DOI: 10.1111/j.1471-0528.2009.02141.
x
www.blackwellpublishing.com/bjog
The management of epilepsy in pregnancy
SP Walker,a,b M Permezel,a,b SF Berkovicc
a
Department of Perinatal Medicine, Mercy Hospital for Women, Heidelberg, Vic., Australia b Department of Obstetrics and Gynaecology,
University of Melbourne, Parkville, Vic., Australia c Department of Medicine and Epilepsy Research Centre, University of Melbourne, Austin
Health, Heidelberg West, Vic., Australia
Correspondence: Assoc. Prof Sue Walker, Department of Perinatal Medicine, Mercy Hospital for Women, 163 Studley Road, Heidelberg, Vic.
3084, Australia. Email: spwalker@unimelb.edu.au
Accepted 26 January 2009.
While most women with epilepsy can expect a normal pregnancy
outcome, epilepsy remains a significant contributor to both
maternal and perinatal morbidity. Pre-pregnancy planning must
address reliable contraception and optimisation of antiepileptic
drug (AED) regimens to minimise teratogenic risk while
maintaining seizure control. The most recent data from the AED
registries regarding malformations is presented in this review, as is
Please cite this paper as: Walker S, Permezel M, Berkovic S. The management of epilepsy in pregnancy. BJOG 2009;116:758767.
Introduction
Epilepsy is the most commonly encountered serious neuro-
logical problem faced by obstetricians, gynaecologists and
primary care physicians. Its importance lies in the fact that
the majority of women with epilepsy (WWE) will need to
continue antipepileptic drugs (AEDs) prior to and during
pregnancy. The disease and these medications may signifi-
cantly impact on reproductive function, contraceptive
choice and efficacy. During pregnancy, the clinician faces
the dual challenge of maintaining seizure control, yet mini-
mising teratogenic risk. The purpose of this review is to
provide an update on management of WWE prior to and
during pregnancy. In particular, pre-pregnancy and contra-
ceptive recommendations will be addressed, and updated
information provided regarding the teratogenecitiy of
AEDs, including the newer AEDs. This overview will also
examine the role of therapeutic drug monitoring (TDM) in
pregnancy, obstetric complications facing WWE and
recommendations to optimise antenatal, intrapartum and
postpartum care.
Preconception care
Specific considerations for women of reproductive age with
epilepsy include consideration of sexuality and reproductive
function and avoiding unplanned pregnancy with reliable
contraception. When pregnancy is planned, AED medication
758 2009 The Authors Journal compilation RCOG 2009 BJOG An International Journal of Obstetrics and Gynaecology
Review article
the limited data on the newer AEDs and studies linking
neurocognitive outcomes to AED exposure. During pregnancy,
important considerations include; therapeutic drug monitoring,
surveillance for obstetric complications and vigilance for seizures
during the intrapartum and postpartum period.
Keywords Epilepsy, pregnancy, reproduction.
should be optimised and adequate folic acid supplementa-
tion instituted. Awareness of these issues remain poor;
despite a national education programme, a recent study
found that only 46% of WWE recalled being provided with
information on the interactions between AEDs and contra-
ceptives, 63% on the need to plan pregnancy and only 56%
on the need for folic acid supplementation.1
Reproductive function and fertility in WWE
Increased rates of sexual dysfunction are reported among
both men and WWE. This may arise from both neuro-
endocrine disturbances related to seizure activity, as well as
the alteration of endogenous sex steroid metabolism in
the presence of enzyme-inducing AEDs.2 Hypothalamic
amenorrhoaea, hyperprolactinemia and premature meno-
pause are over-represented among WWE, thought partly
because of interference with normal hypothalamic and
pituitary function by temperolimbic discharges commonly
involved in epilepsy.3 An increase in anovulatory cycles and
polycystic ovarian syndrome (PCOS) has also been
observed in WWE.3,4 While this may partly relate to distur-
bance of the Hypothalamic-pituitary-adrenal (HPA) axis,
AEDs may also play a role.4 Enzyme-inducing (EI) AEDs
increase serum sex hormone binding globulin (SHBG)
levels, resulting in decreased levels of biologically active
estradiol and testosterone. In addition, valproic acid (VPA)
is associated with an increased rate of hyperandrogenism,
ovulatory dysfunction and PCOS, particularly among

young (<26 years) women,5 suggesting a direct effect on
ovarian androgen production. These observations are con-
sistent with the findings that fertility is lower among
patients with epilepsy, although, a recent Scandinavian
population-based cohort study suggests the impact is rela-
tively modest. The birth rate was lower in WWE than the
population without epilepsy, (hazard ratio 0.83, 95% CI
0.830.93).6 A follow-up study did not find any significant
differences between treated and untreated women,7 suggest-
ing that while women may have a mild reduction in
fertility associated with epilepsy, the use of AEDs does not
significantly impact further.
Contraception
The efficacy of hormonal contraception may be reduced by
EI AEDs, such as phenobarbitol, primidone, phenytoin,
carbamazepine, oxcarbazepine, felbamate and topiramate,
all of which by inducing hepatic enzymes in the cyto-
chrome P-450 system increase clearance of contraceptive
steroids.8,9 In addition, EIAEDs increase the level of SHBG,
which in turn decreases the levels of freely circulating prog-
estins.9 Hormonal contraceptive efficacy is not affected by
non enzyme-inducing AEDs, such as including VPA,
zonisamide, benzodiazepines, gabapentin, levetiracetam,
pregabalin, tiagabine and vigabatrin.9 While lamotrigine
has been previously thought not to impact on contraceptive
efficacy, a recent study has demonstrated a significant
decrease in plasma levonorgestrel concentration and some
reduction in hypothalamic-pituitary suppression, albeit
without evidence of breakthrough ovulation.10
The accelerated metabolism of estrogens and progesto-
gens in the combined oral contraceptive pill (COCP)
means that plasma concentrations may fall below the levels
required for inhibition of ovulation. Contraceptive alterna-
tives, such as depo medroxyprogesterone acetate (DMPA),
a levonogestrel releasing intrauterine contraceptive device
(Mirena) or barrier methods may be considered preferable
for WWE taking EIAEDs.11,12 Where COCP use is neces-
sary, a higher estrogen dose COCP (e.g. 50 lg of ethinyl
estradiol) has traditionally been recommended.13,14 Never-
theless, it is the increase in progestin dose that is necessary
for ovulation suppression12; hence, the recommendation to
increase both estrogen and progestin (for example, by
taking 2 Microgynon 30 tablets daily).11 A residual risk of
breakthrough pregnancy remains, because the extent of
enzyme induction varies among women. To improve
contraceptive efficacy further, tricycling the pill is recom-
mended (i.e. three cycles of hormonal contraception with-
out a break) followed by a shorter pill free interval
(4 days).11 Extended cycle regimes such as this more reli-
ably inhibit ovulation by preventing follicular development
during the pill-free period, and may further improve
contraceptive efficacy by uninterrupted thickening of cervi-
2009 The Authors Journal compilation RCOG 2009 BJOG An International Journal of Obstetrics and Gynaecology
Epilepsy and pregnancy
cal mucus and modulation of the endometrium.12 The
reduction in circulating levels of levonorgestrel among
patients receiving EIAEDs means that the low dose (or
mini-pill) progestin-only pill is not recommended for these
patients.1114
With regard to the effect of COCPs on AED levels, recent
studies suggest that administration of COCPs increase
metabolism of lamotrigine (via increased glucuronuidation),
reducing levels by approximately 50%.8,10,12,1517 This has
been associated with a significant worsening of seizure con-
trol.9,12,15 An increase in lamotrigine dose is therefore
required when commencing the COCP with appropriate
reduction upon cessation.12 The benefit of continuous
(uninterrupted) oral contraceptive use among lamotrigine
users is thus two-fold; to improve contraceptive efficacy and
maintain stable plasma lamotrgine concentrations.12 The
metabolism of oxcarbazepine, like lamotrigine, is via
glucuronidation, so a similar effect on oxcarbazepine levels
would be expected and warrants further exploration.8
A small study of women using levonorgestrel implants
(Norplant) for contraception reported lower levonorgestrel
levels among women using phenytoin compared with con-
trol women. Two subsequent breakthrough pregnancies
were associated with low plasma levonorgestrel concentra-
tions around the time of conception suggesting that paren-
teral levonorgestrel is ineffective among patients receiving
EIAEDs.18 Several case reports have followed,19,20 resulting
in the recommendation that this form of contraception be
avoided among women taking EIAEDs.11,12,14 The contra-
ceptive efficacy of the etonogestrel implant (Implanon) has
likewise been reported to be reduced among WWE using
EIAEDs.21 In the first 3 years of marketing in Australia,
218 unplanned pregnancies were reported in the 204,486
subsidised insertions, giving an approximate failure rate of
1:1000. Eight of these Implanon failures were in association
with EIAEDs with seven of the eight women using carba-
mazepine.22 Likewise, 39 unintended pregnancies were
reported after 17 months of Implanon use in France; 2 in
association with hepatic EI medication.23 The product
information recommends the use of an additional barrier
method of contraception in WWE taking hepatic EIAEDs.
Despite the disappointing results from subcutaneous
progestin implants, administration of high dose DMPA
continues to provide effective contraception in women tak-
ing hepatic EIAEDs. That DMPA has been shown to reduce
seizure frequency in some WWE means that DMPA may be
a preferred contraceptive method.9 The disadvantages of
DMPA as a long term contraceptive include delayed return
to fertility, irregular bleeding and adverse effects on bone
mineral density, particularly among adolescents who may
not achieve peak bone density.12 The United States FDA
recommends that the benefits and risks be discussed with
women prior to commencement of DMPA and reassessed
759
 Walker et al.
after 2 years of continuous use.9 While some authorities
suggest administering DMPA every 10, rather than 12,
weeks to women receiving EIAEDs, DMPA is subject to
100% first pass hepatic metabolism, such that the presence
of enzyme inducers cannot accelerate metabolism further.11
The levonorgestrel-releasing intrauterine device (Mirena)
is a highly effective form of contraception as the progester-
one effect is locally mediated and less affected by the
EIAEDs.9 Given that it is both reversible and highly effective,
with an estimated failure rate of 1% among these women,24
a levonorgestrel-releasing IUCD has been suggested as the
first line contraceptive choice for WWE using EIAEDs11 or
lamotrigine.12 With appropriate pre-insertion counselling
and advice, Mirena is gaining increasing acceptance for
nulliparous women, including young women and adolescents.11
Optimising AEDs for pregnancy
There are widespread concerns about the teratogenic risks
posed by AEDs, but any potential benefit of ceasing or
changing medication must be weighed against a risk of
increased seizure frequency, with the attendant risk to the
patient, her fetus and possibly other children. Women with
well controlled epilepsy (e.g. seizure free for 25 years)
may be eligible to stop or reduce their medication prior to
pregnancy, and women taking more than one AED may
consider a trial of monotherapy. The risk of seizure relapse
appears to be lower in the presence of a normal neurological
examination/IQ, normal EEG and normal neuroimaging.
However, certain syndromes that are easily controlled with
medication have a high rate of relapse off medication, such
as juvenile myoclonic epilepsy (JME).25 The risk of seizure
relapse is highest soon after drug withdrawal or dose
reduction, and it is preferable that pregnancy is deferred
until stabilisation is achieved.26 During this transition per-
iod, WWE should be particularly wary of lifestyle exacerb-
ants, such as sleep deprivation, stress and alcohol
consumption. They should be aware of the implications for
their driving license in the event of a seizure. The complexity
of this decision-making underscores the value of WWE
consulting both their neurologist and obstetrician when
contemplating a pregnancy.
Teratogenicity of epilepsy and AEDs
The risk of congenital malformation is higher in WWE. In
an effort to better quantify the risk of treated versus
untreated epilepsy, a Finnish population-based study has
compared the risk of major malformation in WWE, with
and without treatment.27 This study confirmed that major
congenital malformations were more common among
women on AEDs (4.6%) than among untreated patients
(2.8%), OR 1.7 (95% CI 1.052.81). Given the differing
patterns of both seizure severity and type between treated
and untreated patients, the pathogenesis of fetal malforma-
760 2009 The Authors Journal compilation RCOG 2009 BJOG An International Journal of Obstetrics and Gynaecology
tions is likely to be multifactorial. In addition to the direct
affect of AEDs, there may be contribution from toxic AED
metabolites, reduced folate availability, hypoxic injury asso-
ciated with seizures and genetic predisposition.28
While specific dysmorphic phenotypes have been
described with many of the commonly used AEDs, it is the
incidence of major congenital malformation that causes
most concern. The precision of risk estimation with any
individual AED is imperfect as there is a paucity of
controlled data, and an uncertain impact of potential
confounders, such as type of epilepsy, seizure frequency,
family history of birth defects, socio-economic factors,
nutrition and exposure to additional teratogens.29 The
development of AED registries addresses many of these
problems by prospectively enrolling large numbers of WWE
taking AEDs at the start of pregnancy with systematic follow
up of pregnancy outcomes. These registries are one of three
types; independent academic registries, pharmaceutical drug
registries and population-based registries. The independent
registries include; the European and International Registry
of Antiepilpeptic Drugs and Pregnancy (EURAP), originally
established in Europe in 1999 and later extended to include
30 countries in Europe, Asia, Oceania and South America,30
the North American Antiepileptic Drug Pregnancy Registry
(established in 1997),31 the United Kingdom Epilepsy and
Pregnancy Group (established in 1996),32 and the Australia
Pregnancy Registry of Women taking Antiepilpeptic Drugs
(established in 1999).33 Two pharmaceutical registries
include the GlaxoSmithKlines International Lamotrigine
Pregnancy Registry,34 and the recently launched UCB An-
tiepileptic drugs (AED) registry [formally the Keppra (lev-
etiracetam) registry]. The Swedish and Finnish national
registries provide information on the prevalence of birth
defects linked to antenatal or national prescription data
identifying WWE.27,35
While AED registries provide the most robust data on
teratogenic risk when compared with the cohort and case
control studies that preceded them, their individual
strengths and limitations need to be appreciated. National
registries provide the best population-based data, but detail
on epilepsy type and drug dosing is often limited, and inci-
dence data is limited by lack of information on termination
of pregnancies. The independent academic registries suffer
from methodological differences between registries,
incomplete information regarding dosages and confounding
variables and incomplete enrolment (for example, 30% in
the UK Registry, which has among the highest participation
rates).36 It is estimated that approximately 500 monothera-
pies are required to confidently identify differences in
major congenital malformations between AEDs.37 Larger
numbers again are required to examine for a dose-response
relationship and to adjust for confounding variables.37
Notwithstanding these limitations, these registries provide
 Epilepsy and pregnancy

Table 1. Risk of major malformation with antiepileptic drug (AED) monotherapy

Phenobarbitone Phenytoin Carbamazepine VPA Lamotrigine Levetiracetam Topiramate Gabapentin

North American AED Registry

Holmes 200138 3/64 (4.7) 3/87 (3.4) 3/58 (5.2)
Holmes 200439 5/77 (6.5)
Wyszynski 200540 16/149 (10.7)
Hernandez-Diaz 200741 22/873 (2.5)
Holmes 200842 16/684 (2.3)
UK Epilepsy and Pregnancy Registry
Morrow 200643 3/82 (3.7) 20/900 (2.2) 44/715 (6.2) 21/647 (3.2) 0/22 (0) 2/28 (7.1) 1/31 (3.2)
Hunt 200644 0/37 (0)
Hunt 200845 3/70 (4.8)
Australian Register of AEDs in Pregnancy
Vajda 200733 1/31 (3.2) 7/234 (3) 22/166 (13.3) 2/146 (1.4) 0/5 (0) 0/15 (0) 0/11 (0)
Swedish Birth Registry
Wide 200435 7/103 (6.8) 28/703 (4) 26/268 (9.7) 4/90 (4.4) 0/1 (0) 0/18 (0)
Finnish Birth Registry
Artama 200527 22/805 (2.7) 28/263 (10.6)
Lamotrigine Registry
Cunnington 200746 22/802 (2.7)
Total 8/141 (5.7) 14/303 (4.6) 102/3573 (2.9) 136/1561 (8.7) 63/2369 (2.7) 0/66 (0) 5/113 (4.4) 1/42 (2.4)

Value in parenthesis denotes percentage.

the best available estimates of teratogenic risk for the com-
mon monotherapies. The quality of information will only
improve with time, and it is recommended that all WWE
be registered with their local Anti-Epileptic Drug Regis-
try.36 The most recent published data for the common
AEDs from the above mentioned registries are presented in
Table 1. This data reflects the considerable experience and
safety with carbamazepine as a single agent, although the
accumulating data on lamotrigine also appears reassuring.
These results are similar to the findings of a meta-analysis
published in 2008 including registry and cohort data up until
May 2007.47 The incidence (95% confidence intervals) of
malformations for monotherapy was as follows: carbamaze-
pine 4.6% (3.55.8%), lamotrigine 2.9% (23.8%), pheno-
barbitol 4.9% (3.26.6%), phenytoin 7.4% (3.611.1%) and
valproate 10.7% (8.213.2%). As a single agent, VPA consis-
tently has the highest rate of malformations, and several
investigators have reported a dose-response relationship
between valproate and major malformation.27,4850
The safety data on the newer AEDs is limited. While the
overall incidence of major congenital malformation with
lamotrigine appears acceptable, it remains uncertain
whether lamotrigine is associated with an increased risk of
facial clefting.42,51,52 There have been small case series
suggesting an increase in low birthweight among infants of
WWE receiving topiramate53 and levetiracetam,54 but these
findings warrant validation in larger studies. Similarly,
malformations have been reported in 6/248 (2.4%) of
patients receiving oxcarbazepine in pregnancy,55 and 2/44
(4.5%) of patients receiving gabapentin.56 Vigabatrin is
associated with acquired visual field defects and its safety is
not established in pregnancy.57
The risk of malformation with polytherapy is higher than
with monotherapy. While it is difficult to determine indi-
vidual risks for all possible polytherapy combinations, the
meta-analysis of Meador et al. 47 reported that the rate of
total congenital malformations was significantly higher for
polytherapy (9.84%; 95% CI = 7.82, 11.87) than for mono-
therapy (5.3%; 95% CI = 3.51, 7.09).
In summary, the risk of congenital malformation is
higher among treated WWE than untreated women and
those using polytherapy rather than monotherapy. As a
single agent, VPA (particularly in doses >1100 mg/day)
appears to be associated with the highest risk and this is
further amplified when combined with other AEDs.47 In
the face of this data, modification of AEDs pre-pregnancy
may be indicated to minimise teratogenic risk. To further
minimise this risk, high dose (5 mg) folic acid is generally
recommended for at least 1 month preconceptually and
throughout the first trimester.26 EIAEDs and valproate are
known to interfere with folic acid metabolism,58 and Kjaer
et al. reported fewer congenital malformations in women
taking AEDs with folic acid, compared to those not given
additional supplementation,59
Neurocognitive effects
In addition to structural malformations associated with
AEDs, there has been increasing concern regarding the

2009 The Authors Journal compilation RCOG 2009 BJOG An International Journal of Obstetrics and Gynaecology 761
 Walker et al.
potential adverse effect of AEDs on fetal cognitive develop-
ment. While structural malformation risk is essentially
confined to the first trimester, cognitive effects of AEDs
have the potential to impact throughout gestation. Animal
studies suggest that these cognitive effects may be mediated
by AED-induced neuronal apoptosis.60 Several investigators
have reported an increase in educational requirements,61,62
poorer neuropsychological performance63 and reduced
verbal IQ64 among children exposed prenatally to VPA.
Thomas et al. assessed both motor and mental develop-
mental quotients of 395 infants of mothers with epilepsy at
a mean age of 15 months. Infants of mothers taking AEDs
had significantly lower scores than those infants unexposed.
The most significant effects were seen for polytherapy and
monotherapy with VPA.65
These differences may persist into adulthood. Offspring
of mothers with and without epilepsy were found to differ
in IQ scores and height when assessed at 1819 years of
age. The significant adverse effect persisted when adjust-
ment was made for confounders including maternal educa-
tion, maternal age, birth order, marital status and
birthweight. However, no information on AED use was
available for this large population-based study of
Norwegian male conscripts.66
Taken collectively, the data consistently demonstrates
stronger associations between VPA and both major malfor-
mations and neurocognitive effects, but it must be emphas-
ised that data on neurocognitive outcomes is relatively
recent, methodologically challenging and further prospec-
tive studies are essential. Large numbers will be needed
before there is a reasonable probability of separating the
effects of the various AEDs from confounders such as
seizure frequency, type of epilepsy, genetic factors and
parental cognitive function.
Pregnancy care
In the antenatal period, obstetricians caring for WWE need
to consider the likely impact of pregnancy on seizure
frequency, the potential impact of epilepsy on obstetric
outcomes, the role of TDM of AEDs, surveillance for
congenital malformations and the place of vitamin K
supplementation. In women who present during pregnancy
with their first seizure, consideration should also be given
to alternate diagnoses, such as eclampsia, a primary neuro-
logical event, metabolic disturbance or drug toxicity or a
seizure complicating a vaso-vagal faint.
The behaviour of epilepsy in pregnancy,
and its effect on pregnancy outcomes
Until recently, there was limited prospective data on sei-
zure frequency during pregnancy. The EURAP registry
has recently reported on 1882 WWE where seizure
762 2009 The Authors Journal compilation RCOG 2009 BJOG An International Journal of Obstetrics and Gynaecology
control and treatment was prospectively recorded. 58% of
participants were seizure free during pregnancy. When
first trimester seizure activity was used a reference, 64%
had no change in the second and third trimester, 16%
improved, while only 17% deteriorated.67 In the absence
of information on pre-pregnancy seizure control, this
study cannot fully address the impact of pregnancy on
epilepsy, but it suggests it is probably modest. One nota-
ble exception is that tonic-clonic seizures occurred more
frequently among women taking oxcarbazepine monother-
apy.67 The increased clearance of lamotrigine and
oxcarbazepine observed with COCP use is also observed
in pregnancy,16,68 and suggests these WWE may be par-
ticularly vulnerable to breakthrough seizures with falling
AED levels.
The Australian Register of AEDs in pregnancy also found
that pregnancy had little impact on seizure frequency
among treated women. Seizures occurred during pregnancy
in 418/841 (49.7%) of AED-treated pregnancies. A
12 month seizure-free period prior to pregnancy was asso-
ciated with a 5070% reduction in seizure risk during preg-
nancy.69 If seizure control deteriorates in pregnancy,
potential contributors include: decreased medication com-
pliance because of concern about teratogenesis; decreased
drug absorption because of nausea and vomiting, impaired
sleep and decreased drug levels because of both increased
volume of distribution in pregnancy and increased drug
metabolism.
While the fetus is relatively resistant to short hypoxic
episodes, prolonged convulsive seizures may result in
sustained fetal hypoxia. Protecting the fetus from the con-
sequences of frequent or sustained seizures is a compelling
argument for maintaining AED use in pregnant WWE.
This notwithstanding, the EURAP registry has provided
some reassuring data regarding the impact of seizures on
pregnancy outcome. Among 1956 WWE, 30 stillbirths
(1.5%) were recorded, which is somewhat higher than the
0.5% that might be expected in a non-selected population.
Half of these were among the 943 (1.5%) women with
seizures and the other 15 stillbirths occurred in the 1013
(1.5%) who were seizure free.67 Status epilepticus compli-
cated 36/1956 (1.8%) pregnancies. Thirty-four of these
pregnancies resulted in a livebirth, one ended with a
miscarriage and one with stillbirth. This suggests that status
epilepticus may not have as poor an outcome in pregnancy
as previously believed. This apparent improvement may be
a consequence of both better data collection and better
treatment of status epilepticus, including a lowered thresh-
old for delivery. Overall, this data suggests that the rate of
fetal loss because of epilepsy (or AED treatment) is low,
but more information on longer-term infant outcome
would be of value. The advent of large prospective regis-
tries should facilitate better obstetric data collection,

thereby improving precision in the estimate of the true
fetal and obstetric risk.
The impact of epilepsy on other obstetric outcomes
appears modest. A prospective cohort of 414 WWE
revealed increased rates of pregnancy-induced hypertension
and induction of labour, but no other increased obstetric
morbidities.70 A single centre prospective study from
Finland of 179 pregnancies of WWE and 24 778 controls
found no significant differences in the rate of pre-eclamp-
sia, preterm delivery, caesarean section or perinatal
mortality. The number of small for gestational age infants
(defined as less than the 10th centile for gestational age)
was higher (17.3% versus 9.3% in control pregnancies), as
was the rate of neonatal unit admission (13.4% versus
7.4%).71 A Swedish study of 1207 women taking AEDs in
pregnancy compared with 559 491 controls found a signif-
icant increase in the incidence of pre-eclampsia (OR 1.66,
95% CI 1.431.89), and caesarean section (OR 1.64, 95%
CI 1.322.08).72 The observed increase in postpartum
bleeding and neonatal respiratory distress may have been
partly attributable to this latter observation. An Israeli
study of 220 WWE also observed an increase in the
caesarean section rate.73 This higher incidence of caesarean
delivery among WWE is likely to be multifactorial, but
may be partly mediated by the observed increase in fetal
growth restriction and hypertensive disorders of preg-
nancy. In the future, the linking of obstetric outcomes to
AED registries should generate more precise estimates of
these risks.
TDM in pregnancy
Antiepileptic drug pharmacokinetics may be significantly
altered in pregnancy by changes in body weight and effects
on drug absorption, protein binding, metabolism and
excretion. Serum concentrations of older AEDs, such as
phenobarbitone, primidone, carbamazepine, phenytoin and
VPA have all been shown to be decreased in pregnancy.74
Some of this reduction is related to the reduction in serum
protein in pregnancy, meaning that the total drug concen-
tration is lower, but the unbound (active) concentration is
stable. This is particularly relevant for highly protein bound
drugs, such as VPA and phenytoin.75,76 As noted above, a
clinically significant reduction in plasma concentrations of
both lamotrigine and oxcarbazepine occurs in preg-
nancy,16,68 as well as levetiracetam.7476 There is a paucity
of data on the pharmacokinetics of the newer AEDs, such
as gabapentin, topiramate and zonisamide.75
In WWE, the goal of therapy is to maintain seizure
control using the lowest effective AED dose. The
International League Against Epilepsy position paper rec-
ommends that drug concentrations be determined during
pregnancy.76 It is recommended that prior to pregnancy
an individual therapeutic level during a period of
2009 The Authors Journal compilation RCOG 2009 BJOG An International Journal of Obstetrics and Gynaecology
Epilepsy and pregnancy
optimal seizure control should be determined, which can
then serve as a target level for pregnancy.74,76 Among
patients with good control, serum concentration should
be performed each trimester, but more frequent (for
example, monthly) levels may be required in patients
with complicated epilepsy, breakthrough seizures, signifi-
cant side effects and those WWE requiring lamotrigine
and oxcarbazepine where highly variable and more clini-
cally significant fluctuations in drug concentration have
been observed.74,76
Surveillance for birth defects
In WWE, especially those taking AEDs, an 1113 weeks
ultrasound examination should be offered. Acrania (the
precursor of anencephaly) should be recognised at this
gestation, and an increased nuchal translucency is also a
useful screening test for cardiac and other structural
defects.77 At midtrimester, an expert morphological assess-
ment should be performed. Note should be made on the
referral of the history of epilepsy, and the medication regi-
men so that a targeted assessment, particularly of the neu-
ral axis, heart and face can be performed. Where there is
adequate provision of expert ultrasound services, the place
of adjuvant screening for neural tube defects with midtri-
mester serum alpha-fetoprotein is limited. While serum
screeing will detect virtually all pregnancies with anenceph-
aly, the sensitivity for detecting neural tube defects overall
is only 65%, rising to 86% if gestational age is confirmed
on ultrasound.78 In contrast, detection rates with high level
ultrasound for open NTDs are from 97% to 100%, with
those undetected being covered defects, less likely to have
the characteristic head signs.78,79
Vitamin K supplementation
It has been previously proposed that the use of enzyme-
inducing AEDs may induce fetal hepatic enzyme activity
culminating in vitamin K deficiency and increased risk of
neonatal bleeding, and that vitamin K should be adminis-
tered to such women in late pregnancy to minimise this
risk.14 Several case control studies have challenged this
recommendation after observing no increase in bleeding
complications between neonates born to WWE receiving
enzyme-inducing AEDs and healthy controls.8082 In the
largest study, however, the authors acknowledged the
following caveats; these findings could not be generalised
to preterm infants, all neonates in their study were admin-
istered Vitamin K and they acknowledged the study was
underpowered to detect a small, but clinically significant
increase in neonatal bleeding.81 Nevertheless, the findings
of these studies have formed the basis of some consensus
statements (for example, the NICE guidelines) that no
longer recommend supplemental vitamin K for WWE
receiving enzyme-inducing AEDs in late pregnancy, but just
763
 Walker et al.
Table 2. Intrapartum care of women with epilepsy
Intravenous access should be secured in labour in anticipation of
a seizure
Women should continue to take their usual AEDs in labour
Hyperventilation and maternal exhaustion should be avoided
Labouring in water is not recommended for women with epilepsy
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
In the event of benzodiazepine (e.g. lorazepam or diazepam) being
used to terminate the seizure, loss of baseline variability of the fetal
heart rate tracing can be expected to follow for approximately
1 hour
Women should deliver in a centre with adequate facilities for
maternal and neonatal resuscitation
administration of konakion (or phytomedanione) to the
neonate.83
Intrapartum care of WWE
Labour and delivery is a relatively high risk time for seizure
recurrence. The reasons for this are multifactorial including
poor bioavailability and compliance with AEDs, sleep
deprivation, anxiety and hyperventilation in labour. The
EURAP registry reported seizures occurring in 60/1956
(3.5%) of epileptic women in labour.67 Although the pres-
ence of seizures occurring earlier in pregnancy was associ-
ated with seizures in labour (OR 4.8; 95% CI 2.310.0), a
significant minority (14/60) had been seizure free for the
entire pregnancy. All centres delivering obstetric care
should therefore be mindful of the increased risk of seizure
in labour, and manage WWE accordingly14,83,84 (Table 2).
Postpartum care of WWE
Maternal plasma levels of AEDs may fluctuate up until the
eighth postpartum week and monitoring of plasma AED
levels may be required. If doses have been increased during
pregnancy, toxicity may occur and AED requirement is
likely to fall in the puerperium. Lamotrigine and
oxcarbazepine doses in particular may need to be reduced
postpartum.
Most AEDs are compatible with breast feeding. The optimal
method of estimating drug exposure is to measure the milk
drug concentration and multiply it by the estimated daily
intake. Typically, a value 10% of the weight-based thera-
peutic drug dose is considered safe. The estimated levels
for carbamazepine, phenytoin and VPA are 35% of
therapeutic dose and are considered safe.85 Estimates for
lamotrigine and levetiracetam are approximately 10%, and
gabapentin approximately 12%.85,86 The product informa-
764 2009 The Authors Journal compilation RCOG 2009 BJOG An International Journal of Obstetrics and Gynaecology
tion for these drugs recommends breast feeding only if the
benefits outweigh the risks; further data is needed to estab-
lish the safety of these newer AEDs.
During their postnatal stay, WWE and all their maternity
care providers should be aware of the risk of postpartum
seizures, particularly in the setting of sleep deprivation.
Ensuring such women get adequate sleep, and attention to
medication compliance is of the utmost importance. Hos-
pital staff should be particularly vigilant of women feeding
alone in a single room at night. The womans neurologist
and family doctor should be notified of delivery, and the
predetermined regimen for AED medication and contra-
ception in the puerperium instituted.
Upon discharge, WWE will be anxious about the pros-
pect of having a seizure whilst caring for a baby at home
alone. Although the risk to the infant from maternal
seizures is generally low, women with JME are a particular
concern, since myoclonic jerks tend to be more frequent in
the early morning, often around the time of infant wak-
ing.14,87 WWE should be given advice regarding minimising
the risk of seizures at home. This involves reinforcing the
importance of medication compliance, and attention given
to adequate sleep. The latter may be accomplished by
expressing breast milk so that their partner can give the
night feed. To minimise the risk of harm if a seizure
occurs, changing or feeding the baby on the floor is recom-
mended, the use of baby slings should be avoided, stair
climbing should be minimised where possible and bathing
the baby should be avoided when alone.14,87 The impor-
tance of adequate postnatal social supports cannot be over-
emphasised.
Conclusion
Most WWE will have a successful pregnancy, but pre-
pregnancy counselling is necessary to optimise maternal
and infant outcome. This allows for appropriate contra-
ceptive planning, administration of high dose folic acid,
and adjustment of medication to minimise teratogenic
risk while maintaining seizure control. During pregnancy,
prenatal detection of many structural malformations
should be achievable with high quality ultrasound, yet an
increased risk of undetectable malformation, including
impaired neurocognitive development, remains. Prospec-
tive registration of all patients on AEDs will improve the
precision of these risk estimates in the future. Increased
surveillance for obstetric complications during pregnancy
is necessary, as is appropriate TDM. The intrapartum
and postpartum period is associated with an increased
risk of seizure frequency, and all hospitals delivering
obstetric care should have guidelines on how to minimise
the risk of seizure and a protocol for their acute
management. A multidisciplinary approach is necessary to

provide adequate support with postnatal care and dis-
charge planning.
Contribution to authorship
All three authors have contributed to this review, with SW,
MP and SB all involved in the final drafting of the manu-
script. j
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