48 SUPPLEMENT TO JOURNAL OF THE ASSOCIATION OF PHYSICIANS OF INDIA AUGUST 2013 VOL.

61
and information on how to cope with the pregnancy,
childbirth, lactation, and contraception.
Introduction
I
t is estimated that about 50 million people worldwide have
epilepsy and women constitute half of this number. In India,
about 5.5 million people have epilepsy. 2.5 million of them are
women and 1.3 million of these women with epilepsy (WWE)
belong to the reproductive age group.
There is signifcant gender based diference in the biological,
pharmacological, psycho social and economical profile of
epilepsy. The biological variations are atributed to the infuence
of female reproductive hormones on epileptogenesis and
seizure recurrence. Seizure exacerbations with menarche and
menopause and catamenial worsening are examples. WWE
also sufer a more severe psycho social impact when compared
to men with epilepsy. Continuous use of AEDs can increase the
risk of sexual dysfunction, infertility and fetal malformations.
Most of the recent literature regarding WWE and their
reproductive problems has come from the various epilepsy and
pregnancy registries. Worldwide, there are 5 registries which
follow up WWE.
*
Senior Research Fellow,
**
Professor of Neurology, Department
of Neurology, Kerala Registry of Epilepsy and Pregnancy, Sree
Chitra Tirunal Institute for Medical Sciences and Technology,
Trivandrum 695011.
Women with Epilepsy in Reproductive Age Group :
Special Issues and Management Strategies
Shehanaaz Begum
*
, Sanjeev V Thomas
**
Unlike others, the European registry and the UK registry do
not include WWE who are not taking any AEDs. KREP, EURAP
and the Australian registry collect data from the maximum
number of contacts. Of these, the Australian registry collects
data over telephone. They also difer in their duration of follow
up, outcome ascertainment methods, outcome classifcation,
control selection methods etc. Among the fve, KREP is the only
one providing pre conceptional counseling. Under KREP, WWE
and their children are followed up to the age of 12yrs.
KREP has an important role in the Indian scenario as it is
generating data from our country. The genetic constitution,
socio economic environment and health care delivery system
that would influence the foetal and maternal outcome for
persons with epilepsy are diferent in diferent populations. The
fnal outcome of the disease and the efect of AEDs in diferent
populations may vary based on many such factors. For example,
the US registry has found an increase in the incidence of cleft
lip and palate in their population
1
while the UK or European
registries
2
have not.
Social issues in WWE
WWE experience a broader spectrum of problems and social
stigma associated with epilepsy than their male counterparts.
3

Abstract
Women with epilepsy (WWE) have several gender based problems pertaining to social and biological domains.
The stigma of epilepsy and its consequences appear to be more for women than men. They have more difficulty in
getting married and sustaining a married life. The cyclical variations in the reproductive hormones can adversely
impact the seizure pattern in WWE. Epileptiform discharges in the brain can influence the hypothalamic functions
and lead to sexual dysfunction. The Antiepileptic drugs (AED) may alter their metabolic and hormone profile and
contribute to this disorder. Most WWE tend to have uneventful pregnancies and healthy babies. Nevertheless, the
risk of fetal malformations appears to be increased when AEDs are used during pregnancy. This risk is higher for
those who are on polytherapy, or using valproate. Recent studies have also demonstrated that antenatal exposure
to AEDs could lead to neurocognitive and developmental impairment, low IQ or language problems in exposed
infants. Clinicians need to consider these special issues while initiating AED therapy in adolescent girls. All
WWE need to have a detailed pre conception evaluation wherein the need to continue AEDs, the ideal AED and
dosage are reassessed. The AED therapy would have to be individualized according to the clinical situations,
obstetric background and family concerns. Folic acid should be prescribed to all women who could potentially
become pregnant. Detailed screening for fetal malformations by estimation of serum alpha fetoprotein and fetal
ultrasonography need to be carried out between 14 - 18 weeks of pregnancy. The dosage of AEDs may have to be
escalated in the second half of pregnancy in selected patients. The family should be provided detailed counseling
Table 1 : Characteristics of various epilepsy and pregnancy registries
UK US KREP EURAP Australia
Year of commencing 1996 1997 1998 1999 2000
Pre conceptional evaluation No No Yes No No
Includes those not on AED Yes No Yes No Yes
Exclusion criteria AED change AED change
Data collection 2 contacts 3 contacts 4 contacts 4 contacts 4 (phone)
Malformation ascertainment at <12 wks < 12 wks 12 months 12 months 12 months
Control selection Internal External
Non epileptic
External
Internal
Internal Internal
External
Abbreviations: UK, United Kingdom; US, United States; KREP, Kerala Registry of Epilepsy and Pregnancy; EURAP = An International Registry of
Antiepileptic Drugs in Pregnancy; AED, Anti-epileptic Drug
In a comparison of young men and women with JME (Juvenile
Myoclonic Epilepsy) or TLE (Temporal Lobe Epilepsy) living
in India, it was found that there were signifcant gender based
diferences in the profle of epilepsy. WWE were found to have
SUPPLEMENT TO JOURNAL OF THE ASSOCIATION OF PHYSICIANS OF INDIA AUGUST 2013 VOL. 61 49
higher odds ratio for remaining unmarried (OR 2.81) than men
(OR 1.63) across all age groups from 20-44yrs. WWE were also
observed to have higher rates of unemployment and divorce.
4
Infertility
Issues regarding reproduction are a major concern in WWE.
Earlier studies have indicated that WWE have reduced fertility.
5

Infertility is defned as the inability to conceive even after 12
months of unprotected intercourse. A prospective study over
10 years under KREP had shown that WWE have a greater risk
for infertility, especially with polytherapy.
6
The prevalence of
infertility among WWE was more than double (38.4%) that
among women in the general population (15.15%). Also, the
WWE who conceived had a fewer number of children than the
rest. Infertility was least for those who were not on any AEDs
(7.1%) while it was 31.8% for those taking one AED, 40.7% for
those taking two AEDs and 60.3% for those taking three or
more AEDs. Those exposed to Phenobarbital had a signifcant
risk of infertility (OR 1.517 for monotherapy and OR 1.43 for
polytherapy) but no such trend was observed with valproate or
other drugs in that study.
6
Efect of Pregnancy on Epilepsy
Another concern is the recurrence of seizures during
pregnancy. In general, 20-30% of WWE may have exacerbation
of seizures during pregnancy, 20-30% show improvement and
40-50% experience no change in seizure patern.
7
The cause for
seizure recurrence varies with the stage of pregnancy. In the
frst trimester recurrence is mostly due to mental stress, sleep
deprivation, hormonal changes etc. Patients may be apprehensive
about the adverse efects of AEDs on the fetus and may tend to
discontinue treatment. Another issue is hyperemesis which
indirectly results in drug default. Either ways non compliance
is a major cause of seizure recurrence in pregnancy. During the
second and third trimesters there is signifcant hemodilution
which causes a reduction in the blood levels of AEDs. This
compounded with increased elimination of drugs, especially
lamotrigine and oxcarbazepine and to some extend leviteracetam
can result in break through seizures. Therefore patients on these
AEDs can be prescribed to take an increased dose of the same.
Of the 1,297 pregnancies in WWE enrolled in KREP, all the
three paterns were observed. 47.8% remained seizure free
during pregnancy. Seizure relapse was highest during the three
peripartum days. Recurrence was more with localization related
epilepsy (LRE) than generalized epilepsy (OR-1.6, CI-1.2-2.0).
Also, patients with poor seizure control in the pre pregnant
month were more likely to have seizure recurrence in pregnancy
when compared to those with seizure free pre pregnant period.
Polytherapy was signifcantly associated with seizure relapse
than monotherapy.
8
Efect of Epilepsy on Pregnancy
There is no undue risk of pregnancy and childbirth in
WWE.
9-11
WWE are found to have an adverse maternal outcome
of pregnancy. In a prospective study
9
where the complications
of 643 completed pregnancies were compared with 18,272
pregnancies managed in a teaching hospital, it was found that
WWE had a higher chance for some complications like, anemia,
ovarian cyst, fbroid uterus, spontaneous abortions and seizures
in the peri partum period. The risk of caesarean section was not
increased in WWE.
Teratogenic Efects
Ante natal use of AEDs has been associated with increased
risk of fetal malformations. Various mechanisms have been
proposed as to how AEDs exert their teratogenic efects.
12
AEDs
may lead to folate defciency and thus predispose to neural
tube defects. AEDs that are metabolized by cytochrome P450
enzymes in the liver increase the levels of arene oxide which is a
byproduct of this metabolism. Arene oxide is a potent teratogen.
Other mechanisms include alteration of homeobox (HOX)
genes, retinoic acid signaling pathway, histone deacetylators,
polymorphisms involving AED transporters and oxidative
stress.
13,14
Considerable amount of data has come from the various
registries regarding fetal malformations.
2,15-17
But it is important
to consider the characteristics of the registry, their selection
criteria, case ascertainment methods and follow up duration
while interpreting their results.
Under KREP, malformations are defned as serious defects
which interfere with the quality of life unless they are managed.
Others which produce only a cosmetic efect and do not interfere
with the quality of life are considered as anomalies and do not
qualify as major malformations.
AEDs can induce malformations in almost all organs. These
can be broadly classifed into cardiac malformations (tetralogy
of Fallot, atrial septal defect, ventricular septal defect, patent
ductus arteriosus, pulmonary atresia, single ventricle etc),
malformations of the nervous system (neural tube defects),
skeletal defects (club foot, hip dislocation etc), cranio facial
defects (cleft lip and palate), malformations of the gastro
intestinal system (esophageal atresia, congenital hypertrophic
pyloric stenosis, inguinal, diaphragmatic and umbilical hernias
and omphalocele), malformations of the genitor urinary system
(renal agenesis, hydronephrosis, hypospadias and undescended
testis) and malformations involving multiple systems. In a
prospective study from the UK epilepsy and pregnancy register,
4.2% of live births to WWE had major congenital malformations.
The rate of major congenital malformation was more with
polytherapy than monotherapy (adjusted OR 1.83).
17
In a larger
study involving patients from Europe, Australia and India, it
was observed that there was a dose dependent increase in the
risk of malformations for carbamazepine, lamotrigine, valproate,
and Phenobarbital.
2
Long Term Outcome
Until recently, not much research was directed to the adverse
efects of AEDs on the long term language and IQ development of
children exposed to AEDs in utero. A long term adverse efect of
ante natal use of AEDs is impaired neurocognitive development
in infants exposed to AEDs prenatally. A prospective evaluation
of 15 month old infants of mothers with epilepsy enrolled in
KREP showed that about one third of them had a signifcantly
impaired mental (MeDQ) and motor (MoDQ) development
quotient. Those exposed to polytherapy had a signifcantly lower
development quotient than those exposed to monotherapy.
Valproate monotherapy was associated with signifcantly lower
MeDQ and MoDQ when compared to carbamazepine.
18

In a follow up study under KREP where children of mothers
with epilepsy, of age 6 years and above were compared against
age and socio economic status matched controls, it was found
that the test group scored signifcantly less than the controls
in both full scale IQ test (FSIQ) and language test. It was also
observed that children with low MeDQ and MoDQ at one year
of age continued to have low FSIQ and MLT at 6 years of age
50 SUPPLEMENT TO JOURNAL OF THE ASSOCIATION OF PHYSICIANS OF INDIA AUGUST 2013 VOL. 61
(p value 0.05, 0.05 and 0.02 respectively). Also the polytherapy
group had lower mean FSIQ than monotherapy group. Those
exposed to higher cumulative load of AEDs had signifcantly
lower FSIQ and MLT scores compared to those exposed to lower
drug load.
19
The fndings were later confrmed in a sample drawn
from UK and USA as well as Europe.
20,21
Management Approach
The AED therapy in adolescent girls should ideally be
tailored considering their reproductive needs. WWE should
be advised to consult their neurologist before starting a family.
Their diagnosis should be actively re-assessed at this point of
time (Figure 1). It is not rare to fnd women who are inadvertently
started on AEDs for non epileptic conditions misdiagnosed as
epilepsy. Some are found to be in remission and in them drugs
may be withdrawn following the general principles. However,
the risk of recurrence of seizures, particularly with the risk of
marriage and its impact needs to be addressed. Patients with
Juvenile Myoclonic Epilepsy need to be continued on AEDs as
they are at high risk of seizure relapse on complete withdrawal.
Any changes in the patern of drug therapy may be planned prior
to pregnancy. Reduction of doses, change over to less teratogenic
drugs and conversion of polytherapy to monotherapy may
be done depending on the disease status of individuals. Pre
pregnancy blood levels of AEDs can also be checked.
22,23
WWE who are likely to get pregnant may be started on folic
acid 5mg/day pre conceptionally. WWE and their families may
be counseled regarding the need to continue AEDs in order to
remain seizure free, that >90% of infants born to WWE on AEDs
are healthy, the risk of a major malformation is 6-8% and that this
is seen mostly with WWE taking polytherapy and high doses
of AEDs. The need to take folic acid daily has to be reinforced.
Under KREP, pregnant WWE are screened for malformations
at 16-18 weeks of pregnancy with serum alpha feto protein
levels at 16 weeks as well as a fetal ultra sonogram at 18 weeks
of pregnancy (Figure 2). This provides a margin of 2 weeks
time for a safe termination before 20 weeks in the event of a
malformation. Malformation focused ultrasonography can be
done as early as 12 weeks. But it has been found that the expertise
regarding malformation detection with an early scan is highly
variable among radiologists and in some instances may not be
helpful. Therefore an ultra sonogram at 18 weeks is preferred.
In the second trimester blood levels of AEDs tend to fall
due to hemodilution and other metabolic changes. Periodic
monitoring of blood levels especially free blood levels in frst,
second and third trimesters can guide the physicians in adjusting
the dosage of AEDs. Anticipatory increase of AED dose may be
done with lamotrigene and oxcarbazepine as their blood levels
fall signifcantly and in most instances lead to break through
seizures. With other AEDs, dose is usually increased only if
break through seizures occur as most of the WWE go through
their second and third trimesters uneventfully even with pre
pregnant doses.
We advise all WWE to take two doses of vitamin K 10mg IM
at 34 and 36 weeks of pregnancy respectively as vitamin K tablets
are not available in India. This is to prevent hemorrhagic disease
of the newborn. Mode of delivery is generally dictated by the
obstetric needs. Routine doses of AEDs must be administered
to the lady in the labor room also. If she has an increased
propensity to develop seizures an elective caesarean section
may be performed.
Post partum Management
The necessity of contraception and birth spacing in WWE
cannot be over emphasized. Oral contraceptives are generally
avoided in those taking enzyme inducing AEDs for fear of
failure. But if the couple prefers oral contraceptive pills, high
estrogen pills may be prescribed, i.e. pills containing 50g of
estrogen. Medroxy Progesterone Acetate depot injection once
Fig. 1 : Algorithm for follow up of women with epilepsy during
pregnancy
ALGORITHM FOR PRECONCEPTION MANAGEMENT OF
EPILEPSY IN WOMEN
NO
YES
NO
YES
YES

NO
NEED
FOR AED
CHANGE
AED
FOLIC
ACID
FOLLOW UP
NEW AED
REGIME
PREGNANCY
EPILEPSY
DEFINITE
ENTRY
EXCLUDE
Fig. 2 : Algorithm for antenatal screening for congenital
malformations
ALGORITHM FOR MANAGING EPILEPSY IN PREGNANT WOMEN
A / N VISIT
<< 12 wk
YES
NO
YES NO
TITRATE
AED
28 Wk.
<20 Wk
LSCS
CONTRACEPTION
BREAST FEEDING
VAGINAL
INDUCTION MTP
VITAMIN K
(Prior to delivery)
FOLIC ACID
TYPE OF
DELIVERY
MALFORM:
SCREEN
II A / N VISIT
16 - 20 Wk
TERMINATE
28 Wk.
TITRATE
AED
TITRATE
AED
36 Wk.
SUPPLEMENT TO JOURNAL OF THE ASSOCIATION OF PHYSICIANS OF INDIA AUGUST 2013 VOL. 61 51
every 3 months is another alternative. In an Indian seting, intra
uterine contraceptive devices are generally preferred.
Child rearing is a physically and emotionally demanding task
as far as WWE are concerned. Hence they have to be prepared for
this. It is generally seen that WWE either refrain from or are not
given an opportunity to look after their infants due to multiple
reasons. Upbringing of these children by others may interfere
with their development. Therefore, maternal involvement in
child rearing has to be fostered. WWE often skip medications
or refrain from breast feeding for fear of AEDs fnding way
into breast milk. But only traces of AEDs are found to pass into
breast milk. This exposure is not demonstrated to produce any
signifcant adverse efects in children. According to a recent
prospective study no signifcant diference has been found
between children of WWE exposed to AEDs via breast milk and
those with no such exposure regarding IQ at 3 years of age.
24

There are only anecdotal reports of adverse efects of AEDs
in breast fed babies. Moreover, the benefts of breast feeding
far outweigh the adverse efects and needs to be fostered. It is
recommended that mothers frst nurse their babies and then take
medicines so that blood levels will not be very high during breast
feeding. Sleep deprivation for nursing the child at night may
lead to break through seizures especially in those with Juvenile
Myoclonic Epilepsy.
25
In such cases family members should be
adequately counseled and compliance ensured. Mothers can
use expressed breast milk during night. Good compliance to
AEDs and compensatory sleep during daytime needs emphasis
in them. WWE are advised to nurse their babies in such a way
that in the event of a seizure she may not drop the baby or fall
over and sufocate it.
Conclusion
Management of epilepsy in women of child bearing age
involves close interaction between the clinician, patient and
family members. Most women can expect safe pregnancy
and healthy babies. Careful planning of pregnancy, folate
administration, optimization of AED therapy, close monitoring
and screening for fetal malformations are very important.
Neurologist, obstetrician and a neonatologist need to work as
a team to ofer the best medical care for women with epilepsy
and their children.
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