This document discusses several topics related to women with epilepsy (WWE), including: 1. WWE have faced social stigma and legal restrictions on marriage and pregnancy in the past. Some challenges still remain today. 2. Seizures and antiepileptic drugs can disrupt the hormonal system and affect sexual function and fertility in WWE. This poses challenges for planning and having healthy pregnancies. 3. Pregnancies in WWE require careful management to minimize risks to the health of the mother and fetus from seizures and effects of antiepileptic drugs. Close monitoring is needed before, during, and after pregnancy.

4. ◘ WWE have been stigmatized over the centuries
due to misconceptions about seizures.
◘ Sterilization of WWE was legal in parts of the
USA until the latter half of the 20th century, and
until 1980, some states still had laws forbidding
WWE from marriage.
◘ Even today, many WWE still receive explicit or
implicit messages that they should not consider
marriage and pregnancy.

5. ◘ Epilepsy affects about 65 million patients globally
with annual incidence of epilepsy is 50 per 100
000 and prevalence is 700 per 100 000
population.
◘ Epilepsy is the most disabling neurological
disorder during pregnancy.
◘ WWE represent nearly half of epileptics and 0.3 –
0.7% of all gestations.

7. ◘ AEDs disfiguring female shape may be a very
strong initiator of poor compliance with
consecutive poor seizure control.
◘ Phenytoin causes hirsutism, gingival
hyperplasia and coarsening of facial features.
◘ Valproate may result in hair loss, acne,
hirsutism and weight gain.
◘ Topiramate can cause significant weight loss
which may not be desired by thin females.

8. ◘ Seizures onset in young females may affect sex
hormones secretion with consecutive
maturational, and sexual fitness impairments.
◘ Up to two thirds of WWE show reduced blood
flow to genital organs in response to visual erotic
stimuli leading to lack of orgasms, dyspareunia,
vaginismus, and reduced vaginal lubrication
during sexual intercourse.

9. ◘ Both gonadal hormones and many AEDs are
metabolized through the CYP450 and specifically
the CYP 3A4 isoenzyme.
◘ Phenytoin, carbamazepine, phenobarbital, and
primidone are enzyme inducers resulting in
increased metabolism of the sex hormones in
addition to increased production of sex hormone
binding globulin with consecutive reduced
bioavailability of the free fraction.

10. ◘ VPA and other enzyme inhibitors decrease the
activities of aromatase enzyme (a member of
CYP450 group) which in turn decrease the
conversion of androgens to estrogen leading to
hirsutism and decreased libido.
◘ Oxcarbazepine and lamotrigine have lower effect
on sex hormonal and little endocrinal
dysfunctions due to little influence on CYP450,
but this safety seems to be dose dependent.

11. ◘ Brain regulation of sex hormones occurs via the
hypothalamic–pituitary–gonadal axis with
regular pulsatile stimulation.
◘ Synchronized ictal as well as interictal discharges
disrupt this regular pulsatile stimulation leading
to impaired GnRH secretion and
hyperprolactinemia.
◘ Prolactin provides sexual gratification by
inhibiting dopamine release during sexual
intercourse, but chronic hyperprolactinemia has
been associated with hyposexuality.

12. ◘ Estrogen has a proconvulsant effect through
inhibiting GABA-A receptors and increasing
the NMDA receptors containing excitatory
synapses as well as the density of the
dendritic spines which may results in
kindling and increased seizure frequencies at
puberty.
◘ Progesterone has anticonvulsant properties
by inhibiting glutamate and stimulates
GABA-A.

13. ◘ CE is derived from the Greek word “katamenios”,
which means “monthly”.
◘ In 1857, Sir Charles Locock first described that some
seizures are associated with the menstrual cycle. In
1881, Gower, had documented premenstrual
clustering of seizures.
◘ Herzog defined CE as a twofold increase in seizure
frequency during one of 3 vulnerable time periods
(C1, C2, C3) compared to seizure frequency during
the rest of the menstrual cycle due to increased
estrogen / progesterone ratio.

14. (1) C1 perimenstrual pattern: seizures occur
predominantly between day --3 and day +3 of
the menstrual cycle due to rapid fall of
progesterone
(2) C2 periovulatory pattern: seizures are seen
mostly on days +10 to –13 due LH surge with
rapid rise of estrogen levels while progesterone
remain low.
(3) C3 anovulatory pattern: occur due to
inadequate LH secretion resulting in deficient
progesterone from the ovulation time till menses
(day +10 to day +3 of the next cycle).

15. ◘ Cyclic progesterone lozenges 200 mg 3 times
daily from days 14–28 of the cycle have greater
efficacy in C1 CE where progesterone withdrawal
is implicated.
◘ Depot medroxyprogesterone acetate
(DMPA) at a dose of 150 mg every 3 months
reduces seizure frequency of up to 39%.
◘ Acetazolamide at 250 mg twice daily,
clobazam 20–30 mg daily or slight increase in
baseline AED are used 2-days prior to the date
of seizure exacerbation for up to 10 days.

16. ◘ Use the lowest effective AED
monotherapy to achieve the least
endocrinal side effects.
◘ Seizure diary and menstrual calendar
should be correlated for possible CE
which affects > one-third of WWE.
◘ Hyposexuality in WWE needs
psychological support, lubricants and
hormonal assay to correct disrupted
hormones and hyperprolactinemia.

18. ◘ WWE have reduced fertility:
- Up to 60% with 3 AEDs.
- 40% with 2 AEDs.
- 30% in monotherapy
- Compared to 7.1% for epileptics before AED
treatment.
◘ > 35% of cycles of women with partial seizure of
temporal origin are anovulatory (compared to 8%
in controls) due to inadequate LH secretion.

19. ◘ PCOS affects 20% of WWE (5 times than control)
manifested by menstrual dysfunction, infertility,
hirsutism, obesity and hyperinsulinemia.
◘ PCOS is common in the following:
(1) VPA use due to inhibition of CYP 450 with
consequent reduced conversion of androgens to
estrogen.
(2) Left temporal lobe seizures which increase
GnRH secretion with resultant increased LH and
FSH leading to altered follicular development in
the ovaries and increasing testosterone levels.

21. ◘ Pregnancies in WWE are challenging due to the
need of good seizure control as well as
avoidance of the harmful effect of both
seizures / AEDs on the mother and fetus.
◘ Pregnancies exposed to AED monotherapy have
4.5% chance of fetal major congenital
anomalies (2 – 3 times higher than general
population) which is increased to 8.6% with
polytherapy.

22. ◘ Major congenital malformations are defined as
abnormalities having surgical, functional, or
cosmetic significance.
◘ These anomalies occur during the period of
organogenesis in the first 8–weeks of
gestation often before a woman knows that
she is pregnant.

23. ◘ Preconception concerns should start at the time
of epilepsy diagnosis as > 50% of pregnancies
are unplanned where choosing the first AED
should fit for future pregnancies and lactation.
◘ Ideally, the process of tapering AEDs should
begin at least 1 year before conception.
◘ On practical basis most WWE will need to
remain on AEDs during pregnancy.
◘ Monotherapy at the lowest dose is the best
option.

24. ◘ VPA has the highest teratogenicity risks (4.7–
13.8%), specifically neural tube defects.
However, the risk is dose dependent which is
higher in women receiving > 1000 mg/day.
◘ Carbamazepine and barbiturates are associated
with neural tube defects, cardiac defects,
congenital hip dislocation and facial clefts.
◘ Phenytoin and topiramate have increased
incidence of cardiac defects, cleft lip,
hypospadias and digital malformations.

25. ◘ Oxcarbazepine has 2% chance of congenital
anomalies especially clefting abnormalities.
◘ Lamotrigine is fairly safe during pregnancy (2.2%
teratogenicity risk), but needs frequent
gestational assessment and dose adjustment to
ensure seizure control.
◘ Levetiracetam looks promising with estimated
teratogenicity risk of 1.6 – 2.4% yet larger case
control randomized prospective studies are
needed.

26. ◘ Folic acid is essential for nucleic acid and amino
acid synthesis, cell division, DNA methylation,
and tissue growth.
◘ Many AEDs have antifolate properties leading to
increased risk of congenital malformation
especially neural tube defects.
◘ Preconception and first trimester prescription of
folic acid at a dose of 0.4 – 4 mg daily is
recommended in WWE especially those treated
on VPA and carbamazepine.

27. ◘ Enzyme inducers AEDs cross the placenta and
promote oxidative degradation of vitamin K1 in
the fetus leading to neonatal bleeding tendency.
◘ Consider antenatal prophylaxis with oral vitamin
K1 20 mg per day in the last 4 weeks of
pregnancy if enzyme-inducing drugs are used.
◘ If vitamin K1 has not been given antenatally,
administer IV vitamin K1 10 mg by slow
injection over 5 minutes during labor to the
mother or 1 mg IM to the fetus postnately.

28. ◘ The majority of WWE will have normal
pregnancy and delivery, an unchanged
seizure frequency and over a 90%
chance of a healthy baby.
◘ Ensure adequate contraception to avoid
unplanned pregnancies.
◘ Consider prepartum medication change
for AEDs with higher rates of
teratogenesis, such as VPA, topiramate,
and phenobarbital.

30. ◘ The risk of epilepsy inheritance is low due to its
polygenic nature, and the variety of etiological,
epigenetic and precipitating factors.
◘ The fetus seems relatively resistant to the effects of
seizures.
◘ Nonconvulsive seizures are associated with
ictal increased uterine contractions and fetal heart
rate, but no significant harms had been reported
unless seizure resulted in an accident.

31. ◘ GTCC and convulsive status
epilepticus are associated with increased
risks of maternal injuries, ruptured
membranes and hypoxia with acidosis,
which can be transmitted to the fetus
resulting in growth restriction, small-for-
gestational-age infants and increased risks of
abortion or stillbirth.
◘ Juvenile myoclonic epilepsy exerts its
impact through the risk of falling.

32. ◘ EURAP study, 2013 reported no changes in
gestational seizure frequencies than pre-
gestational one in up 70% of WWE.
◘ WWE with ≥ 9 months pre-gestational seizure
free period have up to 90% chance of seizure
free pregnancy.
◘ 15.9% have decreased gestational seizure
frequencies possibly due to increased
progesterone level that peaks at 36 – 38
weeks.

33. ◘ 17.3% of WWE have increased gestational
seizure frequency especially in the last
trimester due to increased AEDs
metabolism/excretion and increased plasma
volumes.
◘ Despite the reduction in total AEDs level, the
free fraction may increase due to reduced
protein binding.
◘ Following AEDs levels should include both
free and total fractions.

34. ◘ WWE are at increased risks of gestational
hypertension, preeclampsia, small for
gestational age babies, ruptured membrane,
preterm labor, placental abruption, postpartum
hemorrhage and consequently increased rate
of CS.
◘ Neither epilepsy nor AEDs use is absolute
indication of a cesarean delivery (except if
seizure occur during labor).
◘ The risk of seizures in labor is low.

35. ◘ Sleep deprivation, non-intake of AEDs, pain,
tiredness, stress and dehydration are risks of
seizures in labor.
◘ Pethidine analgesia must be used with caution as its
metabolite norpethidine is epileptogenic .
◘ Diamorphine should be used in preference to
pethidine.
◘ If general anesthesia becomes necessary, avoid
ketamine and sevoflurane as they lower the
seizure threshold.

36. ◘ Ensure pre-gestational seizure stability.
◘ Assess the pre-gestational AEDs levels
which will be the reference level
during pregnancy.
◘ Check AEDs level at least once a
trimester and in any breakthrough
seizures.
◘ Fetal ultrasound and alpha-fetoprotein
level are recommended at 12 – 20
weeks for early diagnosis of major
malformations especially neural tube
defects and cardiac anomalies.

38. ◘ The postpartum period can be a time of
increased stress, missed doses and sleep
deprivation due to frequent nighttime feeds,
which might trigger seizures and increase its
frequency.
◘ Assistance from other family members may be
needed to avoid sleep deprivation and taking
diurnal naps with the infant may be also
beneficial.

39. ◘ Current recommendations encourage
breastfeeding in WWE.
◘ Breastfeeding ensure mother-infant bonding,
healthier immunity, and reduced infant
mortality, as well as better cognitive
development.
◘ AEDs are excreted in breast milk at a level
inversely proportional to the degree of maternal
serum protein binding.

40. ◘ Phenobarbitone and primidone are lipophilic with
high concentrations in breast milk resulting in
infant sedation which may necessitate
discontinuation of breastfeeding.
◘ Phenytoin, carbamazepine and valproate are poorly
excreted into breast milk due to their high protein
bounding properties. So, they are fairly safe during
lactation.
◘ Levetiracetam, plasma concentrations in infants are
low despite extensive transfer into breast milk.

41. ◘ Infants exposed to VLP (> 1000 mg) during
pregnancy have 7 – 11 points decrease IQ and
triple risk of autism spectrum than general
population (4.5% vs. 1.5%).
◘ In utero exposure to carbamazepine, lamotrigine
and levetiracetam was not associated with
significant decline in IQ measures but there is
controversial results related to higher autistic
spectrum disorder and ADHD.
◘ ≥ 5 GTCC during pregnancy is associated with
lower verbal IQ.

42. (1) Transport the infant in a small stroller and avoid
carrying in arms.
(2) Diaper changes can be done on a mat on the floor
to reduce the risk of falls.
(3) Feedings can be done with supportive devices.
(4) Avoid bathing the infant alone otherwise give
hem a sponge bath.
(5) Avoid attempt to cook while holding the infant.
(6) When the baby becomes mobile, ensure his
safety if the mother loses awareness for a few
minutes.

43. ◘ The intrauterine device is the most effective form of reversible
contraception and is not limited by significant drug-drug
interactions.

44. ◘ Enzyme inducing AEDs enhance the metabolism
of both EE and progestins with consecutive
possible contraceptive failure.
◘ The CDC and the WHO advise against combining
enzyme inducing AEDs with COC pills, vaginal
rings, or transdermal patches.
◘ Both agencies state that depot medroxy-
progesterone acetate injections (150 mg every 12
weeks) can be used safely in patients taking
enzyme inducing AEDs especially those with CE.

45. ◘ Some authors recommended using COC pills
with a higher dose of EE (50 instead of 20 –
35 µg), but no evidence exists to support this
approach, and many reports of contraceptive
failure had documented.
◘ Breakthrough bleeding mid-cycle may indicate
a low ethinyl estradiol level in the pills.
◘ CYP450 inhibiting AEDs have no influence on
COC effectiveness which needs no doses
adjustment.

46. ◘ Induction of glucuronidation pathways by EE
results in significant decreases in lamotrigine
levels by over 50%, with a resultant loss of
seizure control if dosing is not adjusted.
◘ During the hormone-free week, the induction of
glucuronidation by EE disappears quickly, thus
lamotrigine levels rises with toxicity symptoms.
◘ The WHO and CDC advise against the
combination of lamotrigine and all COC.

48. ◘ Right temporal lobe seizures impairs the
pulsatile hypothalamic stimulation leading to
decreased GnRH, LH and FSH with the
resultant lower estrogen levels, increased
prolactin, hypothalamic amenorrhea and
premature menopause.
◘ Perimenopause is characterized by inadequate
luteal phase with consecutive decrease
progesterone secretion while estrogen secretion
remains high leading to temporary susceptibility
to increased seizure frequency.

49. ◘ Enzyme inducing AEDs are associated with
increased bone demineralization.
◘ Both seizures and AEDs (VPA) may influence the
hypothalamic-pituitary-adrenal axis with
consecutive impairment of bone health.
◘ Post-menopausal regular bone density
monitoring is recommended and hormonal
replacement therapy appears beneficial.

50. ◘ Management of WWE is a dynamic process
needs the consideration of multidirectional
effects of sex hormones and seizure
management.
◘ The epileptologist should have a holistic view
and be aware of the challenges he is facing
including the impacts of AEDs on fertility,
teratogenic risk, libido and contraception as
well as AEDs concentrations change during
pregnancy, postpartum, and lactation.