Managing Epilepsy in Women

1. Women and Epilepsy
Dr. Pramod Krishnan,
Consultant Neurologist and Epileptologist,
Manipal Institute of Neurological Disorders,
Manipal Hospital, Bangalore.

2. Introduction
 Incidence of epilepsy in men and women is similar.
 Fundamental principles of management are the same.
 However, managing women with epilepsy (WWE)
requires attention to special considerations.
 It is estimated that 3 to 5 births per thousand will be
to WWE.
Yerby MS. Neurology 2000; 55: S21–S31.

3. Crawford P, et al. Seizure 1999; 8: 201–17.

4. Are there unusual epilepsy patterns
in women?

5. Catamenial Epilepsy
 Definition: demonstration of a doubled daily seizure
frequency at a particular phase of the ovulatory cycle
in at least six consecutive months.
 Catamenial pattern: 10% and 78%, roughly 30%.
 Estrogens: seizure-promoting effect.
 Progesterone: seizure inhibiting effect.

6. Catamenial Epilepsy
 Three phases with catamenial clustering:
1. Periovulatory estrogen peak (days 10 to 13)
2. Perimenstrually with typical fall in gestagen (day 3)
3. Second half of the cycle in disorders of luteal function,
i.e., inadequate progesterone level (day 10 to day 3 of
next cycle).

7. Treatment: Already on AEDs
 Clobazam: 5-10 mg used perimenstrually. (B)
 Acetazolamide: regular/ perimenstrually. (C)
 Progesterone: intermittent perimenstrual progesterone
supplement, or a synthetic progestogen during days 10
to 26 of the menstrual cycle. (C)
 Others: Danazol, Goserelin, or Clomiphene.
Betts T, Crawford P. Women and Epilepsy. 1998: 27–8.

8. Treatment: Not on AEDs
 Clobazam: 5-30 mg used perimenstrually. (III)
 Progesterone: intermittent perimenstrual progesterone
supplement, or depot progestogen. (III)
 Combined oral contraceptive pill: (III).
Crawford P, et al. Seizure 1999; 8: 201–17.

9. Does Sexual Dysfunction occur in
Epilepsy?

10. Sexual dysfunction
 The majority of WWE have normal sex lives. (II)
 Sexual desire and sexual arousal in WWE may be
affected by epilepsy or by its treatment. (II)
 Enquiry about sexual feelings and function should be
part of the standard assessment of WWE. (C)
 If sexual dysfunction is discovered, psychological and
neuroendocrine evaluations are recommended. (C)

11. Sexual dysfunction
 Enzyme inducing AEDs (especially PHT) increase
the risk of sexual and reproductive dysfunction in
WWE.
 Lamotrigine has been associated with improved
sexual functioning.

12. Is Fertility affected by Epilepsy or
its treatment?

13. Reduced Birth rate
 There is decreased fertility among women with
epilepsy. (II)
 Birth rates of live offspring to WWE are decreased
compared to the general population and same sex
siblings.
 All WWE should be counseled about their fertility and
the possible effects of their AED treatment. (C)
Artama M, et al. Am J Epidemiol. 2004; 159: 1057-63.

14. Reduced birth rate
 Psychosocial factors:
1. Delayed marriage
2. Choosing not to have children.
 Biologic factors:
1. Higher number of anovulatory menstrual cycles/
year for WWE.
2. Higher frequency of amenorrhoea.
3. PCOS
Morrell MJ, et al. Epilepsy Res. 2003; 54: 189-199.

15. Is Polycystic Ovarian Syndrome
related to Epilepsy or its treatment?

16. Polycystic Ovarian Syndrome (PCOS)
2 out of 3 of the following: Other features:
Polycystic ovaries on imaging Elevated LH/ FSH ratio
Oligo/ anovulation Insulin resistance
Clinical or biochemical evidence
of Hyperandrogenism
Obesity
Prevalence of PCOS in WWE is higher (12-24%) than in women
without epilepsy (6.6%), even in those not on AEDs.
PCOS is more common in women taking VPA, especially those
starting valproate before the age of 20. (II)

17. Ictal and inter-ictal discharges
Hypothalamic dysregulation
Increased GNRH release
Increased LH/FSH ratio
Altered LH pulsatility
Increased steroidogenesis
More immature cystic follicles Lack aromatase
Anovulation/ Irregular cycles Increased androgens

18. How would you counsel a WWE
requiring contraception?

20. Contraception
Non- hormonal methods,
hormonal IUCD
All AEDs
Combined OCPs Non enzyme inducing AEDs
Combined OCPs Enzyme inducing AEDs cause rapid estrogen
metabolism and risk of contraceptive failure.
Use higher strength of ethinyl oestradiol (50-100
ug/day). Use additional barrier methods.
Emergency contraception Higher dose is needed in case of enzyme
inducing AEDs.
Medroxyprogesterone
injections
Effective, but use more frequently (every 10
weeks, instead of 12)
Progesterone only pill Contraindicated due to high failure rate.
Midcycle bleeding indicates risk of contraceptive failure.

21. Effect of OCPs on AEDs
 Estrogen causes increased metabolism of
glucuronidated AEDs (eg LTG, VPA, OXC).
 LTG metabolism is increased by >50% by OCPs,
which can be blocked/ reduced by VPA. (II)
 Sharp rise in LTG levels (upto two fold) therefore
occur in the ‘pill free’ week.
 LTG level monitoring is recommended in the context
of OCP +VPA use.

22. How would you counsel a WWE
planning pregnancy?

23. Preconception MeasuresPreconception Measures
EducationEducation Nutrition, possible complications,Nutrition, possible complications,
Teratogenicity,Teratogenicity,
CounselingCounseling Genetics of their epilepsy and prenatal screening.Genetics of their epilepsy and prenatal screening.
Seizure freedomSeizure freedom Of atleast 9 months.Of atleast 9 months.
AED targetAED target AED withdrawal.AED withdrawal.
Monotherapy.Monotherapy.
Change to less teratogenic AED.Change to less teratogenic AED.
Folic acidFolic acid Atleast 0.5 mg/day. Usually 5 mg/dayAtleast 0.5 mg/day. Usually 5 mg/day

24. Genetic predisposition
 In WWE, the risk of their children developing
epilepsy is low.
 In IGE syndrome, the risk of a child developing the
condition is:
1. One affected first degree relative: 5–20%
2. Two affected first degree relative: More than 25%
3. Overall risk: 9–12%.

25. Do WWE have an increased
risk of pregnancy-related
complications?

26. Risk of complications in WWE on AEDs
Caesarean delivery Class I study: No increase in risk.
Class III study: Moderate increase in risk.
Pre-eclampsia Class I and II: No evidence of increased risk
PIH Class II studies: Conflicting evidence
Class III studies: No increased risk.
Premature labour Class I and III: No evidence of increased risk.
Class II: Increased risk in smokers.
Spontaneous
abortion
No evidence of increased risk.
Pregnancy related
bleeding
complications
Class I and III: No evidence of significant risk
Increased risk= greater than 2 times expected.

27. Do WWE have an increased risk of
epilepsy-related complications
during pregnancy?

28. Epilepsy related complications in WWE during Pregnancy
Seizure frequency Unchanged: 54-80%
Decreased: 3- 24%
Increased: 14- 32%
Seizure increase was more likely in partial epilepsy (29%) than
idiopathic epilepsy (7%).
Status epilepticus Frequency: 0-1.8% (no increased risk)
More likely convulsive type.
Seizure recurrence
in previously
seizure free WWE
If seizure free for >9 months prior to
pregnancy, 75-94% continue to be seizure free
during pregnancy.
Increased risk= greater than 2 times expected.

29. Adverse effect of seizure during
pregnancy
 Nonconvulsive seizures do not adversely affect
pregnancy or fetus apart from the result of trauma.
 Tonic–clonic seizures may cause a fetal bradycardia
or miscarriage, independent of trauma.
 Tonic–clonic status epilepticus in pregnancy carries a
high mortality for both the mother and fetus.
Betts T, Women and Epilepsy. 1998: 27–8.

30. How does Pregnancy affect AED
levels?
Is monitoring of AED levels indicated?

31. Effects of Pregnancy on AEDs
 AED pharmacokinetics are altered:
1. Reduced gastric motility
2. Nausea and vomiting
3. Increased drug distribution
4. Changes in protein binding
5. Increased renal elimination
6. Altered hepatic enzyme activity.
 Reduced AED compliance due to fear of
teratogenicity.

32. AED levels in pregnancy
LTG Markedly increased clearance and reduced LTG
levels, which is associated with an increase in seizure
frequency.
CBZ Small decrease in levels, but active metabolite levels
are unchanged.
PHT, OXC,
LVT
Significant decrease in levels.
PB, VPA,
ESM, PRM
Insufficient data
LTG, CBZ, PHT : Monitoring of levels should be considered (LevelLTG, CBZ, PHT : Monitoring of levels should be considered (Level
B).B).
LVT, OXC: Monitoring of levels may be considered (Level C).LVT, OXC: Monitoring of levels may be considered (Level C).

33. Vitamin K supplementation
 Insufficient evidence of increased risk of hemorrhagic
disease of the newborn in WWE on AEDs.
 Insufficient evidence that Vitamin K supplements
(20mg/d) in the last month of pregnancy prevent
hemorrhagic disease of the new born.
 All newborns should receive 1 mg of Vitamin K
following birth irrespective of AED exposure.
Clarkson P, et al. N Z Med J 1990; 103: 95–6.

34. Labour
 Delivery should be conducted in a well equipped unit.
 Caeseraen section/ induction of labour is not
routinely indicated.
 Continue regular AEDs.
 If corticosteroids are used for fetal lung maturation, a
higher dose may be required in patients taking
enzyme inducing AEDs.
Sabers A. Epilepsy and Pregnancy. 1997: 105–11.

35. Labour
 Over breathing, sleep deprivation, pain, and
emotional stress increase the risk of seizures during
labor.
 So, consider epidural anesthesia early on.
 1-2% of WWE will have a tonic–clonic seizure during
labor.
 Another 1–2% will have a seizure in the following 24 h.
Yerby MS. Baillieres Clin Neurol 1996; 5: 887–908.

36. Do AED exposure in utero lead to
poor perinatal outcomes?

37. Risk of adverse perinatal outcomes in WWE on AEDs
Small for
gestational age
WWE not on AED: No increased risk.
WWE on AEDs: Class II: Increased risk.
Perinatal death Class II: No increased risk.
Low APGAR score
and NICU stay
WWE not on AEDs: No increased risk.
WWE on AEDs: Class II: Increased risk.
IUGR, respiratory
distress
No adequate studies.
Increased risk= greater than 2 times expected.

38. Do AEDs taken during the first
trimester of pregnancy increase
the risk of major congenital
malformations (MCM) in the
offspring?

39. Teratogenicity
 Risk of significant fetal malformation in:
1. Women without epilepsy: 1-2%
2. WWE not on AEDs: 2-3%.
3. WWE on monotherapy: 4-6%.
4. WWE on polytherapy: 6-17 %.
 PB, PRM, PHT, CBZ, LVT, VPA, GBP, LTG, OXC,
TPM cross the placenta in potentially clinically
important amounts.
Vajda FJ, et al. Epilepsia 2004; 45: 234.

40. Risk of Teratogenicity due to first trimester AED exposure
VPA Class II: Increased risk with monotherapy, and more with
polytherapy.
Polytherapy including VPA has higher risk than
polytherapy without VPA.
VPA + LTG is particularly teratogenic.
Recommendation: Avoid VPA as monotherapy or polytherapy.
CBZ Class I: No increased risk
LTG Class I: No increased risk.
AED polytherapy has increased risk compared to monotherapy.
Minor anomalies were not included in the above studies.
Increased risk= greater than 2 times expected.

41. Common teratogenic associations of AEDs
VPA Neural tube defects, facial clefts, hypospadias.
PHT Cleft palate
CBZ Posterior cleft palate
PB Cardiac anomalies
VGB, LEV, TPM,
OXC
Teratogenic in animals.
Data is lacking for all the newer AEDs.
Teratogenicity due to VPA occur at a daily dose of 1000 mg or more.
MCM type is not specific to any AED.
Increased risk= greater than 2 times expected.

44. Is cognition of offspring affected
by maternal epilepsy or AEDs?

45. Cognitive teratogenesis
Cognitive risk due to AEDs is present throughout pregnancy.
WWE not on AEDs No increased risk of poor cognitive outcome.
WWE on AEDs Class II and III: Conflicting conclusions.
CBZ Class II and III: No increased risk.
VPA Class II: Increased risk. Avoid in pregnancy
PHT Class II and III: Increased risk. Avoid.
PB Class III: Increased risk. Avoid.
Polytherapy Class II: Increased risk. Avoid.
Increased risk= greater than 2 times expected.

46. Puerperium
 If the dose of an AED has been increased during
pregnancy, gradually reduce it to the preconception
dose over a few weeks following delivery, to reduce
the risk of toxicity.
 Increased risk of seizures due to sleep deprivation,
stress, irregular food and medications timings.
Betts T, Women and Epilepsy. 1998: 27–8.

47. Puerperium
 JME patients are at high risk because of interrupted
sleep due to odd waking hours of their children.
 Risk of injury to the child due to the mother’s seizures
is very low and depends on the seizure type, severity
and frequency.
 The risk can be reduced by training mothers and
caregivers in safety precautions.

48. Breast- feeding
 WWE should be encouraged to breastfeed.
 WWE are less likely to breastfeed and are more likely
to feed for a shorter duration compared to others.
 Amount of AED transferred via breast milk is much
smaller than the amount transferred via the placenta.
 As drug metabolism is immature in early infancy,
accumulation of AED may occur in the infant.
Ito S, et al. Am J Obstet Gynecol 1995; 172: 881–6.

49. Breast- feeding
AED Comment
None of the currently available AEDs are contraindicated during
lactation (C)
LTG Can accumulate in the infant and therefore infant LTG
levels to be monitored when mother is on high dose LTG.
BZD Infant drowsiness
PB Infant drowsiness
PRM, LVT, TPM, GBP are significantly penetrate into breast milk
VPA, PB, CBZ, PHT have lesser penetration.
Liporace J, et al. Epilepsy Behav 2004; 5: 102–5.

50. Menopause
 Early menopause, especially with frequent seizures.
1. Worsening of seizures: in 40% of WWE.
2. Improvement: in 27%, especially in those with a
catamenial pattern.
3. No change: in 33%.
 HRT is associated with increased seizure frequency
and is probably dose related.
 More likely in those with a catamenial pattern.
Harden C, et al. Epilepsia 2004; 45: 230.

51. Bone health
 More than half of all epilepsy patients on long-term
AED treatment suffer from AED-induced
osteopathy.
 Risk of fractures is 5 to 6 times higher in WWE.
 Increased risk of fractures, osteoporosis, and
osteomalacia due to AED effects on bone and
Vitamin D metabolism.
Elliott JO, et al. Epilepsia 2004; 45: 258.

52. Bone health
 Enzyme-inducing AED are more likely involved.
 Valproate is thought to alter the ratio of osteoblasts
and osteoclasts in favor of the latter.
 WWE on long-term AEDs should have:
1. Regular bone density monitoring
2. Calcium and Vitamin D supplements, if indicated.

53. Summary and Conclusions
 Epilepsy and AEDs affect various aspects of
reproductive health ranging from sexuality, fertility,
pregnancy, lactation, teratogenicity and menopause.
 Most of the effects are minor and with correct
management, overall outcome is near normal in all
these parameters.
 Overall benefits of seizure control with AEDs far
outweighs the adverse effects of seizures on QOL and
pregnancy outcome.

54. Summary and Conclusions
 Avoid Valproate, PHT and PB in women.
 CBZ and LTG are relatively safer.
 Data for most newer AEDs is lacking.
 Watch for PCOD.Watch for PCOD.
 Careful while using OCPs in women on enzymeCareful while using OCPs in women on enzyme
inducing AEDs.inducing AEDs.
 Overall risk of teratogenicity on monotherapy is low.Overall risk of teratogenicity on monotherapy is low.
 No contraindications for breast-feeding.No contraindications for breast-feeding.

55. THANK YOU