Presentation on theme: "Women and Epilepsy FACES Patricia Dugan, MD"— Presentation transcript:
1Women and Epilepsy FACES Patricia Dugan, MD 2014 Annual Epilepsy ConferenceApril 27, 2014Patricia Dugan, MDAssistant Professor of NeurologyNYU Langone Medical CenterComprehensive Epilepsy Center
2Beyond Seizure Control: Key Issues That Affect Women Taking AEDs Menstrual cycle abnormalitiesCosmetic side effectsBone healthSexual dysfunctionFamily planningPregnancy and Fetal OutcomesBreast-feeding
3Puberty: onset of reproductive life Age of onset 7-14 yrsChanges in epilepsy phenotype-genetic syndromes may remit or ariseChanges in AED pharmacokineticsCompliance/seizure provoking behaviors
4Sex Steroid Hormones and Epilepsy Estrogen may be proconvulsantReduces inhibition at GABAA receptorAlters mRNA for GAD and inhibits GABA synthesisProgesterone may be an anticonvulsantIncreases inhibition at GABAA receptorAttenuates excitation of glutamate in hippocampusAlters mRNA for GAD and increases GABA synthesisGABA = -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.
5Catamenial Seizures Katamenios = “monthly” The tendency for increased seizures related to the menstrual cycleChanges in seizure patterns may begin with hormonal fluctuations at menarche and continue during the menstrual cyclea,b30%-50% have epileptic patterns that correspond to their menstrual cycleb,cVulnerability 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: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:
6Treatment of Catamenial Epilepsy Difficult to control with AEDsIncreasing doses of AEDs premenstrually may be beneficialImportant to monitor serum levels to avoid under- or overdosingAcetozolamide of limited benefitNatural progesterone for women with regular menses
7Cosmetic side effectsConnective tissue effects & coarsening of features: PHT & PBHirsuitism: PHTHair loss: VPAWeight gain: VPA, PGB, GBP, CBZ
8Effects of AEDs on Body Weight Weight change important considerationLeads to health hazardsImpairs body image and self-esteemLeads to noncomplianceMost data anecdotalActual incidence and magnitude unknownMechanisms unclearBiton V. CNS Drugs. 2003;17(11):
9Effects of AEDs on Body Weight GainNeutralLossValproateLamotrigineTopiramateGabapentinLevetiracetamZonisamideCarbamazepinPhenytoinFelbamatePregabalineLacosamide
10Manifestations of Bone Disease Osteopenia/OsteoporosisAEDs reported as a secondary causeIncreased rates at multiple sites including hip and lumbar spineOsteomalaciaIncreased osteoid or unmineralized boneMost studies in institutionalized personsConfounded by poor diet, inadequate sunlight, limited exerciseAndress DL, et al. Arch Neurol. 2002;59(5):Farhat G,et al. Neurology. 2002;58(9):Pack AM, et al. Epilepsy Behav. 2003;4(2):Sato Y, et al. Neurology. 2001;57(3):Valimaki MJ, et al. J Bone Miner Res. 1994;9(5):
11Percentages of Osteopenia and Osteoporosis at Femoral Neck Men and Women < 50Men and Women ≥ 50Hip fractures increased by 29% in women > 65 y/o taking AEDs!Pack et al. Epil and Behav. 2003;4:Ensrud et al. Neurology 2004;62(11):2051-7
12Antiepileptic Drugs Associated with Bone Disease Phenobarbital, primidone, phenytoinAssociated with bone loss and fractures(Gough et al., 1986; Valimaki et al., 1994; Pack et al, 2005)CarbamazepineAssociated with bone loss and fracture (Hoikka et al., 1984; Verrotti et al., 2000)ValproateAssociated with bone loss (Sheth et al., 1995; Sato et al., 2001)LamotrigineNot associated with bone loss (Pack et al, 2005)Limited information on new drugsMore severe with polytherapy and prolonged use and institutionalization (Bogliun et al., 1986; Gough et al., 1986; Chung et al., 1994)
13Sexual Dysfunction and Hormones in Women With Epilepsy Women ages 18 to 40, cycling, at least 4 years post-menarche and taking a single AEDSexual dysfunction more prevalent in women receiving enzyme-inducing AEDs than in controls (P<.05)Deficits in sexual desire correlated with reductions in androgensDeficits in sexual arousal correlated with reductions in estrogenSexual dysfunction also associated with comorbid depressionMorrell M, et al. Epilepsy Behav 2005;6(3):360-5.
14AEDs and Contraception High potential for interaction between some AEDs and oral contraceptives (OCs) since both utilize isoenzyme CYP 3A4OCs are metabolized by liver, highly protein-bound and have low and variable bioavailabilityInducing effects of some AEDs on estradiol and progesterone may explain OC failure
15Family Planning for Women Taking AEDs: Interaction With Hormonal Contraception Potential Interaction No Reported InteractionCarbamazepine* BenzodiazepinesPhenobarbital* GabapentinLamotrigine LevetiracetamPhenytoin* PregabalinOxcarbazepine* ValproateTopiramate*†*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:
16Issues 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?”
17Issues for women with Epilepsy planning pregnancy Drugs generally contraindicated in pregnancyWomen with epilepsy are unable to stop using AEDsIncreases risk of seizuresInjuryMiscarriageDevelopmental delayLoss of job or driving privilegesRisk of cognitive declineComplications of pregnancy and laborRisk of congenital malformations may be increased by AED therapy
19Fertility Rate in Women with Epilepsy (WWE) Population:Fertility rate:WWE*47.1 livebirths per 1,000 womenWomen in the general population*62.6 livebirths per 1,000 women*Women aged years in England and Wales,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:
20Do WWE choose to have children less often? 33% of WWE do not consider having children because of their epilepsyCrawford P and Hudson S. Understanding the information needs of women with epilepsy at different lifestages: results of the ‘Ideal World’ survey. Seizure 2003; 12:
21Does 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 childrenSchupf N and Ottoman R. Likelihood of pregnancy in individuals with idiopathic/cryptogenic epilepsy: social and biological factors. Epilepsia 1994; 35(4):
22Does 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 Oct 12;75(15):1351-5
23Does frequency of sexual activity in WWE affect fertility rates? Individuals with epilepsy have higher prevalence of sexual dysfunctionContributing factors: psychosocial influences, comorbid depression, effects of epilepsy and AEDsThe stigma of epilepsy may affect sexual experience and satisfactionHarden, C. Sexuality in women with epilepsy. Epilepsy and Behavior 2005; Suppl 2:S2-6.
24Reproductive dysfunction Common among WWE and manifested as:menstrual disorder, hirsutism, infertilityBoth epilepsy and AEDs can target a number of substrates that affect hormone levels. This include:limbic systemhypothalamuspituitaryperipheral endocrine glandsliveradipose tissue?Herzog et al, 2003
25Menstrual 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
26Polycystic 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, acneElevated androgens and LH/FSH ratioChronic anovulationInsulin resistancePolycystic ovaries not requiredSyndrome associated with:Carbohydrate intolerance (weight gain)Elevated LDL and reduced HDL3 increased risk for endometrial cancer2001 Novartis Core T3Martha 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:
27Clinical Features of PCOS Hyperandrogenism Symptoms may include:HirsutismAcneMale pattern balding and/or male distribution of body hairHirsutismClinical 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.1Reference1. Lobo RA, et al. Ann Intern Med. 2000;132:AcneLobo RA, et al. Ann Intern Med. 2000;132:
28How about ovulation?20% of cycles are anovulatory in women with catamenial epilepsyCould impact pregnancy ratesQuigg et al, Epilepsia Jun;49(6):
29Should I be on an AED?Women should only have AEDs discontinued in preparation for pregnancy IF:They have been seizure free for ≥ 2 yearsThey accept the risk of seizure recurrenceThey are willing to wait AT LEAST 6 months before attempting pregnancy
30AED management before pregnancy You may choose to switch to another drug with more expected safety in pregnancyThis 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 effectsChanging to another AED during pregnancy poses risk of multi-drug exposure, allergy and other serious side effects
31Major Malformation Rates AED TeratogenicityMajor Malformation RatesAED Monotherapy 4.5%AED Polytherapy 8.6%No AED 0%Healthy Controls 1.8%128,049 women screened at delivery from in BostonHolmes et al. NEJM 2001;344:1132-8
32Major Malformations Associated with Commonly Used AEDs DrugPhenytoinPhenobarbitalValproic AcidCarbamazepineCardiac defectsYesOrofacial cleftingGU defectsNT defectsDysmorphic syndromeGU=genitourinary; NT=neural tube
33AAN/AES GUIDELINESIt 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.
34Single 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. 1,2BUT…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 20012. Artma et al., Neurology 2005
35Risks of Seizures Fetal Risks Maternal Risks Intracranial Hemorrhage WeissFetal RisksIntracranial HemorrhageSuppression of Fetal HRMiscarriagesAbruptio Placenta:Minor blunt trauma 1-5%Major blunt trauma 20-50%Maternal RisksDeath rate during pregnancy in women with epilepsy increased X10, primarily due to seizures in UK studyTrauma leading cause of non-obstetrical cause of death in pregnant women with epilepsy
36So what about ? ?No evidence that folic acid specifically reduces the risk of teratogenicity due to AEDsNew evidence may indicate that folic acid improves cognitive functional outcomesAll 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.
37Will seizure control change during pregnancy? Reasons for changes in AED levels during pregnancy“Reasoned” noncomplianceMalabsorptionIncreased AED EliminationChange in Volume of Distribution40-60% decrease in total ABLs for CBZ, PB, & PHT (less for free levels)Mean clearance of LTG increased 185%
38Monitoring AED levelsIdeally should be done regularly throughout pregnancy in women receiving:LamotrigineCarbamazepinePhenytoinLevetiracetam, oxcarbazepine*AED doses are increased systematically during pregnancyAfter delivery, need to reduce some AED doses rapidly to prevent toxicity – discuss action plan well before delivery date!
39Delivery!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 deliveryWWE 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 AOGAlso, 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
40Breastfeeding and AEDs Breastfeeding is not contraindicated!Assess risks and benefits for individual patientsGenerally safe. Benefit of breast-feeding in general population is established but risk if mother is taking AED is unknownAED concentration in breast milk related to protein binding1PB and other sedating AEDs may cause sedation or poor feeding1American Academy of Neurology encourages breastfeeding with close observation of baby2Zahn CA, et al. Neurology. 1998;51:Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 1998;51:
41Role of Pregnancy Registries To facilitate monitoring fetal outcomes of pregnant women1Systematic epidemiology study2Collection 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 pregnancy2Provides information that can be included in product labeling2Can assess suspected or unknown risks21Lamotrigine [product information]. Research Triangle Park, NC: GlaxoSmithKline, 2003.2FDA Guidance for Industry: Establishing Pregnancy Registries. Draft Guidance. Accessed June 27, 2002.
42Epilepsy at Menopause Perimenopause Menopause Fluctuations in ovarian steroid levels may exacerbate or diminish seizuresa,bMenopauseSeizures may improvebImprovement most likely in those with catamenial patternbHRT with menopause may worsen seizuresbHRT= hormone replacement therapyaAbbasi F, et al. Epilepsia. 1999;40(2):bHarden CL, et al. Epilepsia. 1999;40(10):
43CONCLUSIONS TALK TO YOUR EPILEPTOLOGIST ABOUT: PREGNANCY: Menstrual historyContraceptive planningSexual dysfunctionWeightBone healthPREGNANCY:Most WWE who become pregnant will have a healthy pregnancy and healthy babyGood care before & during pregnancy is keySpecial attention is warranted to keep the women and their children safe, and to ensure the optimal outcome.SUPPLEMENTATION:Folic acid in women of childbearing potentialCalcium and vitamin D for all agesVitamin K during the last month of gestationSUPPORT PREGNANCY REGISTRIES!
44Maternal 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.
45MONEAD Interested in enrolling? Up to 20 weeks pregnant Between years oldSite Investigator: Jacqueline French, M.D. Contact: Ben Kaufman Phone:
46Thank you for your attention! Many thanks to Dr. Jackie French and Dr. Blanca Vazquez for generously loaning their slides!