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EDITORIAL

Women with : 5 clinical pearls for contraception and preconception counseling For women with epilepsy, intrauterine devices are the optimal reversible contraceptive, and, preconception, the use of antiepileptic drugs with the lowest teratogenic potential should be considered

Robert L. Barbieri, MD Editor in Chief, OBG Management Chair, Obstetrics and Gynecology Brigham and Women’s Hospital, Boston, Massachusetts Kate Macy Ladd Professor of Obstetrics, Gynecology and Reproductive Biology Harvard Medical School, Boston

n 2015, 1.2% of the US population bazepine (Aptiom), (Fel- becoming pregnant while taking the was estimated to have active epi- batol), (Trileptal), oral contraceptive.6 , Ilepsy.1 For neurologists, key goals (Fycompa), phenobarbi- a strong inducer of hepatic , in the treatment of epilepsy include: tal, (Dilantin), was the most frequently used AED in controlling , minimizing (Mysoline), (Banzel), this sample. adverse effects of antiepileptic drugs and (Topamax) (at dos- Many studies report that carba- (AEDs) and optimizing quality of ages >200 mg daily). According to mazepine accelerates the metabo- life. For obstetrician-gynecologists, Lexicomp, the following AEDs do not lisms of estrogen and progestins and women with epilepsy (WWE) have cause clinically significant changes reduces contraceptive efficacy. For unique contraceptive, preconcep- in hepatic enzymes that metabolize example, in one study 20 healthy tion, and obstetric needs that require steroid hormones: women were administered an ethi- highly specialized approaches to (Diamox), (Klonopin), nyl estradiol (20 µg)-levonorgestrel care. Here, I highlight 5 care points (Zarontin), (100 µg) contraceptive, and randomly that are important to keep in mind (Neurontin), (Vimpat), assigned to either receive carbamaze- when counseling WWE. (Keppra), pine 600 mg daily or a placebo pill.7 In (Lyrica), (Gabitril), viga- this study, based on serum progester- 1 -inducing AEDs batrin (Vigadrone), and one measurements, 5 of 10 women in reduce the effectiveness (Zonegran).2,3 In addition, lamotrig- the carbamazepine group ovulated, of estrogen-progestin and ine (Lamictal) and (Depa- compared with 1 of 10 women in the some progestin contraceptives. kote) do not significantly influence placebo group. Women taking car- AEDs can induce hepatic enzymes the metabolism of contraceptive bamazepine had integrated serum that accelerate steroid hormone steroids,4,5 but contraceptive steroids ethinyl estradiol and levonorgestrel metabolism, producing clinically significantly influence their metabo- concentrations approximately 45% important reductions in bioavail- lism (TABLE 2, page 16). lower than women taking placebo.7 able steroid hormone concentra- For WWE taking an AED that Other studies also report that carbam- tion (TABLE 1, page 10). According accelerates steroid hormone metab- azepine accelerates steroid hormone to Lexicomp, AEDs that are induc- olism, estrogen-progestin contracep- metabolism and reduces the circulat- ers of hepatic enzymes that metab- tive failure is common. In a survey of ing concentration of ethinyl estradiol, olize steroid hormones include: 111 WWE taking both an oral con- norethindrone, and levonorgestrel by carbamazepine (Tegretol), eslicar- traceptive and an AED, 27 reported about 50%.5,8

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WWE taking an AED that induces an estrogen-progestin contracep- The effectiveness of levonorg- hepatic enzymes should be coun- tive is to be prescribed, safeguards to estrel emergency contraception seled to use a copper or levonorg- reduce the risk of pregnancy include: may also be reduced in WWE tak- estrel (LNG) intrauterine device • prescribe a contraceptive with ing an enzyme-inducing AED. In (IUD) or depot medroxyprogesterone ≥35 µg of ethinyl estradiol these cases, some experts recom- acetate (DMPA) for contraception.9 • prescribe a contraceptive with mend a regimen of two doses of WWE taking AEDs that do not induce the highest dose of progestin with levonorgestrel 1.5 mg, separated by hepatic enzymes can be offered the a long half-life (drospirenone, 12 hours.10 The effectiveness of pro- full array of contraceptive options, as , levonorgestrel) gestin subdermal contraceptives outlined in Table 1. Occasionally, a • consider continuous hormonal may be reduced in women tak- WWE taking an AED that is an inducer contraception rather than 4 or ing phenytoin. In one study of 9 of hepatic enzymes may strongly pre- 7 days off hormones and WWE using a progestin subdermal fer to use an estrogen-progestin con- • recommend use of a barrier con- implant, phenytoin reduced the traceptive and decline the preferred traceptive in addition to the hor- circulating levonorgestrel level by option of using an IUD or DMPA. If monal contraceptive. approximately 40%.11

TABLE 1 Lexicomp risk, severity, and reliability rating of potential interactions between AED and accelerated metabolism of estrogen and progestin contraceptive hormones2,a Is the antiepileptic medication an inducer of hepatic enzymes that can accelerate the inactivation of estrogen and/or progestin contraceptive hormones?

YES NO

Lexicomp risk (letter grade), severity, and reliability rating for Antiepileptic AED interaction with estrogen- Antiepileptic Lexicomp rating- interaction with medication progestin contraceptive medication estrogen-progestin contraceptive Carbamazepine D rating-consider therapy modification, Acetazolamide A rating. No known interactions with (Tegretol) Severity Major, Reliability Good (Diamox) estrogen or progestin hormones Eslicarbazepine D rating-consider therapy modification, Clonazepam A rating. No known interactions with (Aptiom) Severity Major, Reliability Good (Klonopin) estrogen or progestin hormones Felbamate (Felbatol) D rating-consider therapy modification, Ethosuximide A rating. No known interactions with Severity Major, Reliability Good (Zarontin) estrogen or progestin hormones Oxcarbazepine D rating-consider therapy modification, Gabapentin A rating. No known interactions with (Trileptal) Severity Major, Reliability Good (Neurontin) estrogen or progestin hormones Perampanel D rating-consider therapy modification, Lacosamide B rating. May increase the serum (Fycompa) Severity Major, Reliability Fair (Vimpat) concentration of ethinyl estradiol by 20%. Severity Minor, Reliability Fair D rating-consider therapy modification, Levetiracetam A rating. No known interactions with Severity Major, Reliability Fair. Also (Keppra) estrogen or progestin hormones induces CYP3A4 Phenytoin (Dilantin) D rating-consider therapy modification, Pregabalin (Lyrica) A rating. No known interactions with Severity Major, Reliability Fair estrogen or progestin hormones Primidone (Mysoline) D rating-consider therapy modification, Tiagabine (Gabitril) A rating. No known interactions with Severity Major, Reliability Fair estrogen or progestin hormones Rufinamide (Banzel) D rating-consider therapy modification, A rating. No known interactions with Severity Major, Reliability Fair (Vigadrone) estrogen or progestin hormones Topiramate D rating-consider therapy modification, Zonisamide A rating. No known interactions with (Topamax) Severity Major, Reliability Good (Zonegran) estrogen or progestin hormones

aLamotrigine (Lamictal) and valproate (Depakote) are not strong inducers of hepatic enzymes. Hence, they do not accelerate the metabolism of estrogen and progestin contraceptive hormones. However, the metabolism of and valproate is accelerated by estrogen (see Table 2).

Abbreviation: AED, antiepileptic drug.

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TABLE 2 Metabolism effects of lamotrigine and valproate by estrogen medicationsa Antiepileptic medication Lexicomp risk (letter grade), severity, and reliability rating Lamotrigine (Lamictal) Estrogen may reduce lamotrigine levels. D rating-consider therapy modification, Severity Major, Reliability Good Valproate (Depakote) Estrogen may reduce valproate levels. C rating-monitor therapy. Severity Moderate, Reliability Fair

aThe metabolism of lamotrigine and valproate is accelerated by estrogen medications, resulting in a possible reduction in circulating medication concentration, increasing the risk of . Lamotrigine and valproate do not significantly accelerate the metabolism of ethinyl estradiol or levonorgestrel.

14,15 2 Do not use lamotrigine concentration, as noted in Table 2. major congenital malformations: with cyclic estrogen- In one study, estrogen-progestin spina bifida, ventricular and atrial progestin contraceptives. contraceptive was associated with septal defects, pulmonary valve atre- Estrogens, but not progestins, are 18% and 29% decreases in total sia, hypoplastic left heart syndrome, known to reduce the serum con- and unbound valproate concen- cleft palate, anorectal atresia, and centration of lamotrigine by about trations, respectively.14 Valproate hypospadias.18 50%.12,13 This is a clinically sig- may induce polycystic ovary syn- In a study of 7,555 pregnan- nificant pharmacologic interac- drome in women.16 Therefore, it cies in women using a single AED, tion. Consequently, when a cyclic is common that valproate and an the risk of major congenital anoma- estrogen-progestin contraceptive estrogen-progestin contraceptive are lies varied greatly among the AEDs, is prescribed to a woman taking co-prescribed. In these situations, the including: valproate (10.3%), phenobar- lamotrigine, oscillation in lamotrig- neurologist should be alerted prior bital (6.5%), phenytoin (6.4%), carba‑ ine serum concentration can occur. to prescribing an estrogen-progestin mazepine (5.5%), topiramate (3.9%), When the woman is taking estrogen- contraceptive to WWE taking valpro- oxcarbazepine (3.0%), lamotrigine containing pills, lamotrigine levels ate so that dosage adjustment may (2.9%), and levetiracetam (2.8%).19 decrease, which increases the risk occur, if indicated. Valproate does not For WWE considering pregnancy, of seizure. When the woman is not appear to change the metabolism of many experts recommend use of taking the estrogen-containing pills, ethinyl estradiol or levonorgestrel.5 lamotrigine, levetiracetam, or oxcar- lamotrigine levels increase, possi- bazepine to minimize the risk of fetal bly causing such adverse effects as 4 Preconception anomalies. nausea and vomiting. If a woman counseling: Before taking lamotrigine insists on using conception consider using an 5 Folic acid: Although the an estrogen-progestin contracep- AED with low teratogenicity. optimal dose for WWE tive, the medication should be pre- Valproate is a potent teratogen, and taking an AED and planning to scribed in a continuous regimen and consideration should be given to become pregnant is unknown, the neurologist alerted so that they discontinuing valproate prior to con- a high dose is reasonable. can increase the dose of lamotrig- ception. In a study of 1,788 pregnan- The American College of Obstetri- ine and intensify their monitoring cies exposed to valproate, the risk cians and Gynecologists (ACOG) of lamotrigine levels. Lamotrigine of a major congenital malformation recommends that women plan- does not change the metabolism was 10% for valproate monotherapy, ning pregnancy take 0.4 mg of folic of ethinyl estradiol and has mini- 11.3% for valproate combined with acid daily, starting at least 1 month mal impact on the metabolism of lamotrigine, and 11.7% for valpro- before pregnancy and continuing levonorgestrel.4 ate combined with another AED, through at least the 12th week of but not lamotrigine.17 At a valpro- gestation.20 ACOG also recommends 3 Estrogen-progestin ate dose of ≥1,500 mg daily, the risk that women at high risk of a neural contraceptives require of major malformation was 24% for tube defect should take 4 mg of folic valproate dosage adjustment. valproate monotherapy, 31% for val- acid daily. WWE taking a teratogenic A few studies report that estrogen- proate plus lamotrigine, and 19% for AED are known to be at increased progestin contraceptives acceler- valproate plus another AED, but not risk for fetal malformations, includ- ate the metabolism of valproate lamotrigine.17 Valproate is reported ing neural tube defects. Should these and reduce circulating valproate to be associated with the following women take 4 mg of folic acid daily?

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45% who were taking an enzyme- Epilepsy and operation of a motor vehicle inducing AED and an estrogen- progestin oral contraceptive For most women with epilepsy, maintaining a valid driver’s license is important for reported that they had not been completion of daily life tasks. Most states require that a patient with seizures be warned about the potential inter- seizure-free for 6 to 12 months to operate a motor vehicle. Estrogen-containing action between the medications.25 hormonal contraceptives can reduce the concentration of some AEDs, such as lamotrigine. Hence, it is important that the patient be aware of this interaction and Surprisingly, surveys of neurolo- that the primary neurologist be alerted if an estrogen-containing contraceptive is gists and obstetrician-gynecologists prescribed to a woman taking lamotrigine or valproate. Specific state laws related also report that there is a low level to epilepsy and driving are available at the Epilepsy Foundation website (https:// of awareness about the interac- www.epilepsy.com/driving-laws). tion between AEDs and hormonal contraceptives.26 When providing ACOG notes that, for women taking The RCOG notes that among WWE contraceptive counseling for WWE, valproate, the benefit of high-dose taking an AED, intelligence quotient prioritize the use of a copper or folic acid (4 mg daily) has not been is greater in children whose mothers levonorgestrel IUD. When providing definitively proven,21 and guide- took folic acid during pregnancy.24 preconception counseling for WWE, lines from the American Academy Given the potential benefit of folic educate the patient about the high of Neurology do not recommend acid on long-term outcomes and the teratogenicity of valproate and the high-dose folic acid for women known safety of folic acid, it is rea- lower risk of malformations asso- receiving AEDs.22 Hence, ACOG does sonable to recommend high-dose ciated with the use of lamotrigine, not recommend that WWE taking an folic acid for WWE. levetiracetam, and oxcarbazepine. AED take high-dose folic acid. By contrast, the Royal College Final takeaways of Obstetricians and Gynecologists Surveys consistently report that (RCOG) recommends that all WWE WWE have a low-level of aware- planning a pregnancy take folic acid ness about the interaction between [email protected] 5 mg daily, initiated 3 months before AEDs and hormonal contraceptives conception and continued through and the teratogenicity of AEDs. For Dr. Barbieri reports no financial rela- the first trimester of pregnancy.23 example, in a survey of 2,000 WWE, tionships relevant to this article.

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