1. 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

2. 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

3. 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

4. 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.

5. 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:
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:

6. 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

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

8. 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):

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

10. 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):
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):

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

12. 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)

13. 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.

14. 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

15. 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:

16. 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?”

17. 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

18. Can I get pregnant?

19. 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 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:

20. 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:

21. 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):

22. 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 Oct 12;75(15):1351-5

23. 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.

24. 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

25. 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

26. 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:

27. 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:
Acne
Lobo RA, et al. Ann Intern Med. 2000;132:

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

29. 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

30. 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

31. 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 in Boston
Holmes et al. NEJM 2001;344:1132-8

32. 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

33. 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.

34. 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

35. 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

36. 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.

37. 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%

38. 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!

39. 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

40. 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:
Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 1998;51:

41. 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. Accessed June 27, 2002.

42. 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):
bHarden CL, et al. Epilepsia. 1999;40(10):

43. 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!

44. 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.

45. MONEAD Interested in enrolling? Up to 20 weeks pregnant
Between years old
Site Investigator: Jacqueline French, M.D.  Contact: Ben Kaufman  Phone:  

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