Women and Epilepsy FACES Patricia Dugan, MD 2014 Annual Epilepsy Conference April 27, 2014 Patricia Dugan, MD Assistant Professor of Neurology NYU Langone Medical Center Comprehensive Epilepsy Center

Beyond Seizure Control: Key Issues That Affect Women Taking AEDs Menstrual cycle abnormalities Cosmetic side effects Bone health Sexual dysfunction Family planning Pregnancy and Fetal Outcomes Breast-feeding

Puberty: onset of reproductive life Age of onset 7-14 yrs Changes in epilepsy phenotype-genetic syndromes may remit or arise Changes in AED pharmacokinetics Compliance/seizure provoking behaviors

Sex Steroid Hormones and Epilepsy Estrogen may be proconvulsant Reduces inhibition at GABAA receptor Alters mRNA for GAD and inhibits GABA synthesis Progesterone may be an anticonvulsant Increases inhibition at GABAA receptor Attenuates excitation of glutamate in hippocampus Alters mRNA for GAD and increases GABA synthesis GABA = -aminobutyric acid; mRNA = messenger ribonucleic acid; GAD = glutamic acid decarboxylase. Morrell MJ. Neurology. 1999;53(suppl 1):S42-S48. Woolley CS, Schwartzkroin PA. Epilepsia. 1998;39(suppl 8):S2-S8.

Catamenial Seizures Katamenios = “monthly” The tendency for increased seizures related to the menstrual cycle Changes in seizure patterns may begin with hormonal fluctuations at menarche and continue during the menstrual cyclea,b 30%-50% have epileptic patterns that correspond to their menstrual cycleb,c Vulnerability to seizures is highest just before and during flow and at ovulation (relatively high estrogen and low progesterone levels) aHerzog AG, et al. Epilepsia. 1997;38:1082-1088. bCramer JA, Jones EE. Epilepsia. 1991;32(suppl 6)S19-S26. cMorrell MJ. In: Wyllie E, ed. The Treatment of Epilepsy: Principles and Practice. 2nd ed. Baltimore, Md: Williams & Wilkins; 1997:179-187.

Treatment of Catamenial Epilepsy Difficult to control with AEDs Increasing doses of AEDs premenstrually may be beneficial Important to monitor serum levels to avoid under- or overdosing Acetozolamide of limited benefit Natural progesterone for women with regular menses

Cosmetic side effects Connective tissue effects & coarsening of features: PHT & PB Hirsuitism: PHT Hair loss: VPA Weight gain: VPA, PGB, GBP, CBZ

Effects of AEDs on Body Weight Weight change important consideration Leads to health hazards Impairs body image and self-esteem Leads to noncompliance Most data anecdotal Actual incidence and magnitude unknown Mechanisms unclear Biton V. CNS Drugs. 2003;17(11):781-791.

Effects of AEDs on Body Weight Gain Neutral Loss Valproate Lamotrigine Topiramate Gabapentin Levetiracetam Zonisamide Carbamazepin Phenytoin Felbamate Pregabaline Lacosamide

Manifestations of Bone Disease Osteopenia/Osteoporosis AEDs reported as a secondary cause Increased rates at multiple sites including hip and lumbar spine Osteomalacia Increased osteoid or unmineralized bone Most studies in institutionalized persons Confounded by poor diet, inadequate sunlight, limited exercise Andress DL, et al. Arch Neurol. 2002;59(5):781-786. Farhat G,et al. Neurology. 2002;58(9):1348-1353. Pack AM, et al. Epilepsy Behav. 2003;4(2):169-174. Sato Y, et al. Neurology. 2001;57(3):445-459. Valimaki MJ, et al. J Bone Miner Res. 1994;9(5):631-637.

Percentages of Osteopenia and Osteoporosis at Femoral Neck Men and Women < 50 Men and Women ≥ 50 Hip fractures increased by 29% in women > 65 y/o taking AEDs! Pack et al. Epil and Behav. 2003;4:169-174 Ensrud et al. Neurology 2004;62(11):2051-7

Antiepileptic Drugs Associated with Bone Disease Phenobarbital, primidone, phenytoin Associated with bone loss and fractures (Gough et al., 1986; Valimaki et al., 1994; Pack et al, 2005) Carbamazepine Associated with bone loss and fracture (Hoikka et al., 1984; Verrotti et al., 2000) Valproate Associated with bone loss (Sheth et al., 1995; Sato et al., 2001) Lamotrigine Not associated with bone loss (Pack et al, 2005) Limited information on new drugs More severe with polytherapy and prolonged use and institutionalization (Bogliun et al., 1986; Gough et al., 1986; Chung et al., 1994)

Sexual Dysfunction and Hormones in Women With Epilepsy Women ages 18 to 40, cycling, at least 4 years post-menarche and taking a single AED Sexual dysfunction more prevalent in women receiving enzyme-inducing AEDs than in controls (P<.05) Deficits in sexual desire correlated with reductions in androgens Deficits in sexual arousal correlated with reductions in estrogen Sexual dysfunction also associated with comorbid depression Morrell M, et al. Epilepsy Behav 2005;6(3):360-5.

AEDs and Contraception High potential for interaction between some AEDs and oral contraceptives (OCs) since both utilize isoenzyme CYP 3A4 OCs are metabolized by liver, highly protein-bound and have low and variable bioavailability Inducing effects of some AEDs on estradiol and progesterone may explain OC failure

Family Planning for Women Taking AEDs: Interaction With Hormonal Contraception Potential Interaction No Reported Interaction Carbamazepine* Benzodiazepines Phenobarbital* Gabapentin Lamotrigine Levetiracetam Phenytoin* Pregabalin Oxcarbazepine* Valproate Topiramate*† *P450 inducers may decrease efficacy of oral contraceptives. †At higher dosages only. ‡ Oral contraceptives may reduce lamotrigine plasma levels. Morrell MJ, et al. J Womens Health Gend Based Med. 2000;9:959-965.

Issues for women with Epilepsy planning pregnancy Fertility “Can I get pregnant?” AED selection “Should I be on an AED?” “If so, am I on the best AED?” Seizure control “Will my seizure control change during pregnancy?”

Issues for women with Epilepsy planning pregnancy Drugs generally contraindicated in pregnancy Women with epilepsy are unable to stop using AEDs Increases risk of seizures Injury Miscarriage Developmental delay Loss of job or driving privileges Risk of cognitive decline Complications of pregnancy and labor Risk of congenital malformations may be increased by AED therapy

Can I get pregnant?

Fertility Rate in Women with Epilepsy (WWE) Population: Fertility rate: WWE* 47.1 livebirths per 1,000 women Women in the general population* 62.6 livebirths per 1,000 women *Women aged 15-44 years in England and Wales, 1991-1995 Wallace H, Shorvon S, Tallis R. Age-specific incidence and prevalence rates of treated epilepsy in an unselected population of 2,052,922 and age-specific fertility rates in women with epilepsy. Lancet 1998; 352: 1970-73.

Do WWE choose to have children less often? 33% of WWE do not consider having children because of their epilepsy Crawford P and Hudson S. Understanding the information needs of women with epilepsy at different lifestages: results of the ‘Ideal World’ survey. Seizure 2003; 12: 502-7.

Does the marriage rate in WWE affect the fertility rate? Individuals with epilepsy are less likely to marry. The fertility deficit persists when analysis is restricted to married individuals only. Individuals with epilepsy are less likely to choose to have children Schupf N and Ottoman R. Likelihood of pregnancy in individuals with idiopathic/cryptogenic epilepsy: social and biological factors. Epilepsia 1994; 35(4): 750-56.

Does polytherapy worsen infertility? A prospective cohort of WWE enrolled in the Kerala (India) Registry of Epilepsy and Pregnancy (1998–2007) in the preconception stage. Out of 375 women followed up for 1–10 years, 231 had pregnancy and 144 remained infertile (38.4%). Infertility was least (7.1%) for those with no antiepileptic drug (AED) exposure and higher (p = 0.001) with AED exposure (31.8% with 1 AED, 40.7% with 2 AED, and 60.3% with 3 or more AED exposure). Sukumaran SC, Sarma PS, Thomas SV. Polytherapy increases the risk of infertility in women with epilepsy. Neurology. 2010 Oct 12;75(15):1351-5

Does frequency of sexual activity in WWE affect fertility rates? Individuals with epilepsy have higher prevalence of sexual dysfunction Contributing factors: psychosocial influences, comorbid depression, effects of epilepsy and AEDs The stigma of epilepsy may affect sexual experience and satisfaction Harden, C. Sexuality in women with epilepsy. Epilepsy and Behavior 2005; Suppl 2:S2-6.

Reproductive dysfunction Common among WWE and manifested as: menstrual disorder, hirsutism, infertility Both epilepsy and AEDs can target a number of substrates that affect hormone levels. This include: limbic system hypothalamus pituitary peripheral endocrine glands liver adipose tissue ? Herzog et al, 2003

Menstrual irregularities Estimated to occur in one third of WWE as compared with 12 to 14% of women in the general population. Cycle intervals between 26 and 32 days, rather than the currently popular broader range of 21 to 35 days, should be considered normal in women with epilepsy because in WWE ovulatory rates drop from 75% to less than 50%, outside of the 26 to 32 day range. Herzog and Friedman, 2001

Polycystic Ovary Syndrome (PCOS) It occurs in 10 to 20% of women with epilepsy compared with 5 to 6% of women in the general population. Syndrome defined by: Hirsutism, obesity, acne Elevated androgens and LH/FSH ratio Chronic anovulation Insulin resistance Polycystic ovaries not required Syndrome associated with: Carbohydrate intolerance (weight gain) Elevated LDL and reduced HDL 3 increased risk for endometrial cancer 2001 Novartis Core T3 Martha J. Morrell M.D. LH = luteinizing hormone; FSH = follicle-stimulating hormone; LDL = low-density lipoprotein; HDL = high-density lipoprotein. Azziz R, et al. J Clin Endocrinol Metab. 2004;89:2745-2749.

Clinical Features of PCOS Hyperandrogenism Symptoms may include: Hirsutism Acne Male pattern balding and/or male distribution of body hair Hirsutism Clinical Features of PCOS. Hyperandrogenism. Hyperandrogenemia is a key feature of PCOS, and it may appear as hirsutism, acne, male pattern balding, and/or male distribution of body hair.1 Reference 1. Lobo RA, et al. Ann Intern Med. 2000;132:989-993. Acne Lobo RA, et al. Ann Intern Med. 2000;132:989-993.

How about ovulation? 20% of cycles are anovulatory in women with catamenial epilepsy Could impact pregnancy rates Quigg et al, Epilepsia. 2008 Jun;49(6):1081-5.

Should I be on an AED? Women should only have AEDs discontinued in preparation for pregnancy IF: They have been seizure free for ≥ 2 years They accept the risk of seizure recurrence They are willing to wait AT LEAST 6 months before attempting pregnancy

AED management before pregnancy You may choose to switch to another drug with more expected safety in pregnancy This must be done long before conception as the risk of birth defects is higher in the 1st trimester of pregnancy. It’s not known how well the new AED will work or if it’ll have side effects Changing to another AED during pregnancy poses risk of multi-drug exposure, allergy and other serious side effects

Major Malformation Rates AED Teratogenicity Major Malformation Rates AED Monotherapy 4.5% AED Polytherapy 8.6% No AED 0% Healthy Controls 1.8% 128,049 women screened at delivery from 1986-1993 in Boston Holmes et al. NEJM 2001;344:1132-8

Major Malformations Associated with Commonly Used AEDs Drug Phenytoin Phenobarbital Valproic Acid Carbamazepine Cardiac defects Yes Orofacial clefting GU defects NT defects Dysmorphic syndrome GU=genitourinary; NT=neural tube

AAN/AES GUIDELINES It is highly probable that intrauterine first-trimester valproate (VPA) exposure has higher risk of major congenital malformations (MCMs) compared to carbamazepine (CBZ), and possibly compared to phenytoin (PHT) or lamotrigine (LTG). It is probable that VPA as part of polytherapy and possible that VPA as monotherapy contribute to the development of MCMs. AED polytherapy probably contributes to the development of MCM compared to monotherapy. CONCLUSION: If possible, avoidance of VPA and AED polytherapy during the first trimester of pregnancy should be considered to decrease the risk of MCMs.

Single Drug vs. Multidrug It is better to be on one drug at the lowest dose that controls seizures. The risk of major malformations is 2 to 7% for those on a single drug as compared to 6 to 18% for those on a multi-drug regimen, particularly if it includes VPA. 1,2 BUT… Having a tonic-clonic seizure during pregnancy could potentially cause harm to the fetus. Therefore, if one AED does not control seizures, it is better to be on two drugs than to have seizures. 1. Holmes et al., N Engl J Med 2001 2. Artma et al., Neurology 2005

Risks of Seizures Fetal Risks Maternal Risks Intracranial Hemorrhage Weiss Fetal Risks Intracranial Hemorrhage Suppression of Fetal HR Miscarriages Abruptio Placenta: Minor blunt trauma 1-5% Major blunt trauma 20-50% Maternal Risks Death rate during pregnancy in women with epilepsy increased X10, primarily due to seizures in UK study Trauma leading cause of non-obstetrical cause of death in pregnant women with epilepsy

So what about... ? ? No evidence that folic acid specifically reduces the risk of teratogenicity due to AEDs New evidence may indicate that folic acid improves cognitive functional outcomes All women of childbearing potential, with or without Epilepsy should be supplemented with at least 0.4 mg of folic acid daily before conception and during pregnancy, particularly during the first trimester. There is insufficient data addressing folic acid dosing and whether higher doses offer greater protective benefit.

Will seizure control change during pregnancy? Reasons for changes in AED levels during pregnancy “Reasoned” noncompliance Malabsorption Increased AED Elimination Change in Volume of Distribution 40-60% decrease in total ABLs for CBZ, PB, & PHT (less for free levels) Mean clearance of LTG increased 185%

Monitoring AED levels Ideally should be done regularly throughout pregnancy in women receiving: Lamotrigine Carbamazepine Phenytoin Levetiracetam, oxcarbazepine* AED doses are increased systematically during pregnancy After delivery, need to reduce some AED doses rapidly to prevent toxicity – discuss action plan well before delivery date!

Delivery! AAN & AES: for WWE taking AEDS, probably no substantially increased risk cesarean delivery or late-pregnancy bleeding, and probably no moderately increased risk of premature contractions or premature labor and delivery WWE taking AEDs compared to WWE not taking AEDS: do have an increased risk of mild preeclampsia, genstaion HTN, vaginal bleeding late in pregnancy and delivery before 34 wks AOG Also, babies of WWE taking AEDs possibly have an increased risk of complications just right after birth. Therefore, hospital delivery should be encouraged! Seizure provoking factors: sleep deprivation, changes in AED pharmacokinetics

Breastfeeding and AEDs Breastfeeding is not contraindicated! Assess risks and benefits for individual patients Generally safe. Benefit of breast-feeding in general population is established but risk if mother is taking AED is unknown AED concentration in breast milk related to protein binding1 PB and other sedating AEDs may cause sedation or poor feeding1 American Academy of Neurology encourages breastfeeding with close observation of baby2 Zahn CA, et al. Neurology. 1998;51:949-956. Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 1998;51:944-948.

Role of Pregnancy Registries To facilitate monitoring fetal outcomes of pregnant women1 Systematic epidemiology study2 Collection and assessment of postmarketing data on potential adverse health effects to the mother, fetus, or infant caused by exposure to a drug or other biological agent during pregnancy2 Provides information that can be included in product labeling2 Can assess suspected or unknown risks2 1Lamotrigine [product information]. Research Triangle Park, NC: GlaxoSmithKline, 2003. 2FDA Guidance for Industry: Establishing Pregnancy Registries. Draft Guidance. http://www.fda.gov/cber/gdlns/pregnancy.pdf. Accessed June 27, 2002.

Epilepsy at Menopause Perimenopause Menopause Fluctuations in ovarian steroid levels may exacerbate or diminish seizuresa,b Menopause Seizures may improveb Improvement most likely in those with catamenial patternb HRT with menopause may worsen seizuresb HRT= hormone replacement therapy aAbbasi F, et al. Epilepsia. 1999;40(2):205-210. bHarden CL, et al. Epilepsia. 1999;40(10):1402-1407.

CONCLUSIONS TALK TO YOUR EPILEPTOLOGIST ABOUT: PREGNANCY: Menstrual history Contraceptive planning Sexual dysfunction Weight Bone health PREGNANCY: Most WWE who become pregnant will have a healthy pregnancy and healthy baby Good care before & during pregnancy is key Special attention is warranted to keep the women and their children safe, and to ensure the optimal outcome. SUPPLEMENTATION: Folic acid in women of childbearing potential Calcium and vitamin D for all ages Vitamin K during the last month of gestation SUPPORT PREGNANCY REGISTRIES!

Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs Most WWE have normal pregnancies, but appear to be at risk for problems during pregnancy (e.g., seizures, change in medications, depression, c-sections) and adverse outcomes in their children (e.g., lower birth weight, thinking, or behavioral problems). Purpose: to establish the risk and determine the factors which contribute to those risks. Researchers want to know if epilepsy or the medicines that mothers-to-be must take to control seizures have a negative impact on the outcome of their pregnancy (e.g., OB complications, depression, seizures, or effects on their child). Determine impact of different AEDs have on the mother’s epilepsy during pregnancy (CBZ, LTG, LEV) Determine impact on the development of children exposed to these medications during pregnancy.

MONEAD Interested in enrolling? Up to 20 weeks pregnant Between 14-45 years old Site Investigator: Jacqueline French, M.D.  Contact: Ben Kaufman  Benjamin.Kaufman@nyumc.org  Phone: 646-558-0843  www.moneadstudy.org/‎

Thank you for your attention! Many thanks to Dr. Jackie French and Dr. Blanca Vazquez for generously loaning their slides!