This document discusses the effects of epilepsy and anti-epileptic drug (AED) use on reproductive health and pregnancy outcomes. It notes that women with epilepsy have an increased risk of gestational hypertension, preterm delivery, fetal malformations, and low birthweight infants. During pregnancy, AED levels may decrease due to changes in metabolism and clearance, increasing seizure risk. Close monitoring of drug levels and seizures is recommended during pregnancy to adjust dosages as needed. Folic acid supplementation is also advised to reduce the risk of neural tube defects.

2. Osama Ragab
Ass.lec of Neurology
Faculty of Medicine
Tanta University
2013

4. Having a diagnosis of epilepsy can make you re-question
your whole life plan
Work /
Finances
Family / Home Social / Hobbies

5. Approximately one-half million women with
epilepsy are of childbearing age.
It has been estimated that3–5 births per 1000 will
be to women with epilepsy.
Women with epilepsy are at an increased risk of
gestational hypertension, but not preeclampsia.
There is a possible additive effect of epilepsy and
smoking on the rates of preterm delivery.

6. Seizures, including status epilepticus, during
pregnancy can be fatal to both mother and
fetus.
The overall likelihood of major congenital
malformations in neonates exposed to any
AED ranges from 2.2% up to 11%.

7. Infants born to women with epilepsy who are
taking AEDs have twice the risk of being small
for gestational age and low Apgar scores .
AEDs have been associated with a higher rate of
spontaneous abortion (2 times normal)

8. PREGNACY & FETUS

10. Neurons and glia are equipped for local de novo
production of steroid hormones mainly in the
hippocampus .
Neurosteroids are known for their non-genomic acute
effects by direct modulation of NMDA receptors
and GABAA receptors.
Neurosteroids are responsible mainly for “fine
tuning” of neuronal excitability by acting at
synaptic and extrasynaptic receptors.

11. Neurosteroids also play an important role in neuronal
survival in developing as well as aging brain .
Disturbances in the neurosteroid production have
been detected in sclerotic hippocampal tissue from
patients with temporal lobe epilepsy, and other
neurodegenerative disorders (such as Alzheimer's
disease or multiple sclerosis).
Sex hormones are critical for regulating neuronal
excitability and survival.

12. in some women with epilepsy, seizure exacerbation can
be related to periodical hormonal fluctuations
during the ovarian cycles.
Seizures also often change pattern, expression or onset
at the time of natural hormonal changes such as
adolescence . pregnancy , and during the
perimenopause and menopause .

13. Some epileptic syndromes may either remit (benign
rolandic epilepsy, childhood absence) or have their
onset (juvenile myoclonic epilepsy) in adolescence,
indicating the likely influence of hormonal changes
and maturation occurring around puberty.
The dramatic irregular fluctuations in gonadal
hormones during the onset of menopause
(perimenopausal stage) and their loss at menopause
are likely to influence seizure frequency.

14. Chronic administration of progesterone has anti-seizure
effect related to its metabolite
allopregnanolone which modulate GABAA
receptors .
chronic administration of allopregnanolone contributes
to a paradoxical agrevate seizure by increasing the
expression of α4 subunit of GABAA receptors.
The agrevation could be related to progesterone-induced
increase in dendritic spine density with
mushroom like spines .

15. Estradiol has mixed effects when administered acutely
ranging from no effect, mild anticonvulsant to
proconvulsant effects depending whether physiological
or supraphysiological doses have been used.
Seizure limiting effects linked mainly to regulation of
neuropeptide Y (NPY) in the hippocampus . (powerful
inhibitory peptide) .
The neuroprotective effects of estradiol on seizure-induced
damage were linked to the regulation of NPY
expression.
Unlike estradiol, progesterone has only anticonvulsant but
not neuroprotective effects.

16. Effects of epilepsy on
reproductive hormones

18. The hypothalamus receives many direct connections
from parts of the temporal lobe that are involved in
the generation of seizures.
Increased frequency of pulsatile secretion of luteinizing
hormone (LH) has been observed in women with
epilepsy and may contribute greatly to alterations in
ovarian cycle.
Higher LH pulse frequencies positively correlate
especially with localization of the focus in the left
temporal lobe compared to lower LH pulse
frequencies in patients with the right side foci .

19. A significant increase in allopregnanolone serum level
was observed in both male and female prepubertal
children, independent on the type of epilepsy,
during the post-ictal phase but not during the inter-ictal
phase.
AEDs that induce hepatic microsomal enzymes
(EIAEDs) also interact with hormonal
contraceptives to increase estrogen’s metabolism
and progesterone’s protein binding, thereby
decreasing concentrations of both hormones and
thus reducing contraceptive efficacy .

23. A large number of women with epilepsy have some
degree of sexual and/or reproductive dysfunction .
Sexual dysfunction may include difficulty with libido,
arousal, and orgasm.
Libido difficulties are reported more often in
individuals with complex partial than generalized
seizures.
Some women report normal sexual desire but difficult
or painful coitus (dyspareunia).

24. Some women report normal sexual desire but difficult
or painful coitus (dyspareunia).
Physiologically, the areas of the brain that mediate
sexual behavior are the same areas that are involved
in common forms of focal epilepsy.

25. A recent study found improvement in sexual function
for both women and men associated with
lamotrigine (LTG) therapy .
Resective brain surgery as a treatment for medically
refractory seizures has also been shown to restore
sexual function.
Sildenafil is also being studied to improve
vasocongestion in women .

26. Women with epilepsy have a fertility rate 60–80% that
of women without epilepsy.
One-third to one-half of women with temporal lobe
epilepsy report difficulties with their menstrual
cycle, with 20% having amenorrhea ,
oligomenorrhea. Some women experience
anovulatory cycles.
Women with epilepsy are at risk for polycystic ovaries,
a major contributor to infertility

27. The association between epilepsy and reproductive
endocrine disorders is a matter of controversy.
Epilepsy is associated with these disorders by itself.
But AED therapy may have a greater effect on
endocrine function.
Women with epilepsy are eligible for fertility treatment
whether or not they are taking AEDs.

29. An in-depth history should delineate the duration of
epilepsy, frequency of seizures, the use of AEDs,
their type, and the response to these medications.
Attention should be given to past obstetrical history
including maternal as well as neonatal outcomes,
with stresses congenital anomalies.
If the patient has been seizure free for more than one
year, then discontinuation of AEDs can be
considered.
If the seizure-free interval is less than 1 year,
monotherapy of the least teratogenic drug at the
lowest effective dose is recommended.

30. Women who decide with their doctor to try
tapering off AED therapy should begin at
least 6 months prior to becoming pregnant.
Changes in AEDs should also be made prior to
a planned pregnancy to ensure seizure
control.
The adverse structural and functional effects of in
utero exposure to AEDs are dose dependent.
The lowest effective dose to control seizure
activity should be used.

31. Anticonvulsant level, drawn prior to morning
dose of AED, to identify the serum
concentration at which seizures are maximally
controlled. This level will then be used for
future comparison during pregnancy.
the American College of Obstetricians and
Gynecologists recommends 4.0 mg of folic acid
daily for women at risk of having offspring
with neural tube defects (including women
taking AEDs).

33. Pregnancy has a variable and unpredictable effect
on epilepsy.
It is difficult to predict the change in seizure
frequency during pregnancy with the rate of
seizures decreasing in 3–24% of patients,
increasing in 14–32%, and unchanged in 54–
80%.
Remaining seizure free for at least nine months
prior to conception is associated with greater
likelihood (84–92%) of remaining seizure free
during pregnancy.

34. Seizure frequency may increase: due to:
-Enhanced metabolism & increased drug clearance associated with
pregnancy can result in decreased serum drug concentration.
-Increased volume of distribution of the AED.
-Increased serum binding proteins.
-Decreased or non-compliance with medication.
-Sleep deprivation, hormonal changes of pregnancy and associated
psychological and emotional stress of pregnancy: all lower
threshold for seizures.
-Nausea and vomiting.

35. If a patient presents to prenatal care and did not
receive preconceptual drug therapy
optimization, withdrawal of medication should
not be attempted as this may provoke maternal
seizures and possibly status epilepticus.
In addition, changes in medication expose the
fetus to polytherapy and thus increase the risk
of malformations.

36. Maternal plasma drug levels should be monitored
monthly and compared to pre-pregnancy
levels, if possible . Medication dosage is then
adjusted according to both plasma levels and
seizure activity.
Supplemental folic acid should be started prior to
conception and then discontinued after twelve
weeks of gestation

38. The pharmacokinetic and pharmacodynamic effects of
all AEDs can change during pregnancy .
Throughout pregnancy, the plasma volume increases
which will change the drug distribution. Cardiac
output and renal blood flow increase, thus
increasing renal clearance of medications.
Pregnancy induces the cytochrome p450 (CYP 450)
super-families in the liver, thus liver metabolism of
certain drugs increases.

39. Conversely, fat storage increases thus fat-soluble drug
elimination slows down.
Total drug levels may decrease due to a decrease in
AED transporters including albumin and alpha1-
acid glycoproteins, but the unbound concentration
does not change.
The unbound form of the drug determines the
therapeutic, toxic, and teratogenic effects.

40.  Among the AEDs, there is no single best choice for
treatment of seizures.
 The drug with the lowest risk of teratogenesis in
combination with the ability to control seizures with
the lowest dose and monotherapy form is ideal.

41. primarily metabolized in the liver by the CYP450 enzyme.
The rate of major congenital malformations with
phenytoin monotherapy use ranges 0.7–7.4%.
The Fetal Hydantoin Syndrome ,hypoplasia and irregular
ossification of the distal phalanges, facial dysmorphism
epicanthal folds, hypertelorism, broad and depressed
nasal bridge, an upturned nasal tips,intrauterine
growth restriction, and intellectual disability.
The free plasma concentration varies significantly during
the second and third trimesters.

42. Metabolism urs predominantly in the liver by the
cytochrome p450 superfamily.
The free plasma concentration of carbamazepine
increases in a non-significant manner during
pregnancy. Monthly monitoring of carbamazepine
levels is not recommended.
The rate of congenital malformations with
carbamazepine monotherapy use ranges 2.2–6.3%.
The specific congenital malformation associated with in
utero carbamazepine use cardiac malformations and
oral clefts

43.  Valproate exposure is associated with a 1–2% risk of
neural tube defects (i.e. a 10–20-fold increase over the
general population), an increased risk of
neurodevelopmental deficits.
 The most common birth defects with valproate use,
orofacial clefts, congenital heart defects, hypospadias,
and skeletal abnormalities, reduced verbal abilities, and
lower IQ.
 In comparison to other AEDs, valproate has the highest
risk of major congenital malformations.
 Valproic Acid use in pregnancy should be avoided if
possible.

44. Metabolism of lamotrigine occurs through
glucuronidation in the liver.
Several studies suggest that lamotrigine clearance
increases by about 65–94% and therefore should be
monitored frequently during the second and third
trimesters.
The prevalence of fetal congenital malformations with
in utero exposure to lamotrigine is 2–3%, with the
most common malformation being cleft lip/palate.

45. Excreted primarily through the kidneys.
Pregnancy appears to enhance the elimination of
levetiracetam resulting in marked decline in plasma
concentration, which suggests that therapeutic
monitoring may be of value.
Rate of major congenital malformation of 0.70%.
Cognitive defects have not been seen in children
exposed to levetiracetam or lamotrigine.

46.  Plasma concentrations of topiramate vary greatly
during pregnancy, therefore it is necessary to
carefully monitor serum levels.
 The rate of major congenital malformations with
topiramate monotherapy ranges 2–3.8%, with cleft
lip and palate occurring most frequently.

47. Gabapentin It is renally excreted.
There is no data that describes the pharmacokinetics of
gabapentin during pregnancy, thus obtaining
monthly serum levels may be of benefit.
Data regarding the teratogenic effects of gabapentin is
very limited and inconclusive, with rates of major
congenital malformation uncertain (0–6%).

48. Seizures can lead to reduced placental circulation and
secondary ischemia in the fetus.
Optimal reperfusion after the circulation is restored
can lead t o increased oxidative stress, which in
turn could exert teratogenic effects.
AED usage may lead to folate deficiency which in
turn may predispose to neural tube defects.
AEDs increase the levels of arene oxides as a
byproduct of its metabolism. Arene oxide is a
potent teratogen.
Alteration in the homeobox (HOX) genes, retinoic
acid signaling pathways, histone deacetylators and
polymorphisms involving AED transporters.

49.  Neural tube closure occurs at about Day 26 of
pregnancy, often before a woman is aware that she is
pregnant. Neural tube and cardiac defects occur in
the first 28 days following conception, so folate
supplementation should begin before conception is
attempted and continue throughout the pregnancy.
If the folate supplement is begun more than 30 days
after conception, it will not provide protection
against a NTD.

50. Current recommendations For any sexually active
woman of childbearing potential, recommended
daily allowances of folic acid have been increased to
400 μg/day for nonpregnant women, 600 μg/day for
pregnant women and 500 μg/day for lactating
women.
Many epileptologists recommend higher doses (800 μg
to 4 mg/day) for women with epilepsy.

51. The reported frequency of status epilepticus in pregnant
women with epilepsy ranges from 0% to 1.8%.
The aim of management in status epilepticus is to achieve
control of the seizures as rapidly as possible.
There are four main categories of drugs that are used to
treat status epilepticus: benzodiazepines, phenytoin (or
fosphenytoin), barbiturates, and propofol.
Benzodiazepines are the first-line treatment of status
epilepticus due to their fast onset of action. Lorazepam
(0.02–0.03 mg/kg IV) is the initial drug of choice.

53. Women with generalized epilepsy are more at risk for
seizures during delivery than are those with partial
epilepsy .
It is important to remind women with epilepsy to bring
their AEDs to the hospital during labor and to take
regular doses during this period under the
supervision of hospital staff.
Intravenous (Phenobarbital [PB], VPA, LEV)
administration may be needed if the woman is not
able to keep down oral medication.

54. Hyperventilation and maternal exhaustion should be
avoided
Generalised tonic clonic seizures are associated with
hypoxia, and continuous CTG tracing is
recommended in the event of a seizure
An intravenous benzodiazapene (e.g. lorazepam or
diazepam) is recommended to terminate the seizure
Women should deliver in a centre with adequate
facilities for maternal and neonatal resuscitation

55. Emergency C.S. should be performed when repeated
GTCSs cannot be controlled during labor .
Obstetric analgesia may be used to allow for rest before
delivery.
Pethidine should never be used because it is metabolised to
norpethidine, which is epileptogenic. Diamorphine is an
option.
Few cases of postpartum seizures were reported following
epidural analgesia.

56. It is suggested that oral vitamin K supplementation at 10–
20 mg/day be prescribed during the last month of
pregnancy and 0.5 mg administered intramuscularly
immediately after delivery.
This is particularly important for women taking EIAEDs
associated with alterations in vitamin K metabolism.
Vitamin K is recommended for all neonates at birth;
however, neonates born to women with epilepsy should
be monitored for bleeding.
The recommended dosage for neonates is 1 mg
intramuscularly or intravenously at birth.

58. AED therapy should be continued postpartum.
For most AEDs, the pharmacokinetics in the mother
will return to pre-pregnancy levels within 10–14
days after delivery.
Regardless of the AED, patients should be monitored
for signs/symptoms of toxicity closely and dose
adjustments to pre-pregnancy levels are likely.

59. Lamotrigine clearance decreases quickly in the first
week postpartum, and dose adjustments should be
made sooner.
The dose incrementally reduced at postpartum days 3,
7, and 10, with return to preconception dose or
preconception dose plus 50 mg to help counteract
the effects of sleep deprivation.

60. Patients must be advised of the importance of adequate
rest, sleep, and compliance with drug therapy.
Precautions must be taken to protect the infant in the
event the mother has a seizure.
Patients should not bathe their child while they are
home alone, they need to avoid climbing stairs while
carrying baby.

61. All of the AEDs are measurable in breast milk. The
reported percentage of maternal plasma levels in
breast milk varies depending on the drug.
Lamotrigine, one of the newer AEDs, is excreted
extensively in breast milk. No adverse events in
these infants exposed to lamotrigine during
lactation were observed in the first postnatal year.
n.

62. Small studies of levetiracetam, topiramate, and
gabapentin have found that while present in breast
milk in concentrations similar to maternal plasma,
the concentrations in infant plasma were low,
suggesting rapid eliminatio
Most experts believe that taking AEDs does not
generally contradict breastfeeding.
Infant serum anticonvulsant levels should be
monitored if acute changes in behavior occur.

64. It has been estimated that more than 40% of women
with epilepsy have unplanned pregnancies .
Most hormonal OCs combine synthetic estrogen and
progesterone.
In fact, most studies have shown that estrogen-based
contraceptives do not affect seizure frequency

65. Some first- and second-generation AEDs induce
hepatic cytochrome P450 enzyme activity and
increase the metabolism of both estrogen and
progesterone.
Women taking hepatic microsomal EIAEDs may have
as much as a five- to six fold increase in the COC
failure rate.
Most drugs that inhibit or have no effect on the
cytochrome P450 enzyme system do not affect the
efficacy of hormonal contraception .

66. LTG is the exception; though it is not an EIAED, it is
reported to interact with COCs and may reduce
contraceptive effectiveness, and the contraceptive
may interfere with seizure control by reducing the
LTG blood level by as much as 40–60% .

67. Fully effective contraception cannot be guaranteed
with either LTG or topiramate (TPM) (>200
mg/day).
One suggestion for patients taking AEDs that interfere
with COCs is to use a barrier method of
contraception, such as a condom, the diaphragm, or
the cervical cap, in addition to the COC.

68. Non EIAED no
interaction with COCs.
Clozepam ,Clonazepam barbiturate Lamotrigen
Valporoate CBZ
LVT OXC
Vigapatrin , GBP TOP
Felbamate PHT
ETHX PRIM
Zonisamide
Non EIAED interact
with COCs.
EIAED interact with
COCs.

69. It is recommended that injections be administered
every 10 weeks (and some clinicians prefer every 6–
8 weeks) rather than the usual 12 weeks for women
with epilepsy.
Intrauterine devices (IUDs) that secrete progestin may
be used by women with epilepsy and does not appear
to be affected by EIAEDs . A copper IUD, is also
effective for women with epilepsy taking EIAEDs.
EIAEDs appear to reduce the effectiveness of the patch
because of the low progestin dose and increased
metabolism of the steroid components.

70. Combined OCs can increase the elimination of drugs
that are metabolised by glucuronidation.
Among AEDs, this metabolic pathway has been
studied most intensively for lamotrigine.
The metabolism of lamotrigine is accelerated
approximately 50% by co-treatment with combined
OCs .
A drop in the plasma level of the AED following
initiation of OCs may lead to increased seizure
activity