Women and Epilepsy
FACES
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
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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.
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.
bCramer
Treatment of Catamenial Epilepsy
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Difficult to control with AEDs
Increasing doses of AEDs premenstrually
may be beneficial
– Important to monitor serum levels to avoid
under- or overdosing
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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
Valproate
Neutral
Lamotrigine
Loss
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 postmenarche 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
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High potential for interaction between some AEDs
and oral contraceptives (OCs) since both utilize
isoenzyme CYP 3A4
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OCs are metabolized by liver, highly protein-bound
and have low and variable bioavailability
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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
Carbamazepine*
Phenobarbital*
Lamotrigine
Phenytoin*
Oxcarbazepine*
Topiramate*†
No Reported Interaction
Benzodiazepines
Gabapentin
Levetiracetam
Pregabalin
Valproate
*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
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Drugs generally contraindicated in pregnancy
Women with epilepsy are unable to stop using AEDs
– Increases risk of seizures
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Injury
Miscarriage
Developmental delay
– Loss of job or driving privileges
– Risk of cognitive decline
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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:
WWE*
Fertility rate:
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:
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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)
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It occurs in 10 to 20% of women with epilepsy compared with 5 to 6% of
women in the general population.
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Syndrome defined by:
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Hirsutism, obesity, acne
Elevated androgens and LH/FSH ratio
Chronic anovulation
Insulin resistance
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Polycystic ovaries not required
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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 multidrug exposure, allergy and other serious side effects
AED Teratogenicity
Major Malformation Rates
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AED Monotherapy
AED Polytherapy
No AED
Healthy Controls
4.5%
8.6%
0%
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
Phenytoin
Phenobarbital
Valproic
Acid
Cardiac
defects
Yes
Yes
Yes
Orofacial
clefting
Yes
Yes
Yes
GU defects
Yes
Drug
Yes
NT defects
Dysmorphic
syndrome
Yes
GU=genitourinary; NT=neural tube
Carbamazepine
Yes
Yes
Yes
Yes
Yes
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).
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It is probable that VPA as part of polytherapy and possible that VPA
as monotherapy contribute to the development of MCMs.
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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
Weiss
Risks of Seizures
• Fetal Risks
– Intracranial Hemorrhage
– Suppression of Fetal HR
– Miscarriages
Abruptio Placenta:
Minor blunt trauma
Major blunt trauma
• Maternal Risks
1-5%
20-50%
– 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:
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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
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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
2.
1.
Zahn CA, et al. Neurology. 1998;51:949-956.
Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 1998;51:944-948.
CONCLUSIONS
• TALK TO YOUR EPILEPTOLOGIST ABOUT:
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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
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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).
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Purpose: to establish the risk and determine the factors which contribute to those
risks.
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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).
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Determine impact of different AEDs have on the mother’s epilepsy during pregnancy
(CBZ, LTG, LEV)
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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!