Women and Epilepsy

FACES2014 Annual Epilepsy Conference

April 27, 2014

Patricia Dugan, MDAssistant Professor of Neurology

NYU Langone Medical CenterComprehensive 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

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

Pack et al. Epil and Behav. 2003;4:169-174

Ensrud et al. Neurology 2004;62(11):2051-7

Hip fractures increased by 29% in women > 65 y/o taking AEDs!

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 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;9:959-965.

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?”

• 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

Issues for women with Epilepsy planning pregnancy

Can I get pregnant?

Fertility Rate in Women with Epilepsy (WWE)

WWE* 47.1 livebirths per 1,000 women

Women in the general population*

62.6 livebirths per 1,000 women

Population: Fertility rate:

*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

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

Lobo RA, et al. Ann Intern Med. 2000;132:989-993.

Hirsutism

Acne

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

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 PhenobarbitalValproic

Acid Carbamazepine

Cardiac defects

Yes Yes Yes

Orofacial clefting

Yes Yes Yes

GU defects Yes Yes

NT defects Yes Yes

Dysmorphic syndrome

Yes Yes Yes Yes

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– 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

Weiss

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

1. Zahn CA, et al. Neurology. 1998;51:949-956.2. Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 1998;51:944-948.

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

CONCLUSIONS• TALK TO YOUR EPILEPTOLOGIST ABOUT:

– 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

Site Investigator: Jacqueline French, M.D. Contact: Ben Kaufman Benjamin.Kaufman@nyumc.org Phone: 646-558-0843

www.moneadstudy.org/

Interested in enrolling?• Up to 20 weeks pregnant• Between 14-45 years old

Thank you for your attention!

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