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ISSN: Print -2349-0977, Online - 2349-4387


 
 Table of Contents  
PRACTICE CHANGING CONTINUING EDUCATION - CLINICS IN CLINICAL PHARMACOLOGY
Year : 2016  |  Volume : 3  |  Issue : 1  |  Page : 30-35

Contraception in women with epilepsy: Potential drug interactions between contraceptive hormones and enzyme inducing antiepileptic drugs


1 Department of Obstetrics and Gynecology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Neurology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Date of Web Publication20-Oct-2016

Correspondence Address:
Parampreet Kharbanda
Department of Neurology, Post Graduate Institute of Medical Education and Research (PGIMER), Sector-12, Chandigarh - 160 012
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2349-0977.192712

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  Abstract 

Contraception is essential for a woman as it helps to achieve autonomy in personal life and avoid unwanted pregnancy. Adequate contraception is even more essential for women with epilepsy (WWE) due to potential maternal and fetal risks of antiepileptic drugs (AEDs) and poor seizure control. There are several hormonal and nonhormonal contraceptive options available for WWE, with combined oral hormonal pills being used most commonly. The choice of contraception in WWE is influenced by many factors, chief among these being potential drug interactions between contraceptive hormones and enzyme inducing antiepileptic drugs (EIAEDs). While EIAEDs may increase metabolism of contraceptive hormones leading to contraceptive failure, contraceptive hormones in turn may increase metabolism of AEDs resulting in their faster elimination and breakthrough seizures. The co-administration of lamotrigine and oral hormonal pills is especially complicated by unpredictable interactions and requires several considerations. In this review, we try to address various issues concerning the use of different contraceptive modalities in WWE. In addition, we review the current guidelines for concurrent use of hormonal contraception and AEDs in WWE.

Keywords: Antiepileptic drugs, contraception, epilepsy, pregnancy


How to cite this article:
Bansal R, Kharbanda P, Goyal MK. Contraception in women with epilepsy: Potential drug interactions between contraceptive hormones and enzyme inducing antiepileptic drugs. Astrocyte 2016;3:30-5

How to cite this URL:
Bansal R, Kharbanda P, Goyal MK. Contraception in women with epilepsy: Potential drug interactions between contraceptive hormones and enzyme inducing antiepileptic drugs. Astrocyte [serial online] 2016 [cited 2021 Dec 1];3:30-5. Available from: http://www.astrocyte.in/text.asp?2016/3/1/30/192712


  Introduction Top


Epilepsy affects 0.5–1% of the world's population. Approximately half of these are women, many in the reproductive age group. Worldwide, approximately 18 million women suffer from epilepsy, out of which 40% fall in the reproductive age group.[1] Most of the women with epilepsy (WWE) in reproductive age group need to plan their pregnancy due mainly to teratogenic effects of antiepileptic drugs (AEDs) and harmful consequences of seizures on pregnancy. Despite this fact, while most of the WWE in reproductive age group receive adequate counselling regarding possible effects of AEDs or seizures on pregnancy, they are not given adequate information regarding contraception. A recent survey found that <7% of WWE are given contraceptive counselling.[2] The situation is even worse in developing countries where most of the couples do not discuss contraception owing to inherent shyness as well as privacy issues in crowded clinics. Furthermore, clinicians also ignore this important aspect due mainly to their busy schedule as well as lack of knowledge regarding adequate contraception in WWE on AEDs.[3] It is important to note that enzyme inducing antiepileptic drugs (EIAEDs) are also used commonly for other disease indications such as neuropathic pain, trigeminal neuralgias, and migraine. Women suffering from these disorders also need counselling regarding contraception. However, for the purpose of this chapter we will keep our discussion limited to WWE.

Contraception is important for women. It helps them to attain autonomy in personal life, avoid unwanted pregnancies and unintended abortions, space births, and ensure better health both for the mother as well as the child. In addition, barrier contraceptives protect against transmission of human immunodeficiency virus and other sexually transmitted diseases. It is the responsibility of the clinician to provide adequate counselling regarding contraception to WWE taking into account various factors such as age, general health condition, as well as socioeconomic and educational status.[3]

At present, several different contraceptive methods (oral hormonal pills, barrier methods, hormonal intrauterine devices, and copper containing intrauterine devices, etc.) are available. Among these, the hormone based contraceptive methods, especially oral hormonal pills, are the most effective method for contraception, both for women with and without epilepsy.[4] Due to the interaction between oral hormonal pills and EIAEDs, there is high risk of their failure in WWE. Unfortunately, this aspect is often ignored while prescribing contraception to WWE, as exemplified by several studies. In one study from USA,50% of pregnancies in WWE were unplanned. Only 74% of WWE in the same study used contraception, and among these only 53% used a highly effective form of contraception. The highly effective forms of contraception included hormonal pills, intrauterine device insertion, sterilization, as well as patch and injection. Approximately 28.5% of study participants were using both hormonal pills and EIAEDs, thereby increasing chances of unwanted pregnancy.[5] In another study from USA, it was found that 22% of WWE used oral contraceptives (OC) and 50% of these were ignorant about possible interactions between EIAEDs and OC.[6] However, there is paucity of data regarding these facts from developing countries such as India.

Ensuring optimal reproductive health should be an integral part of the overall management of WWE. However, this aspect is often neglected, as indicated by several studies. It has been shown that, more often than not, WWE are not given adequate counselling about issues pertaining to reproductive health such as potential fertility and various contraceptive options as well as their relative efficacies.[7],[8],[9] Therefore, it is imperative that management protocols used in WWE should include guidelines on contraception as well. In this review, we have tried to address the important issue of contraception in WWE.


  Methods of Contraception Which Are Affected by Enzyme Inducing Antiepileptic Drugs Top


These include various hormone-based contraceptive methods such as combined oral contraceptive pill, combined contraceptive patch, combined contraceptive vaginal ring, progesterone only pill, progesterone implant, and postcoital contraception. All these methods are based on the use of sex hormones, either progestogen alone or both progestogen and estrogen. These hormones act in several different ways to prevent pregnancy. However, despite a high degree of efficacy, use of these contraceptive methods is limited in WWE due to existence of a complex two-way pharmacokinetic interaction between several AEDs and sex hormones.[1]

The most widely used contraceptive methods include oral contraceptive (OC) pills due to their high efficacy. Their primary mechanism of action is inhibition of ovulation by suppression of gonadotropins through feedback action of estrogen and progestogen. In addition, they also induce changes in cervical mucus and endometrium making the local uterine milieu less conductive to sperm transport as well as fertilization and implantation. OC pills are of two types, namely, combined pills and progestogen-only pills. The combined OC pills usually contain low dose synthetic estrogen and progestogen and are based on either 7 or 4 days of hormone free intervals.

The conventional combined OC pills are classified into four generations depending on the type of estrogen used. These include first generation (norethynodrel, norethindrone acetate, or ethynodiol acetate), second generation (levonorgestrel), third generation (desogestrel or gestodene), and fourth generation (drospirenone) OC pills. The fourth generation pills have less adverse effects on blood glucose and lipid profile. The combined OC pills can also be divided into three types depending upon the dosing combinations, i.e., monophasic, biphasic, and triphasic. Unlike monophasic pills thatemploy fixed doses of estrogen and progestogen, biphasic and triphasic pills use varying doses of estrogen and progestogen to simulate physiological levels. In a biphasic pill, the dose of progestogen is increased during the last 11 days of the cycle, while in a triphasic pill, three changes are made in the doses of estrogen/progestogen regimen for each cycle.[1],[10] Unlike combined OC pills, progestogen-only pill does not provide a hormone free interval. However, it is used less frequently than combined OC pills.

Nonoral combined hormonal contraception includes skin patches which release a constant quantity of progesterone—Norelgestromin (150 µg/day) and ethinyl estradiol (20µg/day) to the circulation for 3 weeks followed by hormone-free period of 1 week, during which no skin patch is applied. Combined contraceptive vaginal ring (NuvaRing) is once a month vaginal contraceptive, which releases continuous low doses of estrogen and progesterone throughout the month. Other topical methods of hormonal contraception include gels and sprays, which are currently not available in India. In India, another selective estrogen receptor modulator (Ormeloxifene), which selectively modulates the estrogen receptors at the breast and uterus, is available under the brand name Saheli. This molecule retains its contraceptive properties, but has better metabolic and thromobophilic profile than conventional estrogen-based preparations.[1] For postcoital contraception, high dose combination OC pills, or progestogen only pills (morning after pills or postcoital pills) are used with a documented efficacy of 90% if taken within 72 hours after coitus [Table 1].
Table 1: Contraceptive Methods which are Affected by Antiepileptic Drugs

Click here to view


Recently, two new formulations of COCs have become available. COC pill containing estradiol valerate (a prodrug of estradiol) and dinogest is available in 26/2 days regimen. It gives estrogen in a step-down and progestin in a step-up regimen over 26 days followed by 2 days of placebo. Its use is associated with a 90% reduction in the amount of menstrual blood loss over a 6-month period. Its use is also associated with lower risk of withdrawal symptoms as compared to traditional COCs.[11] In addition, a COC pill containing 150 µg of levonorgestrel and 30 µg of ethinylestradiol has been approved in adult women for prevention of pregnancy. It is given for 84 days followed by 7 days of ethinylestradiol 10µg daily. Then, the cycle is repeated again. This 84/7 days cycle is associated with fewer episodes of withdrawal bleeding.[12]

Hormonal contraceptives and risk of seizures

Several studies suggest that hormonal methods of contraception do not increase the risk of seizures in WWE.[13],[14],[15],[16],[17] On the other hand, OC use has been documented to alleviatemenstrual-related seizures. Efficacy of progestogen in decreasing seizure frequency in women with intractable localization-related epilepsy or catamenial seizures has been documented in one study.[1] However, data regarding the safety of OC with regards to exacerbation of seizures in WWE is sparse at the best and future studies are needed to resolve this issue.

Pharmacokinetic interactions between antiepileptic drugsand hormonal contraceptives

A complex pharmacokinetic interaction exists between hormonal contraceptives and AEDs resulting in alteration in blood concentrations of either or both when used together. Both these share a common transporter P-glycoprotein (PGP) for their transport across intestinal mucosa and blood–brain barrier (BBB). Thus, they can competitively inhibit the transport of each other. After absorption, sex steroid hormones (estrogens and progestogen) are transported to liver where they are metabolized to inactive compounds by liver's cytochrome P450 (CYP450) enzymes, especially CYP3A4, through oxidation and glucuronidation. The CYP group of enzymes are coded by approximately 57 human genes and demonstrate considerable tendency for induction, a property which results in over expression of the enzyme.[16],[17],[18]

There are several potential pharmacokinetic interactions between AEDs and hormonal contraceptives. For better understanding of these interactions, it is customary to divide AEDs into two groups, namely, AEDs with enzyme inducing properties (EIAEDs) and AEDs without enzyme inducing properties (ENIAEDS: Enzyme non-inducing AEDs) [Table 2]
Table 2: List of Various Antiepileptic Drugs and their Influence on Hormonal Contraception

Click here to view


Interaction between EIAEDs and hormonal contraceptives

EIAEDS (phenobarbitone, carbamazepine, primidone, phenytoin, felbamate, topiramate and oxcarbazepine) are metabolized through the same CYP3A4 enzyme system, which alsometabolizes sex hormones (estrogens and progestogens). These drugs increase the levels of CYP450 enzymes resulting in increased metabolism of sex steroids with resultant decrease in intensity and duration of their effects.[10],[16],[17],[18] While annual failure rate of OC in healthy women is 1%, it increases to 3–6% in women taking EIAEDs. One out of every 4unplanned pregnancies in WWE is related to OC failure.[19],[20],[21] The blood levels of sex steroid hormones may decrease by as much as 50% (66% for carbamazepine), accounting for decreased efficacy of hormonal contraception and high failure rates in WWE.[22] Another potential way in which some EIAEDs (phenytoin, carbamazepine and phenobarbitone) can cause failure of hormonal contraception is through increase in levels of sex hormone binding globulins (SHBG). This results in a decrease in the amount of unbound (active) fraction of sex hormones, thereby decreasing their efficacy.[23]

Several newer AEDs (felbamate, topiramate, and oxcarbazepine) are less potent inducers of CYP3A4. However, while low doses of these drugs may not result in significant lowering of sex hormone levels, the same is not true for high doses of these two drugs. At dose of 1200mg/day, oxcarbazepine decreases concentration of estrogens and progestogens by approximately 47%. Topiramate (>200 mg/day) decreases blood levels of progestogencomponent by 18–30% without any effect on estrogen concentration whereasfelbamate decreases blood levels of progestogen by 42% without any effect on estrogen component.[24],[25],[26]

Thus, in women on EIAEDs, it is better to use pills with higher concentrations of ethinyl estradiol (at least 50 µg). Even a higher dosage of estrogen component may be required if breakthrough bleeding occurs.[27] At present, it is not clear that how much decrease in levels of estrogens and progestogen will allow pregnancy to occur, and therefore, there are no guidelines regarding estimation of optimal OC regimen for ensuring efficacy. Thus in women using EIAEDs, additional contraception [barrier methods, non hormonal intrauterine devices (IUDs)] may be provided if deemed appropriate.[10] This is especially true with latest generation COCs because these use a lower dose of hormones.

Nonoral hormonal contraceptive methods such as implantable hormonal contraceptives and hormone releasing IUDs may also interact with EIAEDS. For instance, use of norplant [a levonorgestrel (progestogen) based system wherein progestogen is slowly released from small silastic covered rods implanted under skin of lower arm, providing protection for up to 3 years] in combination with EIAEDs may result in unwanted pregnancies.

Interaction between enzyme non-inducingantiepileptic drugs and hormonal contraceptives

ENIAEDS (valproate, gabapentin, levetiracetam, tiagabine, vigabatrin, zonisamide, and pregabalin) are less likely to interact with hormonal contraception, and their use in WWE using hormonal contraception is relatively straight forward. Both levetiracetam and zonisamide do not have any impact on the plasma levels of ethinyl estradiol and norethindrone when co-administered with OC pills.[28],[29]

Effects of sex hormones on antiepileptic drugs

Steroid hormones, particularly estrogens, can induce cytochrome enzymes and lower blood level of AEDs (such asphenobarbitone, phenytoin, carbamazepine, and lamotrigine), resulting in breakthrough seizures in women who start OC pills. Serum levels of valproate are also known to decrease following the use of combined hormonal contraceptive steroids.[1],[10] The interaction between sex hormones and AEDs assumes special importance in women using multiphasic pills. In these women, the interactions between hormones and AEDs are at different levels in different phases of menstrual cycle. Thus, there is a considerable variation in blood levels of AEDs, which can result in either breakthrough seizures ordrug-related side effects. In addition, during the hormonal free period of 4–7 days, the blood levels of AEDs may increase, resulting in adverse effects. Thus, in WWE on AEDs, it is better to select a continuous dosing oral pill rather than a multiphasic pill.[1]

Lamotrigine and hormonal contraception

Lamotrigine does not decrease the levels of estrogen but does decrease progestogen levels byapproximately 20% through induction of several enzymes involved in progestin metabolism (CYP2C19, CYP 3A4, and CYP2C9). Thus, the use of lamotrigine may be associated with contraceptive failure. In addition, ethinyl estradiol increases excretion of lamotrigine by inducing uridine-diphosphateglucuronsyl transferase isoenzymes, which carry out glucuronidation of lamotrigine, its major route of elimination. Combined OC pills may decrease serum levels of lamotrigine by 40–60%, resulting in impaired seizure control. Thus, levels of lamotrigine should be checked before and after starting hormonal contraception and used for adjustments of dose.[30],[31],[32] However, progestogen only pill does not influence levels of lamotrigine.

Another intriguing aspect of co-administration of lamotrigine with combined OC pills in cyclic fluctuations in blood levels of lamotrigine. During day 2–20 of the cycle, the blood levels of lamotrigine remain low and then increase during the hormone free period. Thus, there is risk both of breakthrough seizures during early part of cycle (days 5–20) and drug-related adverse effects (days 22–28) during the hormone free period. This problem can be obviated through the use of progestogen-only pill.[1]

Postcoital (emergency) contraception

EIAEDs also affect the efficacy of postcoital contraception and can result in contraception failure. Thus, first choice for emergency contraception in WWE taking EIAEDs is insertion of a copper intrauterine device. Alternatively, as a second choice, two 1.5 mg tablets of levonorgestrel or two 30 µg tablets of ulipristal acetate can be used for emergency contraception. In many countries, ulipristal acetate (2 tablets of 30 µg) is available for use as emergency contraception. Its main advantage lies in the fact that it can be given for up to 120 hours after unprotected sexual intercourse with an efficacy of 62–85%.[33] To the best of our knowledge, there is no study evaluating efficacy of this pill in WWE on EIAEDS.


  Methods Of Contraception Which Are not Affected by Eiaeds Top


Medroxyprogesterone acetate (Depo-Provera)

This drug has a 100% clearance on its first pass through liver, and thus, problem of enzyme induction does not apply to this drug. However, use of this drug is associated with irregular, frequent, and prolonged bleeding, especially during first year of its use. This problem reduces significantly after 1 year of use. Other potential side effects include weight gain and attainment of suboptimal peak bone mass (especially in adolescent girls). Despite all these side effects, it remains a useful option for WWEbecauseit is free from drug interactions.[34]

Levonorgestrel-releasing intrauterinesystem: Mirena

This system is also not affected by EIAEDs and remains a suitable option for WWEbecauseit is highly effective and not dependent on good compliance [Table 3].
Table 3: Contraceptive Methods that are not Affected by Antiepileptic Drugs

Click here to view


Intrauterine systems and devices

Copper-containing devices release a small quantity of ionic copper into the uterine cavity to prevent fertilization or implantation. The intrauterine system is a T-shaped device embedded with levonorgestrel. These devices are highly effective and can be used as a measure of contraception in WWE.


  Recommendations Top


Women already taking enzyme-inducing antiepileptic drugs

The decision regarding the method of contraception should be taken after considering various individual factors such as duration of contraception requirement, physical and metabolic condition of the woman, and personal preference. For women opting for hormonal contraception, vaginal rings and implants are not commonly used because these are affected by induction and subject to failure. Use of two patches and two rings at the same time is not recommended, and hence, these options are usually not considered for contraception.

If a woman opts for a long acting method there are several options that are safe and reasonable, including

  1. Medroxyprogesterone injection (Depo-Provera)
  2. Levonorgestrel-releasing intrauterine device
  3. Copper-containing intrauterine devices.


If either of these options is not acceptable, one can start contraception with oral hormonal pills with combination contraceptives containing at least 50 µg of ethinyl estradiol and adequate amount of progestogen. Thus, one can use either two tablets of standard pills (ethinyl estradiol 30 µg) instead of one per day or a higher estrogen (>50 µg ethinyl estradiol) pill. Furthermore, becausethere is a chance of pill failure due to lower levels of sex hormones towards the end of 7-day hormone free period despite high doses, pills should be given in a tricycling or continuous regimen.[35] In tricycling regimen, two oral pills (equivalent to 60 µg ethinyl estradiol) are given consecutively for 3–4 cycles followed by a shorter 4-day break. This regimen assures much better contraceptive efficacy. If breakthrough bleeding occurs toward the end of each tricycle, changing to two cycle regimen, but still with a short 4-day break, often helps. In continuous regimen, same dose of pills is given continuously till breakthrough bleeding occurs, when the woman can stop the pill for 3–4 days.[34]

In cases where it is planned to switch over to ENIAEDs, the higher dose of oral pills should be maintained for at least one 28-day cycle because the effects of enzyme induction may last for 4 weeks. Though patients may be concerned about the side effects of high dose oral pills, they should be counselled by explaining that the side effects are related to the blood levels of the hormones, which in any case are expected to be the same.

Emergency contraception in WWE on EIAEDs has already been discussed. Progestogen-only pills are usually not recommended for WWE taking EIAEDs due to high rates of contraceptive failure. In women who are already on progestogen-only pills and are planned for EIAEDs, it is better to switch over to alternate forms of contraception.[34]

If a woman using EIAEDs finally chooses to take COCs, the risk of contraception failure should be discussed in detail and additional contraception [barrier methods, nonhormonal intrauterine devices (IUDs)] may be provided if deemed appropriate after thorough discussion with the woman and her partner.[10]

Women already taking hormonal pills and requiring antiepileptic drugs

Sex hormones (especially estrogens) can induce CYP450 enzymes, thereby increasing the elimination of AEDs metabolized by CYP450 family of enzymes, resulting in breakthrough seizures. This can occur even within a week of starting the hormonal contraception. Thus, it is better to use drugs which are not metabolized by CYP450 group of enzymes such as levetiracetam. Alternatively, dose of AEDs may have to be adjusted based on their blood levels.

Special considerations while using lamotrigine concurrently with hormonal contraception



  1. If AED therapy is required for a woman who is using hormonal contraception other than LNGIUS, consider a drug other than lamotrigine. If still considered, escalate the dose of the lamotrigine to achieve seizure control as is done for all other patients
  2. If hormonal contraception is being planned for a woman who is already taking lamotrigine, consider alternate forms of contraception. If still hormonal contraception is chosen, double the dose of lamotrigine at the same time as starting a COC pill. To avoid side effects related to doubling of lamotrigine levels during the hormone-free period, use tricycling or continuous treatment
  3. While stopping combined hormonal contraception in a woman who is taking lamotrigine, reduce the dose of lamotrigine
  4. The progesterone implant, depot medroxyprogesterone acetate, and LNGIUS are all safe in women taking lamotrigine.


In women who are also taking other EIAEDs with lamotrigine, the dose adjustments are not necessary because EIAEDs also induce glucuronyltransferase activity and estrogens do not add significantly to this effect. Monitoring of blood levels of lamotrigine is helpful in determining appropriate dosing of lamotrigine in women simultaneously taking hormonal pills.[1],[34]

Medical eligibility criteria for contraception

Recently, the WHO working group has given guidelines to use contraception as per grading of the associated medical condition. According to this, risk associated with the use of combined hormonal pills, patches and vaginal rings in women taking EIAEDs or lamotrigine outweighs the benefits. Thus, for WWE on EIAEDs, alternate methods of contraception such as injectable hormonal contraception, intrauterine devices or intrauterine systems should be considered. The Center for Disease Control, Atlanta, USA and the Faculty of Sexual and Reproductive Healthcare, UK have provided similar guidelines.[1]


  Conclusion Top


Using the above-described protocols, physicianscan combine the optimal AED (according to the type of epilepsy and profile of the patient) with a safe and acceptable contraceptive option. However, this decision requires discussion of all the available contraception options and a due consideration to all the potential advantages and the side effects of chosen combinations.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Tables

  [Table 1], [Table 2], [Table 3]


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1 Interactions avec les contraceptifs. RPC Contraception CNGOF
M. Bernier,A.-P. Jonville-Bera
Gynécologie Obstétrique Fertilité & Sénologie . 2018;
[Pubmed] | [DOI]



 

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Methods of Contr...
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