE = women with epilepsy.
Effects Of Contraceptive Methods On Seizures And How They Vary In Relation To Their Combination With The Various Categories Of Antiepileptic Drugs
- The majority of women with epilepsy (WWE) report no change in seizures on any form of contraception
- More WWE report a change (increase or decrease) in seizures on hormonal contraception (28.2%), than on non-hormonal contraception (9.7%)
- On hormonal contraception, more WWE report seizure increase (18.7%) than decrease (9.5%)
- On hormonal contraception, non-enzyme inducing antiepileptic drugs (e.g. levetiracetam, zonisamide) were associated with the lowest rates of reports of seizure increase (11.6%); valproate had the highest rate of reports of seizure increase (29.4%)
The third objective of the EBCR is to determine whether categories of contraception differ in their impact on seizures in women with epilepsy and whether the impact varies by antiepileptic drug category. These findings come from the 2,712 contraceptive experiences that were reported by 1,144 WWE who participated in the EBCR survey.
More women with epilepsy reported a change in seizures on hormonal (28.2%) than on non-hormonal contraception (9.7%). Risk for seizure increase was significantly greater on hormonal (18.7%) than on non-hormonal contraception (4.2%). Note, however, that the risk for seizure decrease was also greater on hormonal (9.5%) than on non-hormonal contraception (5.5%). Overall, the risk for seizure increase was almost two times greater than for seizure decrease on hormonal contraception. In comparison to combined oral contraceptive pills (contain both estrogen and progestin), both hormonal patch and progestin-only pills had greater risks for seizure increase. Depomedroxyprogesterone (DMPA, i.e. injectable progestin) was the only hormonal method that showed a greater percentage of seizure decrease than combined pills (17.5% versus 9.0%) (Table 3). Seizure increase was greater for hormonal than non-hormonal contraception for each antiepileptic drug category. On hormonal contraception, the so called non-enzyme inducing antiepileptic drug category (e.g. levetiracetam, zonisamide) had the lowest rate of reports of seizure increase in comparison to each other category with valproate having the highest risk.
The findings provide community based, epidemiological survey evidence that contraceptive methods may differ in their impact on seizures and that this impact may vary by antiepileptic drug category. Specifically, although the great majority of WWE who used hormonal contraception experienced no change in seizure frequency, a substantial minority (28.2%) did report changes with two times more reports of seizure increase than decrease. We are currently starting a study that follows WWE in real time to determine if these findings stand.
Table 3: Comparisons of Subcategories and Types of Hormonal Contraception Effects on Seizures
|N||Seizure Increase (%)||Seizure Decrease (%)|
|Combined||Oral||Combined OCP||635||115 (18.1%)||57 (9.0%)|
|Non-Oral||Vaginal Ring||104||21 (20.2%)||7 (6.7%)|
|Hormonal Patch||59||18 (30.5%)||5 (8.5%)|
|Progestin- Only||Oral||Progestin OCP||58||17 (29.3%)||5 (8.6%)|
|Non-Oral||Progestin Implant||37||9 (24.3%)||2 (5.4%)|
|DMPA||200||38 (19.0%)||35 (17.5%)|
In comparison to combined oral contraceptive pill (OCP), the most commonly used hormonal contraceptive method, there is a significantly greater risk for seizure increase with hormonal patch and progestin-only oral contraceptive pill and significantly greater chance for seizure decrease with depomedroxyprogesterone (DMPA).
Abbreviations: OCP = oral contraceptive pills; DMPA = depomedroxyprogesterone
Predictors of Unintended Pregnancy in Women with Epilepsy
- 78.9% of women with epilepsy (WWE) reported having at least one unintended pregnancy; 65.0% of their pregnancies were unintended as compared to 49% in the general population.
- Unintended pregnancy was more common among younger, racial minority and Hispanic WWE.
- Among reversible contraceptive categories (barrier, hormonal, IUD), intrauterine device (IUD) had the lowest failure rate.
- On systemic hormonal contraception (HC), oral forms had greater failure rate than non-oral forms. HC combined with enzyme inducing AEDs (see the list above for “Antiepileptic drugs that increase birth control pill metabolism”) had a substantially greater failure rate than HC combined with No AED or any other AED category, a risk even higher than with use of a barrier method. Other AED-HC combinations, in contrast, carried lower risks than barrier.
The fourth objective of the EBCR is to identify predictors of unintended pregnancy in women with epilepsy (WWE), especially whether rates of unintended pregnancy are affected by which category of contraception and antiepileptic drug (AED) WWE use. Among the 1,144 WWE who participated in the EBCR, 437 reported having pregnancies that occurred after the age of seizure onset. 345 (78.9%) of the 437 WWE reported having at least one unintended pregnancy. 523 (65.0%) of their 804 pregnancies were unintended, 276 (34.3%) were intended and 5 (0.6%) were listed as “don’t know.” Unintended pregnancy was more common among younger, racial minority and Hispanic WWE. Among reversible contraceptive categories, IUD had the lowest failure rate (See Table 4 which reports the relative risk as risk ratios (RRs), i.e. the category with the lowest risk is listed as having a RR of 1.00 and the other categories have RRS that indicate how many times greater risk is posed with their use). Failure rates varied greatly on systemic hormonal contraception (HC), depending on whether oral or non-oral forms were used and especially in relation to the category of AED with which HC was combined. Oral forms had greater failure rate than non-oral forms. HC combined with enzyme inducing AEDs had approximately 2.5 times greater failure rate than HC combined with No AED or any other AED category and also in comparison to barrier plus any AED category. Other AED-HC combinations, in contrast, carried lower risks than barrier use with any AED category.
Unintended pregnancy is very common among WWE. One third of the unintended pregnancies occurred in WWE who were on no contraception, perhaps because more educational emphasis needs to be placed on the fact that fertility among WWE is probably only a little less than in the general population. The rates of unintended pregnancy vary substantially among contraceptive and AED categories. Among the reversible methods of contraception (barrier, hormonal, IUD), IUD had the lowest rate of unintended pregnancy by a substantial margin. The use of hormonal contraception by WWE who take an enzyme inducing AED are at a particularly increased risk of unintended pregnancy, perhaps even more so than WWE who use a barrier method, whereas WWE on other categories of AED may be at lower risk of unintended pregnancy on HC than WWE who use a barrier method. In view of the important consequences of unintended pregnancy on pregnancy outcomes, these retrospective findings warrant further prospective investigation.
Table 4. Relative risks of unintended pregnancy on various categories of reversible contraception
|Contraceptive categories||Unintended pregnancies/
frequency of use of contraceptive category (%)
|Risk ratios (95% CI)||p-Value|
|Hormonal||166/1094 (15.2%)||4.94 (2.35-10.39)||<0.0001|
|Barrier||85/711 (12%)||3.89 (1.83-8.29)||0.0004|
|Withdrawal||62/352 (17.6%)||5.74 (2.67-12.31)||<0.0001|
Abbreviations: CI = confidence interval; IUD = intrauterine device.
The relative risks of unintended pregnancy with the use of reversible categories of contraception are standardized in relation to the frequency of use of each contraceptive category by women with epilepsy at risk in the Epilepsy Birth Control Registry and use IUD, the category with the lowest risk, as referent.
Reasons for Discontinuation of the Various Types of Contraception by Women with Epilepsy
These results will be added when published
EBCR findings were published in the following:
Herzog AG, Mandle HB, Cahill KE, Fowler KM, Hauser WA, Davis AR. Contraceptive practices of women with epilepsy: Findings of the epilepsy birth control registry. Epilepsia. 2016 Apr; 57(4):630-7. PMID: 26880331.
Herzog AG, Mandle HB, Cahill KE, Fowler KM, Hauser WA. Differential impact of contraceptive methods on seizures varies by antiepileptic drug category: Findings of the Epilepsy Birth Control Registry. Epilepsy Behav. 2016 Jul; 60:112-7. PMID: 27206228.
Herzog AG, Mandle HB, Cahill KE, Fowler KM, Hauser WA. Predictors of Unintended Pregnancy in Women with Epilepsy. Neurology 2017;88:728-733.
Mandle HB, Herzog AG, Cahill KE, Fowler KM, Hauser WA, Davis AR. Reasons for Discontinuation of Reversible Contraceptive Methods by Women With Epilepsy. Epilepsia (in press).