Teratogenicity 2015.pdf

Epilepsy & Behavior 52 (2015) 212–217 Contents lists available at ScienceDirect Epilepsy & Be...

Epilepsy & Behavior 52 (2015) 212–217 Contents lists available at ScienceDirect Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh Teratogenic medications and concurrent contraceptive use in women of childbearing ability with epilepsy Janki Bhakta, Jacquelyn Bainbridge, Laura Borgelt ⁎ University of Colorado Anschutz Medical Campus Skaggs School of Pharmacy and Pharmaceutical Sciences Aurora, CO, USA a r t i c l e i n f o a b s t r a c t Article history: Background: Many antiepileptic drugs (AEDs) have the potential to cause teratogenicity. We evaluated eight an- Received 10 February 2015 tiepileptic drugs (AEDs) classified as Federal Drug Administration (FDA) pregnancy category D, X, or N designa- Revised 7 July 2015 tions and having documented teratogenic effects. These include carbamazepine, ethosuximide, fosphenytoin, Accepted 4 August 2015 phenobarbital, phenytoin, primidone, topiramate, and valproate. Women with epilepsy (WWE) may need one Available online 6 November 2015 or more of these AEDs for seizure control but may be unaware of the potential teratogenicity associated with their use. In utero exposure to AEDs increases the risks for both congenital malformations and other teratogenic Keywords: Teratogen defects. Given that approximately 50% of pregnancies are unintended, it is likely that women with epilepsy taking Epilepsy these medications could unknowingly put a growing fetus at risk. For women using contraception while taking Contraception these medications, many choose combined hormonal contraceptives (CHCs). Drug–drug interactions exist be- Antiepileptic drug tween AEDs and CHCs that may decrease contraceptive efficacy. The aim of this study was to evaluate prescribing patterns for potentially teratogenic AEDs and contraceptive use in WWE of childbearing ability, including those with potential drug–drug interactions. This study also determined the number of WWE of childbearing ability prescribed potentially teratogenic AEDs and documentation of a pregnancy or contraception plan. Methods: This was a retrospective, observational study of WWE age 15–44 years, of childbearing ability, pre- scribed an AED from July 1, 2011 to June 30, 2012, and who had an appointment at the University of Colorado Hospital Outpatient Neurology Clinic (Anschutz Medical Campus). Results: One hundred fifteen women with an average age of 30.7 years and various types of seizures were eval- uated. The majority of patients were prescribed topiramate (34/115, 30%) or carbamazepine (27/115, 23%). Of the women, 30/115 (26%) had a documented contraception method when taking a potentially teratogenic AED. Of these women prescribed contraception, most (18/30, 60%) used an oral combined hormonal contracep- tive or progestin-only pill, a majority of which had a potential for a drug–drug interaction with their AEDs (16/18, 89%). Less than 7% of women received counseling on a contraception plan, and 18% of subjects received counsel- ing on a pregnancy plan. Conclusions: Most WWE of childbearing ability taking potentially teratogenic AEDs were not using contraception. Those using contraception frequently had a method that has a significant drug–drug interaction which reduces the effectiveness of contraception. Women with epilepsy of childbearing ability prescribed an AED should be using effective contraception or participating in active discussions about pregnancy planning to avoid unplanned pregnancies and possible teratogenic effects of these AEDs. Documentation about pregnancy planning or contra- ceptive use in WWE of childbearing ability is minimal and should be discussed at least annually. It is critical for providers to discuss with WWE of childbearing ability the benefits and risks of various AED treatments; the need to select appropriate, effective contraception when pregnancy is not desired; and the importance of counseling regarding contraceptive or pregnancy planning. © 2015 Elsevier Inc. All rights reserved. 1. Introduction drugs (AEDs) have been known to increase the risk of major congenital malformations and IQ deficits in the developing fetus. At the time this There are an estimated one-half million women of childbearing study was initiated, there were eight antiepileptic drugs (AEDs) age with epilepsy in the United States. The traditional antiepileptic that were documented to have teratogenic effects with FDA labels of category D, X, or N (not classified): carbamazepine, ethosuximide, fosphenytoin, phenobarbital, phenytoin, primidone, topiramate, and ⁎ Corresponding author at: Departments of Clinical Pharmacy and Family Medicine, University of Colorado Anschutz Medical Campus, 12850 E. Montview Blvd., V20-2124, valproate [2–9]. See Table 1 [10–32]. The FDA defined a category D med- Aurora, CO 80045, USA. Tel.: +1 303 724 2650. ication as having positive evidence of human fetal risk, and a category X E-mail address: [email protected] (L. Borgelt). medication as having demonstrated fetal abnormalities and/or positive http://dx.doi.org/10.1016/j.yebeh.2015.08.004 1525-5050/© 2015 Elsevier Inc. All rights reserved.  J. Bhakta et al. / Epilepsy & Behavior 52 (2015) 212–217 213 Table 1 A surprising number of physicians also do not have adequate knowl- Antiepileptic drug (AED) pregnancy category and risks. edge about these potential interactions. A questionnaire revealed that AED & pregnancy Risk nearly 30% of primary care physicians were unaware that there was category an interaction between CHCs and AEDs. In addition, approximately Carbamazepine Use during early pregnancy has been associated with an 50% of women with epilepsy taking CHCs indicate that they have never (D) increased risk of neural tube defects. Craniofacial abnormalities been given information about this specific issue by their prescribing and developmental delay have been associated [10,11]. physicians [48,49]. In addition, a study was done to assess pharmacists’ Ethosuximide Interferes with embryo development in experimental knowledge of women's issues in epilepsy using the Knowledge of (N) animals. Reported human experience with this medication (Australia — D) during pregnancy is too limited to contribute to an estimate Women's Issues and Epilepsy II questionnaire. It revealed that 75% of of birth defect risk. pharmacists knew the drug interaction between enzyme-inducing Fosphenytoin Animal teratogen. Congenital anomaly, abnormal birth AEDs and contraceptives; however, 69.1% stated that they did not (D) weight, and mental deficiency have been associated. know why there was a drug interaction between hormones and seizure Phenobarbital Animal teratogen. Congenital anomaly, abnormal birth (D) weight, and mental deficiency have been associated [14–16]. control. Thus, there are still significant gaps in knowledge for Phenytoin The spectrum of malformations is similar with many patients and health-care providers regarding this issue. Specifically, (D) anticonvulsant drugs including facial clefts and aspects of most of the studies evaluating potentially teratogenic drug use are fetal hydantoin syndrome [16–18]. observational database studies without individual patient level data. Primidone Use of agent during pregnancy has been associated with Additionally, health-care provider and patient knowledge is largely (D) an increase in birth defects [19–22]. Topiramate Produces abnormal pregnancy outcomes in experimental performed through surveys. (D) animals. Human case reports and registry data have Education and awareness of these issues are critical as the American identified both normal and abnormal pregnancy outcome Academy of Neurology has included “counseling for women of child- after topiramate exposure [23–27]. bearing potential with epilepsy” in its quality measurement set. Valproate Known teratogen to humans. Facial dysmorphology, Specifically, this quality measure aims to measure and track “all female (X — migraine) congenital heart defects, spina bifida, cleft lip and palate, (D — other and developmental delays are some of the teratogenic patients of childbearing potential (12–44 years old) diagnosed with ep- indications) effects seen [28–32]. ilepsy who were counseled or referred for counseling for how epilepsy and its treatment may affect contraception or pregnancy at least once a year”. Furthermore, counseling should include a discussion about evidence of human fetal risk in animals or humans. Women may need folic acid supplementation, contraception, potential antiseizure medica- one or more of these medications to control seizure activity, yet may tion effect(s) on pregnancy, safe pregnancies, and breastfeeding. not be aware of the potential adverse effects for a fetus. In utero expo- This retrospective analysis aimed to address these issues by provid- sure to AEDs increases the risks for both congenital malformations ing objective information about prescribing patterns for potentially ter- and other teratogenic defects. The prevalence of major congenital atogenic AEDs and contraceptive use. In addition, this study estimated malformations in offspring of women with epilepsy is estimated at 4% the number of women with epilepsy (WWE) of childbearing ability pre- to 10%, which represents a 2- to 4-fold increase compared with the scribed potentially teratogenic AEDs with a concurrent contraceptive, general population [33–36]. A recent study using the North American and documentation of a pregnancy or contraception plan. For those AED Pregnancy Registry provided estimates of the risk of major WWE using AEDs and contraception, the prevalence of potential drug malformations among infants exposed to specific AEDs as monotherapy interactions was also determined. during the first trimester of pregnancy. The reported risk of malforma- tion was 9.3% for valproate, 5.5% for phenobarbital, 4.2% for topiramate, 2. Materials and methods 3.0% for carbamazepine, and 2.9% for phenytoin. Polytherapy with AEDs is associated with a higher malformation rate than monotherapy This study was a retrospective observational study whose subjects. The most common malformations seen with AEDs are cardiac de- were selected at the University of Colorado Hospital Outpatient Neurology fects, facial clefts, hypospadias, and neural tube defects. Furthermore, Clinics (Anschutz Medical Campus) in Aurora, CO. Patients that met our studies suggest that children exposed to valproate have significantly inclusion criteria were identified using ICD-9-CM codes in the EPIC (TM) lower IQs than children exposed to other AEDs [37–42]. Given that and Epilepsy (TM) electronic health record (EHR) databases. This study approximately 50% of pregnancies are unintended, it is likely that was approved by the Colorado Institutional Review Board. women with epilepsy taking these medications could put a growing fetus at risk unknowingly. 2.1. Study population For those women that do use contraception while taking these medications, many choose combined hormonal contraceptives (CHCs). Subjects were eligible for inclusion if they were reproductive-aged They are prescribed for 17% of fertile women with epilepsy, which is women aged 15 to 44 years; diagnosed with epilepsy; and given a as frequent as all women age 15–44 years [44,45]. Many women are un- prescription for an AED with teratogenic potential (category D, X, or aware of drug interactions between CHCs and AEDs that may decrease N) from July 1, 2011 to June 30, 2012 at the University of Colorado contraceptive efficacy. Estrogens and progestogens are metabo- Hospital Neurology Clinics (Anschutz Medical Campus). The eight lized by cytochrome P450 3A4. Several AEDs, including phenytoin, phe- AEDs with a category D, X, or N are: phenobarbital, primidone, nobarbital, carbamazepine, felbamate, topiramate, oxcarbazepine and phenytoin, fosphenytoin, ethosuximide, carbamazepine, valproate, primidone, induce cytochrome P450 3A4, leading to enhanced metabo- and topiramate. Exclusion criteria included women less than 15 years lism of either or both the estrogenic and progestogenic component of and over 44 years, women that had surgical sterilization, women that CHCs, thereby reducing their efficacy in preventing pregnancy. Alterna- had early menopause, and women who had a hysterectomy. tively, CHCs can also decrease the concentrations of AEDs such as lamotrigine and, thereby, increase the risk of seizures. In one 2.2. Data collection and analysis study, 65% of women prescribed a cytochrome p450-inducing AED were unaware of decreased oral contraceptive efficacy. Forty percent For eligible patients, the EHR was scanned systematically for AEDs of those prescribed category D AEDs were unaware of potential terato- prescribed and a documented pregnancy or contraceptive plan. Data genic effects. Women simultaneously using hormonal contracep- were collected into a Microsoft Access database and included patient tion and AEDs must be aware of the potential drug interactions as well demographics: prescribed AEDs, duration of treatment and dose, con- as potential teratogenic effects. comitant medications (including contraception), documentation of a 214 J. Bhakta et al. / Epilepsy & Behavior 52 (2015) 212–217 Table 2 therapy consisting of phenobarbital, carbamazepine and topiramate in Demographics. 1/115 (~1%). Common combination therapies with a CYP inducer and Demographics Total a noninducer included carbamazepine and valproate in 4/115 (3%), car- (N = 115) bamazepine and phenytoin in 2/115 (~2%), topiramate and valproate in Age 30.7 ± 6.7 4/115 (3%), and valproate and phenytoin in 3/115 (~ 3%). None of the mean ± SD, (range) (16–43) patients received fosphenytoin during the time period as it is only avail- Smoking status, n (%) able as a parenteral formulation and mainly used in a hospital setting for Current smoker 22 (19) seizure control. Former smoker 8 (7) Never assessed 6 (5) No history of smoking 79 (69) 3.2. Contraception use Seizure type, n (%) Unspecified 13 (11) As shown in Fig. 2, 30/115 (26%) of women had a documented Simple partial 18 (16) Complex partial 20 (18) contraception method when taking a potentially teratogenic AED. Of Primary generalized 28 (24) those 30 patients, 15 (50%) were on an oral combined hormonal contra- Other⁎ 36 (31) ceptive, 3 (10%) were on a progestin-only pill or implant, 5 (17%) were ⁎ Lennox–Gastaut, juvenile myoclonic, secondary generalized, un- on depot medroxyprogesterone acetate, and 7 (23%) were on an intra- sure of type, combination of the above. uterine device (either levonorgestrel or copper). For the patients on the combined hormonal contraceptive, 13/15 women had a potential for a drug–drug interaction with their AEDs as well as 1 out of 3 subjects contraceptive or pregnancy plan, pregnancy status, tobacco use (and that were on the progestin-only pill or implant. Two women not taking other illicit drug use) status, and seizure history. Data were analyzed the contraception became pregnant while on the category D or X AED. using descriptive statistics. One had a miscarriage, and one received an abortion after learning of the pregnancy. After the events, one of the patients was immediately 3. Results placed on a contraception plan. 3.1. Sample characteristics 3.3. Counseling on contraception/pregnancy plan A total of 173 patients were screened, and we identified 115 subjects Table 3 describes the percentage of patients that were documented that met inclusion criteria. Table 2 describes the characteristics of the to have received counseling on a pregnancy plan or a contraception study population. The average age was 30.7 years, and seizure types plan between July 1, 2011 and June 30, 2012. Counseling for the contra- varied across the spectrum. Sixty-nine percent of the women had no ception plan included documented discussion between the provider history of smoking. Fig. 1 displays the number of patients who were and patient about any drug–drug interactions between AED and contra- on the AEDs of interest as well as the number of subjects on AEDs that ception, an appropriate type of contraception, and/or documented are CYP inducers. Topiramate, carbamazepine, phenytoin, phenobarbi- referral or discussion with their obstetrician/gynecologist about an ap- tal, and primidone are all CYP inducers. The majority (34/115, 30%) propriate type of contraception. Counseling regarding a pregnancy of patients were prescribed topiramate. Carbamazepine was prescribed plan included documented discussion between provider and patient in 27/115 (23%) of patients. Approximately 25% of the subjects (29/115) about the possible teratogenic effects of the medication on the fetus were on a combination of two or more AEDs that included only CYP in- and a planned pregnancy. In the given time frame, less than 7% of sub- ducers (11/115, 10%) or a non-CYP inducer plus a CYP inducer (18/115, jects received counseling on a contraception plan, and 18% of subjects 16%). Combination therapy with subjects on all CYP inducers included received counseling on a pregnancy plan. For 36 women that were pre- carbamazepine + topiramate in 7/115 (6%), carbamazepine + phenyt- scribed the AED for the very first time or had tried the AED in the past oin in 2/115 (2%), topiramate + phenytoin in 1/115 (~1%), and triple and were restarted in the given year of interest, 4 received counseling Fig. 1. Antiepileptic drug (AED) regimens and CYP inducers.  J. Bhakta et al. / Epilepsy & Behavior 52 (2015) 212–217 215 Fig. 2. Percentage of women on contraception, method, and potential drug interactions. on a contraception plan (11%), and 8 received counseling on a pregnan- various health-care providers resulting in misunderstandings about ep- cy plan (22%). ilepsy and pregnancy, and are vulnerable to deficiencies in epilepsy and contraceptive management. Identifying those women at risk of 4. Discussion unplanned pregnancy, so as to tailor counseling and treatment to their needs, may reduce adverse pregnancy outcomes. Preconception Multiple studies have shown that women are unaware of the poten- counseling for WWE has been reported to be effective in reducing tial teratogenic effects of AEDs. Furthermore, women are unaware fetal adverse effects in children born to WWE receiving AEDs. In ad- of potential drug interactions between their contraception and their dition, planning a pregnancy with alterations in the treatment regimens AED(s). Similar trends have been reported with prescribers and can reduce the frequency of seizures during pregnancy and reduce fetal pharmacists. This study identified a significant gap in the manage- exposure to AED. Furthermore, many women lack the knowledge ment of WWE with respect to pregnancy and contraceptive planning by that being seizure-free for at least nine months prior to pregnancy in- health-care providers. Furthermore, when combined hormonal contra- creases the chance for being seizure-free during pregnancy. Studies ceptives were used, there was a high likelihood of drug interactions be- have consistently shown that women are not routinely given relevant tween the contraceptive and AED. information about pregnancy and contraceptive planning [55,56]. The These results demonstrate that less than 20% of women prescribed a women that unexpectedly became pregnant in this study emphasize category D or X AED medication received counseling regarding a preg- the need for proper counseling to avoid adverse outcomes (miscarriage nancy or contraception plan. Previous studies indicate that knowledge and abortion) while on potentially teratogenic medications. gaps exist regarding the potential teratogenic effects of AEDs and drug In this study, nearly 75% of WWE of childbearing ability prescribed interactions between AEDs and oral contraceptives. The American Acad- a category D or X AED were not on contraception. Given that 43 million emy of Neurology has developed a physician performance measure or 70% of all women in their childbearing years are at risk of unintended specifically dedicated to counseling women of childbearing potential pregnancy, this leaves a large population of WWE vulnerable to preg- with epilepsy at least once a year. This measure involves counseling nancy while taking these medications. Furthermore, of the 26% of about epilepsy and how its treatment may affect contraception and women prescribed contraception, 53% were using a method that may pregnancy. reduce contraceptive efficacy due to potential drug interactions. Any Therefore, discussing pregnancy and contraception plans are im- CHC with less than 50 mcg of estrogen is a target for a drug–drug inter- portant at least annually to determine current status of and desire for action of concurrent AED use. Progestins can also be affected by en- pregnancy. Women planning a pregnancy have been shown to zyme-inducing AEDs, and women taking POPs who are starting therapy seek out information, perceive the teratogenic risks as more threaten- with an enzyme-inducing AED should be advised to choose another ing, and be more proactive in seeking a safe pregnancy. Women form of contraception. The DMPA injection is unaffected by with unplanned pregnancy may have received inadequate advice from enzyme-inducing AEDs because approximately 100% of the drug is cleared during the first-pass effect in the liver [58,59]. Thus, methods Table 3 of contraception that are not affected by enzyme-inducing AEDS in- Counseling on contraception or pregnancy plan. clude: medroxyprogesterone acetate depot injection (Depo-Provera®), Counseling on contraception or pregnancy plan Yes No levonorgestrel-releasing intrauterine systems (e.g., Mirena®, Skyla®), n (%) n (%) and the copper intrauterine device [60–62]. Counseling AED & contraception plan (n = 115) 8 (7%) 107 (93%) There are several limitations to this study. First, this study was a Counseling AED & pregnancy plan (n = 115) 21 (18%) 94 (82%) retrospective observational study that relied solely on documentation. New AED: counseling and contraception plan 4 (11%) 32 (89%) It is possible that providers counseled patients without documentation (n = 36) or provided counseling with documentation prior to the study time New AED: counseling and pregnancy plan (n = 36) 8 (22%) 28 (78%) frame. In addition, the number of subjects on folic acid was not 216 J. Bhakta et al. / Epilepsy & Behavior 52 (2015) 212–217 collected. We believe collecting this information could make an inaccu- Topiramate. In: DRUGDEX® System [database online]. Greenwood Village, CO: Truven Health Analytics, Inc. [Updated periodically, accessed September 18, 2014]. rate assumption about pregnancy counseling because it is available over Valproic acid. In: DRUGDEX® System [database online]. Greenwood Village, CO: the counter and may not be listed in the medication record or solicited Truven Health Analytics, Inc. Updated periodically. Accessed September 18, 2014. by the provider. 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